CN117500781A

CN117500781A - Compositions of substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide and uses thereof

Info

Publication number: CN117500781A
Application number: CN202180095226.2A
Authority: CN
Inventors: E·艾尔丹姆
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 2021-02-17
Filing date: 2021-02-17
Publication date: 2024-02-02
Also published as: AR124907A1; JP2024507822A; WO2022177556A1; TW202245746A; IL304974A; AU2021428932A1; CA3211395A1; KR20230148177A; EP4294789A1

Abstract

The present disclosure relates to: a) A crystalline composition of substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; b) A pharmaceutical composition comprising a crystalline composition of substantially pure form IV of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide and optionally a pharmaceutically acceptable carrier; and c) a method of treating a tumor, cancer, or Rasopathy disease by administering to a subject in need thereof a crystalline composition of substantially pure form IV of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

Description

Compositions of substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide and uses thereof

Technical Field

The present disclosure relates to: a) A crystalline composition in substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; b) A pharmaceutical composition comprising a crystalline composition in substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide and optionally a pharmaceutically acceptable carrier; and c) a method of treating a tumor, cancer, or Rasopathy disease by administering to a subject in need thereof a crystalline composition in substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

Technical Field

N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide ("Midamitinib" or "PD-0325901") is a small molecule drug that has been designed to inhibit mitogen-activated protein kinase 1 ("MEK 1") and mitogen-activated protein kinase 2 ("MEK 2"). MEK1 and MEK2 are proteins that play a key role in the mitogen-activated protein kinase ("MAPK") signaling pathway. The MAPK pathway is critical for cell survival and proliferation, and it has been shown that overactivation of this pathway can lead to tumorigenesis and growth. Middatinib is a highly potent and specific allosteric non-ATP-competitive inhibitor against MEK1 and MEK 2. By virtue of its mechanism of action, midatinib significantly inhibits the phosphorylation of extracellular regulated MAP kinases ERK1 and ERK2, resulting in impaired growth of tumor cells in vitro and in vivo. Furthermore, there is evidence that an increase in inflammatory cytokine-induced MEK/ERK activity can cause inflammation, pain and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.

Crystalline forms of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide have been previously described. WO2002/006213 describes crystalline forms I and II. U.S. patent No. 7,060,856 ("the' 856 patent") describes a method of producing form IV. The '856 patent suggests that the material produced by this method is greater than 90% form IV (' 856 patent, example 1). The' 856 patent also states that differential scanning calorimetry ("DSC") of the resulting material shows a onset of melting at 110℃and a small peak at 117℃consistent with the material being a mixture of the two forms.

WO 2006/134469 ("' 469PCT publication") also describes a method of synthesizing N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. The '469PCT publication reports that the process produces a product that conforms to polymorphic form IV disclosed in U.S. patent application Ser. No. 10/969,681, which is issued as the' 856 patent.

Compositions containing more than one polymorphic form are generally undesirable because tautomerism may exist between polymorphic forms. Polymorphic interconversion can lead to differences in effective dosage or physical properties, affecting the processability of the drug, caused by differences in solubility or bioavailability. Thus, there is a need for a composition for treating tumors, cancers, or Rasopathy diseases containing substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

Drawings

FIG. 1A is an X-ray powder diffraction pattern ("XRPD") of a substantially pure crystalline form IV corresponding to N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

FIG. 1B is a thermogram of a thermogram ("TGA") and a differential scanning calorimetry thermogram ("DSC") corresponding to substantially pure crystalline form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

FIG. 2 is an XRPD corresponding to an initially prepared batch of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide of substantially pure form IV, as well as the XRPD of a known reference standard for form IV.

Fig. 3A is an XRPD corresponding to substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide after storage at 25 ℃ and 65% relative humidity for 68 months after production.

Fig. 3B is an XRPD corresponding to substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide after storage for 140 months at 25 ℃ and 65% relative humidity after production.

Disclosure of Invention

The present disclosure provides useful compositions and methods for treating diseases involving aberrant MEK1 or MEK2 activity (e.g., cancer, tumor, or Rasopathy disease, such as type 1 neurofibromatosis) in a subject in need thereof.

In some aspects, the present disclosure relates to a crystalline composition of substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide having formula (I)

In some aspects, the crystalline composition of substantially pure N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide does not contain any amount of form I or form II detectable by XRPD and/or DSC.

In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 3 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 6 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 1 year under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after 5 years of storage under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 68 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for ≡140 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for ≡14 years under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

In some aspects, the XRPD pattern is generated using: has the following characteristics ofReal-time multiple detector +.>An X' Pert Pro diffractometer using Ni filtered Cu ka (45 kV/40 mA) radiation and a step size of 0.03 ° 2θ, the diffractometer (a) being configured on the incident beam side as follows: a variable divergence slit (10 mm irradiation length), a 0.04 rad Soller slits (rad Soller slits), a fixed anti-scatter slit (0.50 °) and a 10mm beam cover, and (b) on the diffracted beam side is configured as follows: variable anti-scatter slits (10 mm observation length) and 0.04 radson slits; or +.about.with LYNXEYETM detector>ADVANCETM system using Cu ka (40 kV/40 mA) radiation and a step size of 0.03 ° 2θ, the system (a) being configured on the incident beam side as follows: />Mirror, mirror exit slit (0.2 mm), 2.5 ° soxhlet slit, beam knife, and (b) configured as follows on the diffracted beam side: an anti-scatter slit (8 mm) and a 2.5 ° soxhlet slit; wherein the sample is mounted flat on a zero background Si wafer. In some aspects, DSC profiles are generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15 ℃/min.

In some aspects, the crystalline composition contains less than or equal to 0.2% dimeric impurity PF-00191189

In some aspects, the crystalline composition contains from about 0.05 wt% to about 0.19 wt% dimeric impurity PF-00191189. In some aspects, the crystalline composition is free of a detectable amount of dimeric impurity PF-00191189.

In some aspects, the present disclosure provides a pharmaceutical composition comprising a crystalline composition described herein and a pharmaceutically acceptable carrier. In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is in a solid dosage form. In some aspects, the pharmaceutical composition is a tablet or capsule. In some aspects, the pharmaceutical composition is a tablet.

In some aspects, the pharmaceutical composition is a capsule. In some aspects, the capsule comprises about 1mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows: (a) From about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and gelatin capsules encapsulating components a-d. In some aspects, the capsule comprises about 2mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows: (a) From about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) gelatin capsules encapsulating components a-d. In some aspects, the capsule comprises about 5mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows: (a) From about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and (d) gelatin capsules encapsulating components a-c.

In some aspects, at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose.

In some aspects, at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and alginic acid. In some aspects, at least one of the disintegrants is croscarmellose sodium.

In some aspects, at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl behenate, and talc. In some aspects, at least one of the lubricants is magnesium stearate.

In some aspects, the present disclosure provides a method of treating cancer, tumor, or Rasopathy disease, the method comprising administering to a subject in need of such treatment a pharmaceutical composition described herein.

In some aspects, the tumor is a neurofibromatosis. In some aspects, the tumor is a neurofibromatosis associated with a type 1 neurofibromatosis. In some aspects, the tumor is selected from the group consisting of: cutaneous neurofibromas, plexiform neurofibromas, optic-path gliomas, low-grade gliomas, high-grade gliomas or malignant peripheral schwannomas. In some aspects, the tumor is a plexiform neurofibromatosis.

In some aspects, the subject has been diagnosed with Rasopathy disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, costerol syndrome (Costello syndrome), legend Ji Sizeng syndrome (Legius syndrome), noonan syndrome (Noonan syndrome), and Noonan syndrome with multiple freckles.

In some aspects, the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocyte tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer. In some aspects, the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphoblastic leukemia, and chronic myelogenous leukemia. In some aspects, the lymphoma is selected from the group consisting of: b-cell lymphoma, T-cell lymphoma, burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and megaloblastic (waldenstrom macroglobulinemia). In some aspects, the lung cancer is selected from the group consisting of: lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.

In some aspects, the subject has a mutation or other aberration in one or more genes for which the mutation or other aberration results in the acquisition or loss of functional properties of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration of one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

In some aspects, the individual doses of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide are administered as more than one capsule or tablet.

In some aspects, the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 20 mg. In some aspects, the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 10 mg. In some aspects, the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 8 mg. In some aspects, the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 6 mg.

In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is from about 0.1mg to about 20mg. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is about 2mg. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is about 4mg. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is about 6mg. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is about 8mg. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at about 20mg.

In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a dose of about 0.1mg to about 10mg twice daily. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 1mg each time. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 2mg each time. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 3mg each time. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 4mg each time. In some aspects, the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 10mg each time.

In some aspects, the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) 21 days of administration of the total daily dose; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days. In some aspects, the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) administering the total daily dose for 21 consecutive days; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

In some aspects, the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 days of administration of the total daily dose, and (ii) 2 days of no administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days. In some aspects, the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 consecutive days of administration of the total daily dose, and (ii) 2 consecutive days of no administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

In some aspects, the 28-day dosing cycle is repeated until a total of 24 consecutive 28-day dosing cycles are reached.

In some aspects, the present disclosure provides for the use of a pharmaceutical composition described herein in the manufacture of a medicament for treating a tumor, cancer, or Rasopathy.

Method for manufacturing pharmaceutical composition

In some aspects, the present disclosure provides a method of manufacturing a pharmaceutical composition, the method comprising forming a pharmaceutical composition described herein.

Definition of the definition

In order to facilitate an understanding of the disclosure set forth herein, a number of terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, pharmaceutical chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, 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.

In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" and "an" are used interchangeably herein. In certain aspects, the terms "a" or "an" mean "individual. In other aspects, the terms "a" or "an" include "two or more" or "a plurality.

In addition, as used herein, "and/or" should be taken as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and/or" as used herein in the phrase, such as "a and/or B" is intended to include: "A and B", "A or B", "A" (alone) and "B" (alone). Similarly, the term "and/or" as used in the phrase, 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 (alone); b (alone); and C (alone).

The terms "midatinib" and "PD-0325901" refer to the single enantiomer N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

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

As used herein, the terms "treatment", "treatment" and "treatment" mean therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (reduce) an undesired physiological condition, disorder or disease, or to obtain a beneficial or desired clinical result. Thus, those subjects in need of treatment include those subjects who have been diagnosed with or suspected of having the disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; a reduction in the range of a disorder, condition or disease; the condition, disorder or disease is stable (i.e., not worsening); delay of onset or slowing of progression of the condition, disorder or disease; improvement or alleviation (whether partial or complete) of a condition, disorder or disease state, whether detectable or undetectable; an improvement in at least one measurable physical parameter that is not necessarily identifiable by the patient; or promotion or amelioration of a disorder, condition, or disease. Treatment involves eliciting a clinically significant response without undue side effects. Treatment also includes prolonging survival compared to expected survival without treatment. The term "therapeutically effective amount" is intended to include an amount of a compound that, when administered, is sufficient to prevent the development of, or to some extent alleviate, one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or clinician.

In certain aspects, according to the methods described herein, a tumor of a subject is successfully "treated" if the patient exhibits one or more of the following: tumor size is reduced; one or more symptom relief associated with a particular tumor; tumor volume decreases; quality of life is improved; progression Free Survival (PFS), disease Free Survival (DFS), total survival (OS), metastasis Free Survival (MFS) increased, complete Response (CR), minimal Residual Disease (MRD), partial Response (PR), disease Stabilization (SD), progressive Disease (PD) decreased, time To Progression (TTP) increased, or any combination thereof. In some aspects, national or internationally recognized treatment outcome criteria for a given tumor may be used to determine whether an effective amount of midatinib meets any of these particular endpoints (e.g., CR, PFS, PR).

In certain aspects, according to the methods described herein, a subject's cancer (e.g., lung cancer or ovarian cancer) is successfully "treated" if the patient exhibits one or more of the following: the number of cancer cells is reduced or completely disappeared; one or more symptom relief associated with a particular cancer; morbidity and mortality are reduced; quality of life is improved; progression Free Survival (PFS), disease Free Survival (DFS), total survival (OS), metastasis Free Survival (MFS) increased, complete Response (CR), minimal Residual Disease (MRD), partial Response (PR), disease Stabilization (SD), progressive Disease (PD) decreased, time To Progression (TTP) increased, or any combination thereof. In some aspects, national or internationally recognized treatment outcome criteria for a given cancer may be used to determine whether an effective amount of midatinib meets any of these particular endpoints (e.g., CR, PFS, PR).

The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid excipient, solvent or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit/risk ratio. See Remington, the Science and Practice of Pharmacy, 21 st edition, lippincott Williams & Wilkins, philiadelphia, PA,2005; handbook of Pharmaceutical Excipients, 5 th edition, rowe et al, the Pharmaceutical Press and the American Pharmaceutical Association:2005; and Handbook of Pharmaceutical Additives, 3 rd edition, ash and Ash editions Gower Publishing Company:2007; pharmaceutical Preformulation and Formulation, gibson et al, CRC Press LLC: boca Raton, FL,2004 (incorporated herein by reference). Excipients may include, for example: anti-tackifiers, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and hydration water. Exemplary excipients include, but are not limited to: butylated Hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic calcium phosphate), calcium stearate, calcium sulfate, croscarmellose, crospovidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl parahydroxybenzoate, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, pregelatinized starch, propyl parahydroxybenzoate, retinol palmitate, shellac, silica, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin a, vitamin E, vitamin C, and xylitol.

The term "pharmaceutical composition" as used herein means a composition containing a compound described herein formulated with pharmaceutically acceptable excipients and may be manufactured or sold under the approval of a government regulatory agency as part of a therapeutic regimen for treating a disease in a mammal. The pharmaceutical compositions may be formulated for oral administration, for example, in unit dosage forms (e.g., tablets, capsules, caplets, or syrups).

The term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In some aspects, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some aspects, the term "about" or "approximately" means that a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length varies by up to 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% relative to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

As used herein, the term "administering" refers to administering a composition (e.g., a compound or formulation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., a human) can be by any suitable route, such as one described herein.

The term "crystalline" as used herein refers to a solid state form consisting of ordered arrangements of structural units. Different crystalline forms of the same compound, or a salt, hydrate or solvate thereof, result from different packing of the molecules in the solid state, which results in different crystal symmetry and/or unit cell parameters. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability and solubility. See, e.g., remington's Pharmaceutical Sciences, 18 th edition, mack Publishing, easton PA,173 (1990); the United States Pharmacopeia, 23 rd edition, 1843-1844 (1995) (incorporated herein by reference).

The crystalline form is typically characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflectance (peak, typically expressed in degrees 2θ) is generally considered to be a fingerprint of a particular crystalline form. The relative intensities of XRPD peaks can vary widely, depending inter alia on the sample preparation technique, crystal size distribution, filters, sample mounting procedures, and the particular instrument employed. In some cases, a new peak may be observed, or an existing peak may disappear, depending on the type or setting of the instrument. In some cases, any particular peak in the XRPD pattern may appear as a single peak, double peak, triple peak, quadruple peak, or multiple peak, depending on the type or setting of the instrument, the sensitivity of the instrument, the measurement conditions, and/or the purity of the crystalline form. In some cases, any particular peak in the XRPD may appear in a symmetrical shape or in an asymmetrical shape (e.g., with a shoulder). In addition, instrument variations and other factors can also affect the 2 theta value. Those who understand these variations are able to distinguish or determine the defined characteristics or properties of a particular crystalline form using XRPD, as well as using other known physicochemical techniques.

The term "anhydrate" as applied to a compound refers to a crystalline form of the compound that does not contain structural water within the crystal lattice.

As used herein, the term "substantially pure" with respect to form IV means that the composition comprising form IV does not contain a detectable amount of the other polymorphic form (e.g., form I or form II), as determined by the absence of a detectable difference observed in the XRPD and/or DSC diagram between the single form IV crystals and the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. However, the "substantially pure" form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide may contain impurities such as, but not limited to, synthetic reactants or byproducts generated during chemical synthesis.

As used herein, the term "aberration" as applied to a gene refers to a mutation, chromosome loss or fusion, epigenetic chemical modification, or other event that alters the sequence associated with the gene, expression level, or processed mRNA sequence relative to the sequence associated with a wild-type gene, expression level, or processed mRNA sequence.

It will be understood that whenever aspects are described herein by the word "comprising", other similar aspects are also provided as described by "consisting of … …" and/or "consisting essentially of … …".

The details of one or more aspects are set forth in the description below. Other features, objects, and advantages will be apparent from the description and claims.

Detailed Description

Described herein are substantially pure form IV, compositions in substantially pure form IV, and methods of treating a patient in need of a therapeutic agent comprising administering substantially pure form IV.

Crystalline composition

The present disclosure relates to a substantially pure crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. As with all pharmaceutical compounds and compositions, the chemical and physical properties of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide are critical in its commercial development. These properties include, but are not limited to: (1) Bulk properties such as molar volume, bulk density and hygroscopicity; (2) Thermodynamic properties such as melting temperature, vapor pressure, and solubility; (3) Kinetic properties such as dissolution rate and stability (including stability under ambient conditions, in particular in moisture and under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape, (5) mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blending; and (6) filtration properties. These properties can affect, for example, the processing and storage of the compounds and pharmaceutical compositions comprising the compounds.

Crystalline forms of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide that are improved in one or more of these properties relative to other crystalline forms of the compound are desirable. Isolation of pharmaceutically acceptable crystalline forms of compounds that can be manufactured and formulated on a commercial scale can be a challenge.

In some aspects, the disclosure relates to a substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide having formula (I)

In some aspects, the crystalline composition is stable, as evidenced by an XRPD pattern and/or DSC profile that is substantially unchanged over time. In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC profile that is substantially unchanged after storage for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years, 68 months, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 140 months, 12 years, 13 years, 14 years, or 15 years under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 3 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 6 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 1 year under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after 5 years of storage under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 68 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for ≡140 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity). In some aspects, the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for ≡14 years under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

In some aspects, the crystalline composition contains from about 0.05 wt% to about 0.19 wt% dimeric impurity PF-00191189. In some aspects, the crystalline composition contains from about 0.05 wt% to about 0.15 wt% dimeric impurity PF-00191189. In some aspects, the crystalline composition contains from about 0.05 wt% to about 0.10 wt% dimeric impurity PF-00191189. In some aspects, the crystalline composition is free of a detectable amount of dimeric impurity PF-00191189.

In some aspects, the amount of dimeric impurity PF-00191189 is determined using high performance liquid chromatography ("HPLC"). In some aspects, reverse phase liquid chromatography using a 275nm ultraviolet detector is used.

In some aspects, the crystalline composition exhibits a DSC curve that begins without an endothermic event at about 117 ℃.

Form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is characterized by: an XRPD pattern substantially as shown in figure 1A, a TGA profile substantially as shown in figure 1B; and/or a DSC profile substantially as shown in figure 1B.

Pharmaceutical composition

In some aspects, the present disclosure provides a pharmaceutical composition comprising a crystalline composition described herein and a pharmaceutically acceptable carrier. In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is a tablet or capsule. In some aspects, the pharmaceutical composition is a tablet. In some aspects, the pharmaceutical composition is a capsule.

In some aspects, the pharmaceutical composition comprises from about 0.1mg to about 10mg of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition comprises a crystalline composition of about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 4.5mg, about 5mg, about 5.5mg, about 6mg, about 6.5mg, about 7mg, about 7.5mg, about 8mg, about 8.5mg, about 9mg, about 9.5mg, or about 10mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition comprises about 2mg of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition comprises about 3mg of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition comprises about 4mg of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. In some aspects, the pharmaceutical composition comprises about 5mg of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

In some aspects, the pharmaceutical composition comprises from about 0.25 wt/wt% to about 7 wt/wt% of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide described herein. In some aspects of the present invention, the pharmaceutical composition comprises about 0.25 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about% >, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3 wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt%, about 4.7 wt/wt%, about 3.8 wt%, about 4.9 wt/wt%, about 4.1 wt/wt%, about 4.2 wt%, about 4.3 wt/wt%, about 4.6 wt/wt%, about 4.7 wt%, about, about 4.8 wt/wt%, about 4.9 wt/wt%, about 5 wt/wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about 5.3 wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7 wt/wt%, about 5.8 wt/wt%, about 5.9 wt/wt%, about 6 wt/wt%, about 6.1 wt/wt%, about 6.2 wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt%, about 6.5 wt/wt%, about 6.6 wt/wt%, about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9 wt/wt%, or about 7 wt/wt% of the crystalline N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-benzamide composition described herein. In some aspects, the pharmaceutical composition comprises about 0.5% w/w of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide described herein. In some aspects, the pharmaceutical composition comprises about 0.8% w/w of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide described herein.

In some aspects, the pharmaceutical composition comprises one or more diluents. In some aspects, the pharmaceutical composition comprises from about 70 wt/wt% to about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises from about 85 wt/wt% to about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises about 70 wt/wt%, about 71 wt/wt%, about 72 wt/wt%, about 73 wt/wt%, about 74 wt/wt%, about 75 wt/wt%, about 76 wt/wt%, about 77 wt/wt%, about 78 wt/wt%, about 79 wt/wt%, about 80 wt/wt%, about 81 wt/wt%, about 82 wt/wt%, about 83 wt/wt%, about 84 wt/wt%, about 85 wt/wt%, about 86 wt/wt%, about 87 wt/wt%, about 88 wt/wt%, about 89 wt/wt%, about 90 wt/wt%, about 91 wt/wt%, about 92 wt/wt%, about 93 wt/wt%, about 94 wt/wt%, or about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises about 90% w/w of one or more diluents. In some aspects, the pharmaceutical composition comprises about 93 wt/wt% of one or more diluents.

In some aspects, at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose. In some aspects, the diluent is microcrystalline cellulose.

In some aspects, the pharmaceutical composition comprises about 70 wt/wt% to about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 85 wt/wt% to about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 70 wt/wt%, about 71 wt/wt%, about 72 wt/wt%, about 73 wt/wt%, about 74 wt/wt%, about 75 wt/wt%, about 76 wt/wt%, about 77 wt/wt%, about 78 wt/wt%, about 79 wt/wt%, about 80 wt/wt%, about 81 wt/wt%, about 82 wt/wt%, about 83 wt/wt%, about 84 wt/wt%, about 85 wt/wt%, about 86 wt/wt%, about 87 wt/wt%, about 88 wt/wt%, about 89 wt/wt%, about 90 wt/wt%, about 91 wt/wt%, about 92 wt/wt%, about 93 wt/wt%, about 94 wt/wt%, or about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 90% microcrystalline cellulose by weight. In some aspects, the pharmaceutical composition comprises about 93 wt/wt% microcrystalline cellulose.

In some aspects, the pharmaceutical composition comprises from about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants. In some aspects, the pharmaceutical composition comprises about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4.0 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, about 5 wt/wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about 5.3 wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7 wt%, about 5.8 wt/wt%, about 5.9 wt% or about 6.0 wt% of one or more disintegrants. In some aspects, the pharmaceutical composition comprises about 5% w/w of one or more disintegrants.

In some aspects, at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and alginic acid. In some aspects, at least one of the disintegrants is croscarmellose sodium. In some aspects, the disintegrant is croscarmellose sodium. In some aspects, the pharmaceutical composition comprises from about 3.5 wt/wt% to about 6 wt/wt% croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4.0 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, about 5 wt/wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about 5.3 wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7 wt%, about 5.8 wt/wt%, about 5.9 wt% or about 6.0 wt% of the croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 5% w/w croscarmellose sodium.

In some aspects, the pharmaceutical composition comprises from 0 wt/wt% to about 2 wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition comprises 0, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2 weight/wt% of one or more lubricants. In some aspects, the pharmaceutical composition comprises about 1 wt/wt% of one or more lubricants.

In some aspects, at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl behenate, and talc. In some aspects, at least one of the lubricants is magnesium stearate. In some aspects, the lubricant is magnesium stearate. In some aspects, the pharmaceutical composition comprises 0, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2% magnesium stearate. In some aspects, the pharmaceutical composition comprises 0 wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition comprises about 1% w/w magnesium stearate.

In some aspects, the pharmaceutical composition is a capsule. In some aspects, the capsule comprises about 1mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows: (a) A crystalline composition of about 0.25 wt/wt% to about 1.5 wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) gelatin capsules encapsulating components (a) - (d).

In some aspects, the capsule comprises about 2mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows: (a) A crystalline composition of about 0.25 wt/wt% to about 1.5 wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) gelatin capsules encapsulating components (a) - (d).

In some aspects, the capsule comprises about 3mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows: (a) A crystalline composition of about 0.25 wt/wt% to about 1.5 wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) gelatin capsules encapsulating components (a) - (d).

In some aspects, the capsule comprises about 4mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows: (a) A crystalline composition of about 0.25 wt/wt% to about 1.5 wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) gelatin capsules encapsulating components (a) - (d).

In some aspects, the capsule comprises about 5mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows: (a) A crystalline composition of about 2.5 wt/wt% to about 7.0 wt/wt% of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; (b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and (d) gelatin capsules encapsulating components a-c.

Therapeutic method

In some aspects, the present disclosure provides a method of treating a tumor, cancer, or Rasopathy disease, the method comprising administering to a subject in need of such treatment a pharmaceutical composition described herein.

In some aspects, the subject has been diagnosed with Rasopathy disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, coster syndrome, lux Ji Sizeng syndrome, noonan syndrome and noonan syndrome with multiple freckles.

In some aspects, the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocyte tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer. In some aspects, the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphoblastic leukemia, and chronic myelogenous leukemia. In some aspects, the lymphoma is selected from the group consisting of: b-cell lymphoma, T-cell lymphoma, burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and fahrenheit macroglobulinemia. In some aspects, the lung cancer is selected from the group consisting of: lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.

In some aspects, the subject has a mutation or other aberration in one or more genes for which the mutation or other aberration results in the acquisition or loss of functional properties of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

In some aspects, individual doses of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide are administered as more than one capsule or tablet. For example, a 3mg dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide may be administered as two capsules-one capsule containing 2mg and the other capsule containing 1mg, or as three capsules, each capsule containing 1mg.

In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of from about 0.1mg to about 20mg per dose of the pharmaceutical composition described herein. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, or about 20mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 1mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 2mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 3mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 4mg per dose. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided in an amount of about 10mg per dose.

In some aspects, a pharmaceutical composition comprising N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once, twice, three times, or four times per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily.

In some aspects, if N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered more than once a day, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide may be divided, whereby the patient receives equal doses at each administration. For example, if the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is 4mg, administered twice daily, the patient may receive 2mg in the morning (e.g., as two 1mg capsules) and 2mg in the evening (e.g., as one 2mg capsule).

In some aspects, if N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered more than once a day, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide may be divided, whereby the patient receives a different dose at each administration. For example, if the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is 4mg, administered twice daily, the patient may receive 1mg in the morning (e.g., as one 1mg capsule) and 3mg in the evening (e.g., as one 1mg capsule and one 2mg capsule).

In some aspects, the present disclosure provides a method of treating a tumor, cancer, or Rasopathy disease, the method comprising administering to a patient in need of such treatment a pharmaceutical composition described herein, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered from about 0.1mg to about 10mg twice daily.

In some aspects, the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered via a pharmaceutical composition described herein, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is provided at no more than 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, or 20 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 20 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 15 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 12 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 10 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 8 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 6 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 2 mg. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 1 mg.

In some aspects, the present disclosure provides a method of treating a tumor, cancer, or rasopathia disease, the method comprising administering to a patient in need of such treatment a pharmaceutical composition described herein, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 0.1mg to about 20 mg.

In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, about 16mg, about 17mg, about 18mg, about 19mg, or about 20 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 1mg once per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 2mg once per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 3mg once per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 4mg once per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 5mg once per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 6 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 7mg once per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 8 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 9 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 10mg once per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 11 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 12 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 13 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 14mg once per day. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 15 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 16 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 17 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 18 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 19 mg. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 20 mg.

In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a dose of about 0.1mg to about 10mg twice daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a dose of about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, or about 10mg twice daily. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 0.25mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 0.5mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 1mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 2mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 3mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 4mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 5mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 6mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 7mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 8mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 9mg each time. In some aspects, the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 10mg each time.

In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) 21 days of administration of the total daily dose; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) administering a total daily dose for 21 consecutive days; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 days of administration of the total daily dose, and (ii) 2 days of no administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days. In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 consecutive days of administration of a total daily dose, and (ii) 2 consecutive days of no administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

In some aspects, N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle that includes 28 days of administration of the total daily dose.

In some aspects, the present disclosure provides for the use of a pharmaceutical composition described herein in the manufacture of a medicament for the treatment of cancer, tumor, or Rasopathy.

Examples

Time (minutes)	0	15	40	45	46
						% mobile phase B	70	70	100	100	70

Example 1: production of substantially pure form IV

Laboratory scale production of substantially pure form IV

2kg PD-0325901 has been prepared using the following convergent synthesis scheme starting from commercially available 2,3, 4-trifluorobenzoic acid (TFBA), 2-fluoro-4-iodoaniline (FIA) and chiral S-glycerolacetonide (SGA).

Step 1: preparation of "side chain", PD-0337792

Unless otherwise indicated, all reactions were carried out in toluene. The triflic anhydride gives the best yield.

Table 1: step 1 coupling agent

It was recognized that triflate gave the highest yields, and the possibility of eliminating low temperature conditions was investigated, which may be set by the stability problem of the "mesylate" intermediate. The following experiments show that experiments run at-20 ℃ have no significant yield loss.

Table 2: yield of coupling reaction

* 16ml of toluene containing 2g (1 eq.) of SGA was treated with trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid (TFMSA) (4.2 g,1.002 eq.) at-20℃and then stirred for the indicated time before solid N-hydroxyphthalimide (NHP) addition or transfer to a flask containing solid NHP.

The data presented above show that no detrimental effect is observed after prolonged stirring of the "triflate" intermediate prior to N-hydroxyphthalimide addition. Reverse addition of the intermediate mixture to the solid NHP appears to give the highest yield.

An additional advantage of using triflate is that Et can be easily removed simply by washing with water ₃ N-triflate by-product. This gives rise to the highly pure N-hydroxyphthalimide protected alcohol IPGAP (PD-0333760) in toluene, which can be isolated as crystals or else can be carried out until the final deprotection reaction.

Both aqueous and anhydrous ammonia bases were tested as deprotecting agents. The results were all successful. When anhydrous ammonia is used, the phthalimide by-product is simply filtered off from the toluene solution of the product (PD-0337792). Similarly, when aqueous ammonia (28% solution) is used, the by-product is filtered from the solution after azeotropic water removal in toluene. However, anhydrous ammonia requires the reaction to be carried out at a high pressure containment vessel. Experiments performed by spraying ammonia gave acceptable yields; however, they require large volumes and use cryogenic condensers (to avoid gas escaping the reactor headspace).

Table 3: yield of base deprotection

Reagent(s)	Yield ×
		Methyl hydrazine	85% to 95%
Anhydrous NH ₃ (spraying)	78% to 90%
		Anhydrous NH ₃ (50psi)	80 to 92 percent
Aqueous NH ₃	90 to 97%

* From PD-0333760

Step 2: fluorine substitution

Examination of the reaction in the automated reactor revealed that the reaction was essentially dose-controlled after the initiation period. Increasing the amount of lithium amide and increasing the stirring rate appears to shorten the induction time. It has been shown that the addition of water increases the induction time. However, it is not clear whether this is due to the formation of lithium hydroxide.

When 0.1 equivalent of H is added ₂ At O, the induction time increases. However, when 0.1 equivalent of lithium hydroxide was added, the trend reversed. The induction time decreases as the lithium amide equivalent and agitation increases.

CDI-assisted coupling of PD-0315209 acid with side chain reagents followed by acid hydrolysis (under aqueous HCl) consistently produced good results in the laboratory. The focus of this step was to ensure that the impurity levels were within specification limits. Known impurities in the final isolated diol product are excess PD-0315209 acid, dimerization impurities, and chiral impurities. Chiral impurities are controlled by limiting the R-enantiomer in the starting s-glycerolacetonide. It is known that an elevated level of dimeric impurity (d) may lead to difficulties in the polymorphic conversion step. Dimeric impurities are initially formed by: imidazole (CDI activated acid) reaction occurs in the presence of excess acid PD-0315209 to form dimer (a) and possibly (b), which are then carried over to subsequent IPGA coupling and acid hydrolysis steps to form dimers (c) and (d), respectively. Impurity d is known as PF-00191189.

The reaction can be easily performed in the laboratory by: two solids FIPFA and CDI are charged first, followed by a solvent (acetonitrile), or solid CDI is charged to an acetonitrile slurry of FIPFA. All solids were initially insoluble in acetonitrile. The acid activation reaction is very rapid (almost instantaneous) and thus forms a highly soluble imidazolium product that will slurryThe liquid becomes a clear homogeneous solution with CO occurring simultaneously ₂ The gas escapes.

Laboratory experiments typically produce impurity levels below 3% which can be completely removed by subsequent recrystallization in a 3% to 5% ethanol-toluene system. In a few cases, with impurity levels above 0.3%, additional recrystallisation is performed. Table 4 shows the selected results of laboratory experiments in which elevated levels of impurities were observed, and how the impurities were removed in subsequent recrystallisation. Crude PD-0325901 was obtained using an acetonitrile/toluene system and the purified product was recrystallized in a 5% ethanol/toluene system. Entry numbers 4 and 5 use additional solvents to ensure impurity removal, where entry 5 requires two recrystallisations to reach the "ND" level in the polymorphic conversion. The crystallization volume of the crude material of 8-10ml/g is selected to limit product losses while maintaining filterable slurry and ensuring removal of impurities.

Table 4: purification of PD-0325901

Considering the rate of solid CDI addition, an amplification procedure was developed that would give tolerable impurity levels prior to polymorphic conversion<0.3%) without losing too much product in recrystallization. In order to minimize impurity formation, rapid addition is preferred; however, it is necessary to ensure safe removal of the generated CO ₂ Is added at a rate of (2).

Half of the solid CDI was initially added to PD-0325901 acid followed by solvent addition. The remaining CDI was then added through the hopper in less than 30 minutes to ensure that the impurity level was below 3%.

Polymorphic transformations

The three polymorphic forms of PD-0325901 are characterized as follows. Form I has the highest melting point (about 117 ℃) and is tautomeric with form IV (melting point 112 ℃) which is the more stable form below the estimated transition temperature of 73 ℃. Form II is a low melting form (melting point about 85 ℃).

Table 5: melting point and heat of fusion of crystalline form

	Melting point, DEG C	Heat of fusion, DHf (J/g)
			Form I	117	85
Form II	90	70
			Form IV	112	94

Most polymorphic transformations experiments were performed using high purity PD-0325901 containing various forms and generally exhibit low melting points below 80℃as a result of efficient EtOH/toluene recrystallisation directly after the crude crystal separation in the reaction mixture. These different polymorphs were completely dissolved in EtOH and subsequently precipitated by adding water (20 volumes) at 20-25 ℃ over a period of 15-60 minutes. Analysis of the solids sampled at less than 2 hours of agitation showed complete polymorphic conversion to form IV. The only failure occurred when water was added to the EtOH solution (4 volumes) of PD-0325901 at once. In this case, only the undesired polymorphic form I is obtained.

An anomaly in the standard procedure was observed. One batch produced a mixed polymorph but did not have detectable impurity levels after recrystallization. The correction procedure for this case involved all conversion of the low melting form (form II) to form I at temperatures close to or above 73 ℃, followed by slow (about 4h period) cooling to 20 ℃.

EtOH/water systems produce efficient polymorphic transformations. Recrystallized (purified) PD-0325901, which initially consisted of tautomeric polymorphic form I (melting point about 117 ℃) and form IV (melting point about 112 ℃) was completely converted to form IV.

Pilot plant preparation of substantially pure form IV

Step 1: preparation of "side chain", PD-0337792

14.4kg of alcohol (chemical purity 99.4%, optical purity 99.6%, enantiomeric excess) were converted into 97.5kg of 9.7% w/w PD-0337792 (IPGA) in toluene (overall yield about 60%). Triflate activation was performed in a 200L reactor by maintaining the temperature below-20 ℃ during the addition of the triflic anhydride. The resulting activated alcohol was then transferred to a 400L reactor containing solid N-hydroxyphthalimide (NHP) and the reaction was allowed to proceed to completion at ambient temperature. The final base deprotection was performed by adding ammonia (about 28% solution, 5 eq, 34 kg). After the reaction was completed, water was removed from toluene by distillation, and the resulting solid by-product was filtered off to obtain a product solution.

Step 2: preparation of PD-0315209

This procedure yielded 21.4kg (99.4% w/w assay) with lithium amide base (5 kg,3.2 eq.) that was 80% of the theoretical of starting materials 2,3, 4-trifluorobenzoic acid (12 kg,1 eq.) and 2-fluoro-4-iodoaniline (16.4 kg,1.02 eq.). The reaction was initiated by adding a 5% total solution of TFBA and FIA to the lithium amide slurry at 50 ℃. This reaction exhibited a minimum initiation period of about 10 minutes, as observed by color change and slight exotherm. The remaining TFBA/FIA THF solution was slowly added over one hour through the pressure pot while maintaining the reaction temperature within 45-55 ℃. No significant pressure rise (due to ammonia gas release) was observed throughout the operation.

Step 3: preparation of PD-0325901

CDI loading was modified to mitigate potential gas generation. Two aliquots of CDI were added to the solid FIPFA before and after solvent addition (by the granulating loader). The time between two solid CDI additions (4.6 kg each) should not exceed 30 minutes. The two intermediate filter cakes were then dissolved with ethanol. Excess ethanol was distilled and replaced with toluene to about 5% v/v ethanol prior to recrystallization of PD-0325901. Laboratory studies have shown that crystallization in toluene and acetonitrile and recrystallization in toluene containing ethanol do not reduce the impurities necessary for polymorphic transformations. It is known that the presence of dimeric impurities (PF-00191189) at levels greater than 0.2% results in the formation of undesirable polymorphs.

The crude crystallization from the final reaction mixture reduced dimeric impurity PF-00191189 to about 1.9% and the subsequent recrystallization further reduced it to about 0.4%. Thus, an undesirable polymorph is produced. DSC profile indicates two different melting points: about 80 ℃ (low melting form II) and about 117 ℃ (form I). In addition, during processing, the solids crystallize at a much lower temperature than expected (actually about 10 ℃, expected about 40 ℃). Unsuccessful recrystallization is suspected to be due to solvent composition changes caused by incomplete drying of the coarse material. After about 36 hours, when the crude product was about 28kg (26 kg theoretical), the drying of the crude wet cake before ethanol dissolution was stopped.

Polymorphic transformations

About 7.4kg of PD-0325901 (mixed polymorph) from the final EtOH/water crystallization and the precipitated material from the early EtOH/toluene filtrate were transferred to the polymorphic conversion. Both outputs were dried separately in a filter to constant weight and each was dissolved in EtOH. The combined EtOH solutions were analyzed by HPLC and gave 16.4kg of estimated PD-0325901. Recrystallization was initiated after removal of EtOH via vacuum distillation and adjustment of the solvent composition to toluene containing about 5% EtOH at 65 ℃ (i.e., etOH was added drop-wise at 65 ℃ until the solid was completely dissolved).

Slow cooling was performed for 4 hours, ramped down to 5 ℃, followed by 12 hours stirring to ensure satisfactory results. The resulting slurry was filtered and again dried completely in the filter until constant weight (about 3 days). The purified solid showed 99.8% pure PD-0325901 without detection of the level of dimeric impurity PF-00191189.

The dried solid (15.4 kg) was redissolved in just 4 volumes of EtOH (62L) withdrawn from the filter, transferred to the reactor and precipitated by slow (about 3 h) water addition (308L) at 30-35 ℃, cooled to 20 ℃ and stirred for 12h. DSC analysis of the slurry sample taken at 2h showed that the solid was entirely form IV (the desired polymorph).

21.4kg PD-0315209, 9.7kg CDI (1.05 eq.) and 91kg of 9.7% PD-0337792 in toluene (1.1 eq.) were used and 12.74kg PD-0325901 was obtained (assay 99.4%,100% form IV, yield about 48%).

Example 2: determination/impurity and identification of PD-0325901

PD-0325901 is separated from process impurities and degradation products by reverse phase liquid chromatography under UV detection at 275 nm. In addition to HPLC retention time, identification of PD-0325901 can also be performed by obtaining infrared or proton NMR spectra. For purity assessment, process impurities and degradation products were identified by their characteristic relative retention times and quantified by area normalization.

Chromatographic conditions: agilent Zorbax SB C18,5 μm, 4.6x250mm (or equivalent); the flow rate is 1.0mL/min; the column temperature is 30 ℃; the detector wavelength was 275nm; the diluent is 50/50 acetonitrile/water; mobile phase a was water with 0.1% trifluoroacetic acid (TFA); mobile phase B is methanol; and the gradient conditions below. The assay was determined from a reference standard and reported on an anhydrous, solvent-free basis. Quantification of indicated and unspecified impurities is reported as area percent. The total impurity is the sum of all impurities present above the reporting threshold of 0.05%.

Example 3: single crystal X-ray diffraction analysis of form IV

A suitable single crystal of form IV was prepared by a method involving a different coupling agent than that used in the method disclosed in example 1. However, the crystal produced form IV had the same XRPD characteristics as form IV prepared by the method of example 1, and thus had a purity suitable for analysis of form IV.

Using a microfocus source equipped with cukα INCOATEC ImusA Bruker D8 Venture Photon IICPAD diffractometer to analyze single form IV crystals. The simulated PXRD pattern was calculated from the low temperature (100K) structure and room temperature (298K, 25 ℃) unit cell parameters shown below. The unit cell at room temperature was initially determined by the differential vector method based on 235 reflections collected from 151 1 ° diffraction frames. Subsequently, the unit cell parameters are refined during data integration by Saint (Bruker (2020). Saint.data Reduction Software) and are based on the parameters at 19.1 and +. >903 reflections recorded between resolutions. The simulated graph is consistent with the experimental form IV graph shown in fig. 1A.

Table 6: unit cell parameters initially determined at room temperature

/>

Table 7: form IV crystal data and structure refinement

Example 4: capsule preparation

Hg=hard gelatin

^a Based on theoretical efficacy 1.000. The actual amount may be adjusted based on the actual effectiveness.

^b The amount of microcrystalline cellulose may be adjusted for slight potency changes in PD-0325901.

Example 5: form IV stability

The stability of form IV materials is determined by comparing the XRPD pattern of a batch to a reference standard XRPD pattern. This analysis was performed at batch placement and the XRPD pattern obtained corresponded to that of the reference standard of form IV (figure 2). Form IV batches were then stored at 25 ℃ and 65% relative humidity. XRPD analysis of the stored form IV was performed at 68 months (fig. 3A) and again at 140 months (fig. 3B). The appearance of undetectable changes in the XRPD pattern over time indicates that form IV has stability at 25℃and 65% relative humidity.

All publications, patents and patent applications mentioned in this specification are herein incorporated 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. When a term in the present application is found to be defined differently in the documents incorporated by reference herein, the definition provided herein will serve as the definition of that term.

While the invention has been described in connection with specific aspects thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

In addition to the various embodiments described herein, the present disclosure includes the following embodiments numbered E1 through E94. This list of embodiments is presented as an exemplary list, and the application is not limited to these embodiments.

E1. A crystalline composition in substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide having formula (I)

E2. The crystalline composition of E1, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 3 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

E3. The crystalline composition of E1 or E2, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 6 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

E4. The crystalline composition of any one of E1-E3, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 1 year under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

E5. The crystalline composition of any one of E1-E4, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 68 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

E6. The crystalline composition of any one of E1-E5, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for ≡140 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

E7. The crystalline composition of any one of E2-E6, wherein the XRPD pattern is generated using:

has the following characteristics ofReal-time multiple detector +.>X' Pert Pro diffractometer using Ni filtered Cu K alpha (45 kV/40 mA) radiation and step size of 0.03 DEG 2 theta

(a) The arrangement on the incident beam side is as follows: variable divergence slit (10 mm irradiation length), 0.04 radson slit, fixed anti-scatter slit (0.50 °) and 10mm beam cover, and

(b) The configuration on the diffracted beam side is as follows: variable anti-scatter slits (10 mm observation length) and 0.04 radson slits; or alternatively

Having LYNXEYE ^TM Of detectorsADVANCE ^TM A system using Cu K alpha (40 kV/40 mA) radiation and a step size of 0.03 DEG 2 theta, the system

(a) The arrangement on the incident beam side is as follows:mirror, mirror exit slit (0.2 mm), 2.5 ° soxhlet slit, beam knife, and

(b) The configuration on the diffracted beam side is as follows: an anti-scatter slit (8 mm) and a 2.5 ° soxhlet slit; and is also provided with

Wherein the sample is mounted flat on a zero background Si wafer.

E8. The crystalline composition as defined in any one of E1-E7, wherein the DSC profile is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15 ℃/min.

E9. The crystalline composition as defined in any one of E1-E8, wherein the crystalline composition contains ∈0.2% dimeric impurity PF-00191189.

E10. The crystalline composition as defined in any one of E1-E9, wherein the crystalline composition contains from about 0.05 wt% to about 0.19 wt% dimeric impurity PF-00191189.

E11. The crystalline composition as defined in any one of E1-E9, wherein the crystalline composition is free of a detectable amount of dimeric impurity PF-00191189.

E12. A pharmaceutical composition comprising the crystalline composition of any one of E1-E11 and a pharmaceutically acceptable carrier.

E13. The pharmaceutical composition of E12, wherein the pharmaceutical composition is for oral administration.

E14. The pharmaceutical composition of E13, wherein the pharmaceutical composition is in a solid dosage form.

E15. The pharmaceutical composition of any one of E12-E14, wherein the pharmaceutical composition is a tablet or capsule.

E16. The pharmaceutical composition of E15, wherein the pharmaceutical composition is a tablet.

E17. The pharmaceutical composition of E15, wherein the pharmaceutical composition is a capsule.

E18. The pharmaceutical composition of E17, wherein the capsule comprises about 1mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows:

a) From about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents;

c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;

d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and

e) Gelatin capsules encapsulating components a-d.

E19. The pharmaceutical composition of E17, wherein the capsule comprises about 2mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows:

b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents;

c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;

d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and

e) Gelatin capsules encapsulating components a-d.

E20. The pharmaceutical composition of E17, wherein the capsule comprises about 5mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows:

a) From about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline composition of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents;

c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and

d) Gelatin capsules encapsulating components a-c.

E21. The pharmaceutical composition of any one of E18-E20, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate.

E22. The pharmaceutical composition of E21, wherein at least one of the diluents is microcrystalline cellulose.

E23. The pharmaceutical composition of any one of E18-E22, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and alginic acid.

E24. The pharmaceutical composition of E23, wherein at least one of the disintegrants is croscarmellose sodium.

E25. The pharmaceutical composition of any one of E18-E24, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl behenate, and talc.

E26. The pharmaceutical composition of E25, wherein at least one of the lubricants is magnesium stearate.

E27. A method of treating a tumor, cancer, or Rasopathy disease, the method comprising administering to a subject in need of such treatment a pharmaceutical composition of any one of E12-E26.

E28. The method of E27, wherein the tumor is a neurofibromatosis.

E29. The method of E28, wherein the tumor is a neurofibromatosis associated with type 1 neurofibromatosis.

E30. The method of any one of E27-E29, wherein the tumor is selected from the group consisting of: cutaneous neurofibromas, plexiform neurofibromas, optic-path gliomas, low-grade gliomas, high-grade gliomas or malignant peripheral schwannomas.

E31. The method of E30, wherein the tumor is plexiform neurofibromatosis.

E32. The method of E27, wherein the subject has been diagnosed with Rasopathy disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, coster syndrome, lux Ji Sizeng syndrome, noonan syndrome and noonan syndrome with multiple freckles.

E33. The method of E27, wherein the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocyte tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer.

E34. The method of E33, wherein the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphoblastic leukemia, and chronic myelogenous leukemia.

E35. The method of E33, wherein the lymphoma is selected from the group consisting of: b-cell lymphoma, T-cell lymphoma, burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and fahrenheit macroglobulinemia.

E36. The method of E33, wherein the lung cancer is selected from the group consisting of: lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.

E37. The method of any one of E27-E36, wherein the subject has a mutation or other aberration in one or more genes for which the mutation or other aberration results in the acquisition or loss of functional properties of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

E38. The method of any one of E27-E37, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 20 mg.

E39. The method of any one of E27-E37, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 10 mg.

E40. The method of any one of E27-E37, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 8 mg.

E41. The method of any one of E27-E37, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 6 mg.

E42. The method of any one of E27-E41, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily.

E43. The method of E42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 0.1mg to about 20 mg.

E44. The method of E42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 2 mg.

E45. The method of E42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 4 mg.

E46. The method of E42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 6 mg.

E47. The method of E42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 8 mg.

E48. The method of E42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 20 mg.

E49. The method of any one of E27-E42, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily.

E50. The method of E49, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a dose of about 0.1mg to about 10mg twice daily.

E51. The method of E49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 1mg each time.

E52. The method of E49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 2mg each time.

E53. The method of E49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 3 mg.

E54. The method of E49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 4 mg.

E55. The method of E49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 10 mg.

E56. The method of any one of E27-E55, wherein the individual doses of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide are administered as more than one capsule or tablet.

E57. The method of any one of E27-E56, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) 21 days of administration of the total daily dose; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

E58. The method of any one of E27-E56, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) administering the total daily dose for 21 consecutive days; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

E59. The method of any one of E27-E56, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 days of administration of the total daily dose; and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered for 2 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

E60. The method of any one of E27-E56, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 consecutive days of administration of the total daily dose, and (ii) 2 consecutive days of no administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

E61. The method of any one of E57-E60, wherein the 28-day dosing cycle is repeated until a total of 24 consecutive 28-day dosing cycles are reached.

E62. Use of a pharmaceutical composition according to any one of E12-E26 in the manufacture of a medicament for the treatment of a tumor, cancer or Rasopathy.

E63. The use of any one of E62, wherein the tumor is a neurofibromatosis.

E64. The use of E63, wherein the tumor is a neurofibromatosis associated with type 1 neurofibromatosis.

E65. The use of any one of E62-E64, wherein the tumor is selected from the group consisting of: cutaneous neurofibromas, plexiform neurofibromas, optic-path gliomas, low-grade gliomas, high-grade gliomas or malignant peripheral schwannomas.

E66. The use of E65, wherein the tumor is plexiform neurofibromatosis.

E67. The use of E62, wherein the subject has been diagnosed with Rasopathy disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, coster syndrome, lux Ji Sizeng syndrome, noonan syndrome and noonan syndrome with multiple freckles.

E68. The use of E62, wherein the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocyte tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer.

E69. The use of E68, wherein the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphoblastic leukemia, and chronic myelogenous leukemia.

E70. The use of E68, wherein the lymphoma is selected from the group consisting of: b-cell lymphoma, T-cell lymphoma, burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and fahrenheit macroglobulinemia.

E71. The use of E68, wherein the lung cancer is selected from the group consisting of: lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.

E72. The use of any one of E62-E71, wherein the subject has a mutation or other aberration in one or more genes for which the mutation or other aberration results in the acquisition or loss of functional properties of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

E73. The use of any one of E62-E72, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 20 mg.

E74. The use of any one of E62-E72, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 10 mg.

E75. The use of any one of E62-E72, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 8 mg.

E76. The use of any one of E62-E72, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 6 mg.

E77. The use of any one of E62-E75, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily.

E78. The use of E76, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 0.1mg to about 20 mg.

E79. The use of E77, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 2 mg.

E80. The use of E77, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 4 mg.

E81. The use of E77, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 6 mg.

E82. The use of E77, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 8 mg.

E83. The use of E77, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 20 mg.

E84. The use of any one of E62-E76, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily.

E85. The use of E84, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a dose of about 0.1mg to about 10mg twice daily.

E86. The use of E84, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 1mg each time.

E87. The use of E84, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 2mg each time.

E88. The use of E84, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 3mg each time.

E89. The use of E84, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 4mg each time.

E90. The use of E76, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 10mg each time.

E91. The use of any one of E61-E90, wherein the individual dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered as more than one capsule or tablet.

E92. The use of any one of E62-E91, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) 21 days of administration of the total daily dose; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

E93. The use of any one of E62-E91, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) administering the total daily dose for 21 consecutive days; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

E94. The use of any one of E62-E91, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 days of administration of the total daily dose; and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered for 2 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

E95. The use of any one of E62-E91, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 consecutive days of administration of the total daily dose, and (ii) 2 consecutive days of no administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

E96. The use of any one of E92-E95, wherein the 28-day dosing cycle is repeated until a total of 24 consecutive 28-day dosing cycles are reached.

Claims

1. A crystalline composition in substantially pure form IV of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide having formula (I)

2. The crystalline composition of claim 1, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 3 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

3. The crystalline composition of claim 1 or claim 2, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 6 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

4. The crystalline composition of any one of claims 1-3, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 1 year under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

5. The crystalline composition of any one of claims 1-4, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for 68 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

6. The crystalline composition of any one of claims 1-5, wherein the crystalline composition exhibits an XRPD pattern and/or DSC curve that is substantially unchanged after storage for ≡140 months under standard warehouse conditions (15 ℃ -25 ℃ and +.65% relative humidity).

7. The crystalline composition of any one of claims 2-6, wherein the XRPD pattern is generated using:

Wherein the sample is mounted flat on a zero background Si wafer.

8. The crystalline composition as defined in any one of claims 1-7, wherein a DSC profile is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15 ℃/min.

9. The crystalline composition as defined in any one of claims 1-8, wherein the crystalline composition contains less than or equal to 0.2 wt% dimeric impurity PF-00191189.

10. The crystalline composition as defined in any one of claims 1-9, wherein the crystalline composition contains from about 0.05 wt% to about 0.19 wt% dimeric impurity PF-00191189.

11. The crystalline composition as defined in any one of claims 1-9, wherein the crystalline composition is free of a detectable amount of dimeric impurity PF-00191189.

12. A pharmaceutical composition comprising the crystalline composition of any one of claims 1-8 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition is for oral administration.

14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is in a solid dosage form.

15. The pharmaceutical composition of any one of claims 12-14, wherein the pharmaceutical composition is a tablet or capsule.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is a tablet.

17. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is a capsule.

18. The pharmaceutical composition of claim 17, wherein the capsule comprises about 1mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows:

b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents;

c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;

d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and

e) Gelatin capsules encapsulating components a-d.

19. The pharmaceutical composition of claim 17, wherein the capsule comprises about 2mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows:

b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents;

c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;

d) About 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and

e) Gelatin capsules encapsulating components a-d.

20. The pharmaceutical composition of claim 17, wherein the capsule comprises about 5mg of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, wherein each component of the capsule is as follows:

b) About 85 wt/wt% to about 95 wt/wt% of one or more diluents;

c) About 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and

d) Gelatin capsules encapsulating components a-c.

21. The pharmaceutical composition of any one of claims 18-20, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dibasic calcium phosphate.

22. The pharmaceutical composition of claim 21, wherein at least one of the diluents is microcrystalline cellulose.

23. The pharmaceutical composition of any one of claims 18-22, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and alginic acid.

24. The pharmaceutical composition of claim 23, wherein at least one of the disintegrants is croscarmellose sodium.

25. The pharmaceutical composition of any one of claims 18-24, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl behenate, and talc.

26. The pharmaceutical composition of claim 25, wherein at least one of the lubricants is magnesium stearate.

27. A method of treating a tumor, cancer or Rasopathy disease, the method comprising administering to a subject in need of such treatment the pharmaceutical composition of any one of claims 12-26.

28. The method of claim 27, wherein the tumor is a neurofibromatosis.

29. The method of claim 28, wherein the tumor is a neurofibromatosis associated with type 1 neurofibromatosis.

30. The method of any one of claims 27-29, wherein the tumor is selected from the group consisting of: cutaneous neurofibromas, plexiform neurofibromas, optic-path gliomas, low-grade gliomas, high-grade gliomas or malignant peripheral schwannomas.

31. The method of claim 30, wherein the tumor is plexiform neurofibromatosis.

32. The method of claim 27, wherein the subject has been diagnosed with rasopathic disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, coster syndrome, lux Ji Sizeng syndrome, noonan syndrome and noonan syndrome with multiple freckles.

33. The method of claim 27, wherein the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocyte tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer.

34. The method of claim 33, wherein the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphoblastic leukemia, and chronic myelogenous leukemia.

35. The method of claim 33, wherein the lymphoma is selected from the group consisting of: b-cell lymphoma, T-cell lymphoma, burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and fahrenheit macroglobulinemia.

36. The method of claim 33, wherein the lung cancer is selected from the group consisting of: lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.

37. The method of any one of claims 27-36, wherein the subject has a mutation or other aberration in one or more genes for which the mutation or other aberration results in the acquisition or loss of functional properties of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

38. The method of any one of claims 27-37, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 20 mg.

39. The method of any one of claims 27-37, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 10 mg.

40. The method of any one of claims 27-37, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 8 mg.

41. The method of any one of claims 27-37, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered at a total daily dose of no more than 6 mg.

42. The method of any one of claims 27-41, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily.

43. The method of claim 42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of from about 0.1mg to about 20 mg.

44. The method of claim 42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 2 mg.

45. The method of claim 42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 4 mg.

46. The method of claim 42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 6 mg.

47. The method of claim 42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 8 mg.

48. The method of claim 42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 20 mg.

49. The method of any one of claims 27-42, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily.

50. The method of claim 49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a dose of from about 0.1mg to about 10mg twice daily.

51. The method of claim 49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 1 mg.

52. The method of claim 49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 2 mg.

53. The method of claim 49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 3 mg.

54. The method of claim 49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 4 mg.

55. The method of claim 49, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 10 mg.

56. The method of any one of claims 27-55, wherein the individual dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered as more than one capsule or tablet.

57. The method of any one of claims 27-56, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) 21 days of administration of the total daily dose; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

58. The method of any one of claims 27-56, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) administering the total daily dose for 21 consecutive days; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

59. The method of any one of claims 27-56, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 days of administration of the total daily dose; and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered for 2 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

60. The method of any one of claims 27-56, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28-day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 consecutive days of administration of the total daily dose, and (ii) 2 consecutive days of no administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

61. The method of any one of claims 57-60, wherein the 28-day dosing cycle is repeated until a total of 24 consecutive 28-day dosing cycles are reached.

62. Use of a pharmaceutical composition according to any one of claims 12-26 in the manufacture of a medicament for the treatment of a tumor, cancer or Rasopathy disease.

63. The use of any one of claims 62, wherein the tumor is a neurofibromatosis.

64. The use of claim 63, wherein the tumor is a neurofibromatosis associated with type 1 neurofibromatosis.

65. The use of any one of claims 62-64, wherein the tumor is selected from the group consisting of: cutaneous neurofibromas, plexiform neurofibromas, optic-path gliomas, low-grade gliomas, high-grade gliomas or malignant peripheral schwannomas.

66. The use of claim 65, wherein the tumor is plexiform neurofibromatosis.

67. The use of claim 62, wherein the subject has been diagnosed with rasopathic disease selected from the group consisting of: type 1 neurofibromatosis, type 2 neurofibromatosis, heart-face-skin syndrome, coster syndrome, lux Ji Sizeng syndrome, noonan syndrome and noonan syndrome with multiple freckles.

68. The use of claim 62, wherein the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocyte tumor, lung cancer, breast cancer, ovarian cancer, kidney cancer, colorectal cancer, thyroid cancer, bile duct cancer, urothelial cancer, uterine tumor, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic cancer, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and peritoneal serous cancer.

69. The use of claim 68, wherein the leukemia is selected from the group consisting of: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphoblastic leukemia, and chronic myelogenous leukemia.

70. The use of claim 68, wherein the lymphoma is selected from the group consisting of: b-cell lymphoma, T-cell lymphoma, burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma, small lymphocytic lymphoma, and fahrenheit macroglobulinemia.

71. The use of claim 68, wherein the lung cancer is selected from the group consisting of: lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.

72. The use of any one of claims 62-71, wherein the subject has a mutation or other aberration in one or more genes for which the mutation or other aberration results in the acquisition or loss of functional properties of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF 2.

73. The use of any one of claims 62-72 wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 20 mg.

74. The use of any one of claims 62-72 wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 10 mg.

75. The use of any one of claims 62-72 wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 8 mg.

76. The use of any one of claims 62-72 wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a total daily dose of no more than 6 mg.

77. The use of any one of claims 62-75, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily.

78. The use of claim 77, wherein said total daily dose of said N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of from about 0.1mg to about 20 mg.

79. The use of claim 77, wherein said total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 2 mg.

80. The use of claim 77, wherein said total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 4 mg.

81. The use of claim 77, wherein said total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 6 mg.

82. The use of claim 77, wherein said total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 8 mg.

83. The use of claim 77, wherein said total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered once daily at a dose of about 20 mg.

84. The use of any one of claims 62-75, wherein the total daily dose of the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily.

85. The use of claim 84, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a dose of about 0.1mg to about 10mg twice daily.

86. The use of claim 84, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 1mg each time.

87. The use of claim 84, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 2mg each time.

88. The use of claim 84, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 3 mg.

89. The use of claim 84, wherein the total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 4 mg.

90. The use of claim 77, wherein said total daily dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered twice daily at a dose of about 10 mg.

91. The use of any one of claims 62-90, wherein the individual dose of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered as more than one capsule or tablet.

92. The use of any one of claims 62-91, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) 21 days of administration of the total daily dose; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

93. The use of any one of claims 62-91, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) administering the total daily dose for 21 consecutive days; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

94. The use of any one of claims 62-91, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 days of administration of the total daily dose; and (ii) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered for 2 days; and (b) no N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide was administered for 7 days.

95. The use of any one of claims 61-91, wherein the N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is administered in a 28 day dosing cycle comprising: (a) Three 7-day periods, each period comprising (i) 5 consecutive days of administration of the total daily dose, and (ii) 2 consecutive days of no administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide; followed by (b) 7 consecutive days without administration of N- ((R) -2, 3-dihydroxypropoxy) -3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

96. The use of any one of claims 91-95, wherein the 28-day dosing cycle is repeated until a total of 24 consecutive 28-day dosing cycles are reached.