EA039646B1 - Pharmaceutical compositions comprising n-(3,5-dimethoxyphenyl)-n'-(1-methylethyl)-n-[3-(1-methyl-1h-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine - Google Patents

Abstract

The invention relates to pharmaceutical compositions comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, or a pharmaceutically acceptable salt thereof or a solvate thereof; to processes for the preparation of said compositions and to the use of said compositions for the manufacture of a medicament for the prophylaxis or the treatment, in particular the treatment, of diseases, e.g. cancer.

Description

The field to which the invention relates

The invention relates to pharmaceutical compositions comprising N-(3,5-dimethoxyphenyl)N'-( 1 -methylethyl)-N-[3-( 1 -methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl] ethane-1,2-diamine or a pharmaceutically acceptable salt or solvate thereof; to processes for the preparation of said compositions; and to the use of said compositions for the manufacture of a medicament for prophylaxis or treatment, especially for the treatment of diseases such as cancer.

Prerequisites for the creation of the invention

N-(3,5-Dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane1,2-diamine is described in WO2011/135376, which is incorporated herein by reference.

Chemical structure -diamine (hereinafter referred to as compound A) is

The essence of the invention

According to one aspect of the invention, there is provided a pharmaceutical composition comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin- 6yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, a formaldehyde acceptor, and a pharmaceutically acceptable carrier.

According to one aspect of the invention, the use of a formaldehyde scavenger, in particular meglumine, is provided to improve the stability, in particular the chemical stability of N(3,5-dimethoxyphenyl)-N'-( 1 -methylethyl)-N-[3-( 1-methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N-(3,5-dimethoxyphenyl)N'-(1 -methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, in a pharmaceutical composition, in particular a solid pharmaceutical composition, in particular , in capsule or tablet.

figures

Fig. 1 - experimental device for testing formaldehyde load in the solid state quinoxalin-6yl]ethane-1,2-diamine=compound A).

Fig. 2 - decomposition of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4yl)quinoxalin-6-yl]ethan-1,2- diamine (compound A) in powder blends comprising various concentrations of meglumine in the formaldehyde load test: ♦ represents the initial powder blend of 2 w/w% compound A, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate; represents the original powder mixture of 2 wt./wt.% compound A, 1 wt./wt.% meglumine, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate; ▲ represents the original powder mixture of 2 wt./wt.% compound A, 9 wt./wt.% meglumine, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. Compound B is 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro -1H-1,4-benzodiazepine.

Detailed description of the invention

It was found that N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4yl)quinoxalin-6-yl]ethan-1,2 -diamine is weakly resistant to degradation, especially when it is included in a solid pharmaceutical composition. In particular, N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 -diamine is slightly resistant, especially when included in a solid pharmaceutical composition, to conversion to the cyclized product, 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazole-4- yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.

Chemical structure 1H-1,4-benzodiazepine (hereinafter referred to as compound B) is

Without wishing to be bound by any theory, it is likely that the stability, in particular the chemical stability, of N-(3,5-dimethoxyphenyl)-N'-( 1 -methylethyl)-N-[3-( 1 -methyl-1 N-pyrazol-4-yl)quinoxalin-6-yl]

- 1 039646 ethane-1,2-diamine deteriorates due to the effects of formaldehyde, and 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1methyl-1 H-pyrazol-4-yl)quinoxalin- 6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine is formed by the reaction of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-( 1-methyl-1 H-pyrazol-4-yl)quinoxalin-6yl]ethane-1,2-diamine with formaldehyde.

Formaldehyde can come into contact with N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1 ,2-diamine from various sources, for example, from the environment, from other components or excipients present in a pharmaceutical composition comprising N-(3,5-dimethoxyphenyl)-N'-( 1 -methylethyl)-N-[3- (1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2-diamine, from containers or packaging that contain a pharmaceutical composition, in particular a solid pharmaceutical composition comprising N-(3, 5-dimethoxyphenyl)-N'(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine.

Although it was found that 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1Hpyrazol-4-yl)quinoxalin-6-yl]-2.3, 4,5-tetrahydro-1H-1,4-benzodiazepine exhibits FGFR inhibitory activity, yet it is desirable for a pharmaceutical composition that the formation of by-products be prevented, delayed, slowed down or reduced.

It has been found that the stability, in particular the chemical stability, -6-yl]ethane-1,2-diamine, particularly when included in a solid pharmaceutical composition such as, for example, a capsule or tablet, can be increased by the addition of one or more formaldehyde scavengers. Without wishing to be bound by any theory, when incorporated into a solid pharmaceutical composition, such as, for example, a capsule or tablet, the excipients and the active ingredient are in close contact with each other, and this can affect the degree and/or rate of N- (3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2-diamine in 6.8 -dimethoxy-4-(1methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4- benzodiazepine.

Thus, the present invention provides pharmaceutical compositions comprising, as an active pharmaceutical ingredient, N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof with improved stability or longer shelf life. The shelf life of the compositions of the present invention is at least 12 months, at least 18 months, at least 24 months.

Formaldehyde scavengers are compounds that are capable of absorbing formaldehyde. These include compounds containing a nitrogen center which reacts with formaldehyde, thereby forming one or more reversible or irreversible bonds between the formaldehyde acceptor and formaldehyde. For example, the formaldehyde acceptor includes one or more nitrogen atoms/sites that react with formaldehyde to form an imine Schiff base, which is capable of subsequent bonding with formaldehyde. For example, the formaldehyde acceptor includes one or more nitrogen centers that react with formaldehyde to form one or more 5-8 membered cyclic rings. The formaldehyde scavenger preferably includes one or more amine or amide groups. For example, the formaldehyde scavenger may be an amino acid, an amino sugar, an alpha-amine compound, or a conjugate or derivative thereof, or a mixture thereof. The formaldehyde scavenger may include two or more amines and/or amides.

Formaldehyde scavengers include, for example, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, citrulline, taurine, pyrrolysine, meglumine, histidine, aspartame , proline, tryptophan, citrulline, pyrrolysine, asparagine, glutamine, or a conjugate or mixture thereof; or, if possible, their pharmaceutically acceptable salts.

In one aspect of the invention, the formaldehyde scavenger is meglumine or a pharmaceutically acceptable salt thereof, in particular meglumine base.

One aspect of the invention involves the use of a formaldehyde scavenger, in particular meglumine, in a pharmaceutical composition, in particular a solid pharmaceutical composition, in particular a capsule or tablet, to improve the stability, in particular the chemical stability of N-(3,5dimethoxyphenyl)-N' -(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, contained in the specified composition. Stability, in particular chemical stability, is improved compared to a pharmaceutical composition containing no formaldehyde scavengers.

One aspect of the invention includes a process for stabilizing N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan- 1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole4- yl)quinoxalin-6-yl]ethane-1,2-diamine base, in a pharmaceutical composition, in particular a solid pharmaceutical composition such as a capsule or tablet, comprising the addition of ac

- 2 039646 formaldehyde ceptor, in particular, meglumine, to the specified composition.

One aspect of the invention includes the use of a formaldehyde scavenger, in particular meglumine, in a pharmaceutical composition, in particular a solid pharmaceutical composition such as a capsule or tablet, to prevent, delay, slow down or reduce the conversion of N-(3,5dimethoxyphenyl)-N-( 1-methylethyl)-M-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, its pharmaceutically acceptable salt or its solvate contained in the composition, in 6,8-dimethoxy4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1 ,4benzodiazepine, a pharmaceutically acceptable salt thereof, or a solvate thereof.

One aspect of the invention involves the use of a formaldehyde scavenger, in particular meglumine, in a pharmaceutical composition, in particular a solid pharmaceutical composition such as a capsule or tablet, to prevent, delay, slow down or reduce the conversion of N-(3,5dimethoxyphenyl)-N'- (1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine contained in the composition in 6,8-dimethoxy-4 -(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.

One aspect of the invention includes a method for preventing, delaying, slowing down or reducing the conversion of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof contained in a pharmaceutical composition, in particular a solid pharmaceutical composition such as a capsule or tablet, in 6,8-dimethoxy-4-(1 -methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5tetrahydro-1H-1,4-benzodiazepine, a pharmaceutically acceptable salt thereof, or its solvate, including the addition of a formaldehyde acceptor, in particular meglumine, to said composition.

One aspect of the invention includes a method for preventing, delaying, slowing down or reducing the conversion of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6yl]ethane-1,2-diamine contained in a pharmaceutical composition, in particular a solid pharmaceutical composition such as a capsule or tablet, in 6,8-dimethoxy-4-(1-methylethyl)-1-[3 -(1-methyl1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, comprising adding a formaldehyde acceptor, in particular meglumine, to said composition .

One aspect of the invention involves the use of a formaldehyde scavenger, in particular meglumine, in a pharmaceutical composition, in particular a solid pharmaceutical composition, in particular such as a capsule or tablet, comprising N-(3,5-dimethoxyphenyl)-N'-(1- methylethyl)-N-[3-(1-methyl-1Hpyrazol-4-yl)quinoxalin-6-yl]ethan-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof, to prevent, delay, slow or reduce the formation 6,8-dimethoxy-4-(1-methylethyl)1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1Н -1,4-benzodiazepine, a pharmaceutically acceptable salt or solvate thereof, in said composition.

One aspect of the invention involves the use of a formaldehyde scavenger, in particular meglumine, in a pharmaceutical composition, in particular a solid pharmaceutical composition, in particular such as a capsule or tablet, comprising N-(3,5-dimethoxyphenyl)-N'-(1- methylethyl)-N-[3-(1-methyl-1Hpyrazol-4-yl)quinoxalin-6-yl]ethan-1,2-diamine, to prevent, delay, slow down or reduce the formation of 6,8-dimethoxy-4- (1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine in the indicated compositions.

One aspect of the invention includes a pharmaceutical composition comprising N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane -1,2-diamine, a pharmaceutically acceptable salt or solvate thereof; a formaldehyde scavenger, in particular meglumine; and a pharmaceutically acceptable carrier; in particular, a pharmaceutical composition comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6yl]ethane -1,2-diamine; a formaldehyde scavenger, in particular meglumine; and a pharmaceutically acceptable carrier.

One aspect of the invention includes a solid pharmaceutical composition, such as a capsule or tablet, comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4- yl) quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof; a formaldehyde scavenger, in particular meglumine; and a pharmaceutically acceptable carrier; in particular, a solid pharmaceutical composition such as a capsule or tablet comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4- yl)quinoxalin-6-yl]ethane-1,2-diamine; a formaldehyde scavenger, in particular meglumine; and a pharmaceutically acceptable carrier.

In one aspect of the invention, the pharmaceutical compositions described in this application include 0-4 wt./wt.%, or 0-3 wt./wt.%, or 0-2 wt./wt.%, or 0-1, 5 wt./wt.%, or 0-1 wt./wt.%, or 0-0.5 wt./wt.%, or 0-0.1 wt./wt.%, or 0-0, 05 w/w% 6,8-dimethoxy-4-(1methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4 ,5-tetrahydro- 1H-1,4-benzodiazepine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular 0-4 wt./wt.%, or 0-3 wt./wt.%, or 0-2 wt. ./wt.%, or 0-1.5 wt./wt.%, or 0-1 wt./wt.%, or 0-0.5 wt./wt.%, or 0-0.1 wt. ./wt.%, or 0-0.05 wt./wt.% 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl]2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.

- 3 039646

In one aspect of the invention, the pharmaceutical compositions described in this application are suitable for oral administration, for example, capsules or tablets, with a pharmaceutical composition in the form of a tablet, in particular for oral administration, is preferred. In one aspect of the invention, the pharmaceutical compositions described in this application are suitable for rectal administration. The tablets of the invention can be prepared by conventional tabletting techniques using pharmaceutically acceptable excipients (pharmaceutically acceptable carrier) and conventional tableting machines. As is known in the art, tablet blends can be dry granulated or wet granulated prior to tabletting. It should be understood that a person skilled in the art will be able to determine the most appropriate route to obtain the compositions of the present invention. In order to facilitate ingestion of such a pharmaceutical composition for oral administration by a mammal, in particular a human, it is preferable to give the compositions, in particular tablets, a suitable form.

The tablets or capsules of the present invention can then be film-coated, for example to improve taste, ease of swallowing and attractive appearance. Polymeric materials for film coatings are known in the art. The preferred film coatings are water-based film coatings as opposed to solvent-based film coatings, since the latter may contain higher trace amounts of aldehydes. A preferred film coating material is Opadry® aqueous film coating system II, for example Opadry® II 85F, such as Opadry® II 85F92209. Other preferred film coatings are water-based film coatings that protect against ambient moisture, such as Readilycoat® (e.g. Readilycoat® D), AquaPolish® MS, Opadry® amb, Opadry® amb II, which are water-retaining barrier film systems. coatings. A preferred film coating is Opadry® amb II, a high performance water-retaining barrier film coating that is a PVA-based immediate release system, without polyethylene glycol.

In tablets according to the invention, the film coating, by weight, is preferably about 4% w/w or less of the total weight of the tablet.

With respect to capsules according to the present invention, hydroxypropyl methylcellulose (HPMC) capsules are preferred over gelatin capsules.

In one aspect of the invention, the pharmaceutical compositions described herein, particularly in the form of a capsule or tablet, comprise a therapeutically effective amount of N-(3,5-dimethoxyphenyl)-N-(1-methylethyl)-M-[3-(1-methyl -III-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof.

In one aspect of the invention, the pharmaceutical compositions described herein, particularly in the form of a capsule or tablet, comprise 0.5 mg to 20 mg base equivalent, or 2 mg to 20 mg base equivalent, or 0.5 mg to 12 mg base equivalent, or 2 mg to 12 mg base equivalent, or 2 mg to 10 mg base equivalent, or 2 mg to 6 mg base equivalent, or 2 mg base equivalent, 3 mg base equivalent, 4 mg base equivalent , 5 mg base equivalent, b mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent or 12 mg base equivalent N-(3,5-dimethoxyphenyl)- N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof. In particular, the pharmaceutical compositions described herein include 3 mg base equivalent, 4 mg base equivalent, or 5 mg base equivalent N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N[3-( 1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof.

In one aspect of the invention, the pharmaceutical compositions described in this application, in particular in the form of a capsule or tablet, include from 0.5 to 20 mg, or from 2 to 20 mg, or from 0.5 to 12 mg, or from 2 to 12 mg or 2 to 10 mg or 2 to 6 mg or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 mg or 12 mg N-(3,5dimethoxyphenyl)-N '-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2 diamine base. In particular, the pharmaceutical compositions described in this application include 3, 4 or 5 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole -4-yl) quinoxalin-6-yl]ethane-1,2-diamine base. In particular, the pharmaceutical compositions described in this application include 3, 4 or 5 mg of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1Hpyrazole-4 -yl)quinoxalin-6-yl]ethane-1,2-diamine base and from about 0.5 to about 5 wt./wt.%, from about 0.5 to about 3 wt./wt.%, from about 0.5 to about 2 wt./wt.%, from about 0.5 to about 1.5 wt./wt.%, or from about 0.5 to about 1 wt./wt.% formaldehyde scavenger, in particular, meglumine. In particular, the pharmaceutical compositions described in this application include 3, 4 or 5 mg of N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4 -yl)quinoxalin-6-yl]ethane-1,2-diamino base and from about 0.5 to about 1.5 wt./wt.% or from about 0.5 to about 1 wt./ wt.% formaldehyde scavenger, in particular meglumine.

In one aspect of the invention, more than one, for example, two pharmaceutical compositions described in this application, you can enter to obtain the desired dose, for example, daily dose.

One aspect of the invention includes a pharmaceutical composition described in this application, comprising particles of K-(3,5-dimethoxyphenyl)-K'-(1-methylethyl)-K-[3-(1-methyl-1H-pyrazol-4-yl ) quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the particles have a d ^{50 of} about 1500 µm, about 1000 µm, about 500 µm, about 400 µm, about 250 µm, about 200 µm, approx. 150 µm, approx. 125 µm, approx. 100 µm, approx. 95 µm, approx. 90 µm, approx. 85 µm, approx. µm, about 50 µm, about 45 µm, about 40 µm, about 35 µm, about 30 µm, about 25 µm, about 20 µm, about 15 µm, about 10 µm, about 5 µm. Preferably, the particles have a d ^{50 of} about 12 5 µm, about 100 µm, about 95 µm, about 90 µm, about 85 µm, about 80 µm, about 75 µm, about 70 µm, about 65 µm, about 60 µm, about 55 µm , approximately 50 µm. One aspect of the invention includes a pharmaceutical composition described in this application, comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1Hpyrazol-4-yl)quinoxaline -6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the particles have a d ⁵⁰ ranging from 5 µm to 1500 µm, or from 5 µm to 1000 µm, or from 5 µm to 500 µm or 5 µm to 400 µm, or 5 µm to 250 µm, or 5 µm to 200 µm, or 5 µm to 150 µm, or 5 µm to 125 µm, or 5 µm to 100 µm, or 5 µm to 80 µm, or 5 µm to 75 µm, or 5 µm to 70 µm, or 5 µm to 65 µm, or 5 µm to 60 µm, or 5 µm to 55 µm, or 5 µm to 50 µm, or 5 µm to 45 µm, or 5 µm to 40 µm, or 5 µm to 35 µm, or 5 µm to 30 µm, or 5 µm to 25 µm, or 5 µm to 20 µm, 5 µm to 15 µm, or 5 µm to 10 µm, or the particles have a d ⁵⁰ ranging from 50 µm to 125 µm, or 50 µm to 100 µm, or 50 µm to 75 µm.

As used herein, the term d ⁵⁰ has a conventional meaning, as known to those skilled in the art, and which can be measured by known particle size measurement techniques such as, for example, sediment field flow fractionation, photon correlation spectroscopy, laser diffraction, or disk centrifugation. The indicated d ⁵⁰ value may refer to volume-weighted particle distributions. In this case, d ⁵⁰ 50 µm means that at least 50% of the particles have a particle size (defined by volume or equivalent sphere diameter) of less than 50 µm. In the same way, d ⁵⁰ particle size can refer to the weighted average particle number distributions. In this case, d ⁵⁰ 50 µm means that at least 50% of the particles have a particle size (by number) of less than 50 µm. In particular, the indicated value of d ⁵⁰ represents the volume-weighted average distribution of particles, in particular, measured on the Malvern Mastersizer 2000.

Particle size can be an important factor in determining tabletting speed, buoyancy, fluidity, and therefore the ability to produce on a large scale a particular composition, and the quality of the final product.

The amount of formaldehyde scavenger, in particular meglumine, in pharmaceutical compositions in accordance with the present invention may range from about 0.1 to about 10% w/w, from about 0.1 to about 5% w/w. , from about 0.1 to about 3% w/w, from about 0.1 to about 2% w/w, from about 0.1 to about 1.5% w/w, from about 0, 1 to about 1% w/w, from about 0.5 to about 5% w/w, from about 0.5 to about 3% w/w, from about 0.5 to about 2% wt./wt., from about 0.5 to about 1.5% wt./wt., from about 0.5 to about 1 wt./wt.%.

Pharmaceutical compositions of the invention, in particular capsules and/or tablets, may include one or more pharmaceutically acceptable excipients (pharmaceutically acceptable carrier) such as disintegrants, diluents, fillers, binders, buffering agents, lubricants, glidants, thickeners, sweeteners , perfumes, dyes, preservatives and the like. Some excipients may perform different functions.

Suitable disintegrators are those which have a high coefficient of expansion. Examples thereof include hydrophilic insoluble or slightly water soluble crosslinked polymers such as crospovidone (crosslinked polyvinylpyrrolidone) and croscarmellose sodium (crosslinked carboxymethylcellulose sodium). The amount of disintegrant in tablets in accordance with the present invention for convenience may be from about 2.5 to about 15 wt./wt.%, and preferably from about 2.5 to 7 wt./wt.%, in particular, from about 2 .5 to 5 wt./wt.%. Because disintegrants, by their very nature, provide sustained release formulations when

- 5 039646 they are used in bulk, preferably they are diluted with an inert substance called a diluent or filler.

Various substances can be used as diluents or fillers. Examples include lactose monohydrate, lactose anhydrous, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g. microcrystalline cellulose (Avicel™), silicified microcrystalline cellulose), dihydrated or anhydrous dibasic calcium phosphate, and others known in the art and their mixtures (eg, spray-dried mixture of lactose monohydrate (75%) with microcrystalline cellulose (25%), which is commercially available as Microcelac™). Microcrystalline cellulose and mannitol are preferred. The total amount of diluent or excipient in the pharmaceutical compositions of the present invention may conveniently be from about 20% to about 95% w/w, and preferably from about 55% to about 95% w/w, or from about 70 % to about 95 wt./wt.%, or from about 80% to about 95 wt./wt.%, or from about 85% to about 95%.

Lubricants and glidants can be used to make some dosage forms and are used to make tablets. Examples of lubricants and glidants include hydrogenated vegetable oils, such as hydrogenated cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, colloidal anhydrous silica talc, mixtures thereof, and other substances known in the art. Lubricants of interest include magnesium stearate and mixtures of magnesium stearate with colloidal silicon dioxide, with magnesium stearate being preferred.

The preferred glidant is colloidal anhydrous silica.

If present, glidants typically comprise 0.2 to 7.0 w/w% of the total weight of the composition, in particular 0.5 to 1.5 w/w%, more preferably from 1 to 1.5 wt./wt.%.

When present, lubricants typically comprise from 0.2 to 7.0 wt./wt.% of the total weight of the composition, in particular from 0.2 to 2 wt./wt.%, or from 0. 5 to 2 wt./wt.%, or from 0.5 to 1.75 wt./wt.%, or from 0.5 to 1.5 wt./wt.%.

Binders are used but are optional in the pharmaceutical compositions of the present invention. Suitable binders include water soluble polymers such as alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; carboxyalkylcelluloses such as carboxymethylcellulose; alkali metal and carboxyalkylcellulose salts such as sodium carboxymethylcellulose; carboxyalkylalkylcelluloses such as carboxymethylethylcellulose; carboxyalkyl cellulose esters; starches; pectins such as sodium carboxymethyl amylopectin; chitin derivatives such as chitosan; di-, oligo- and polysaccharides such as trehalose, cyclodextrins and their derivatives, alginic acid, their alkali metal and ammonium salts, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, gaur gum and xanthan gum; polyacrylic acids and their salts; polymethacrylic acids, their salts and esters, methacrylate copolymers; polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and its copolymers, for example PVP-VA. Preferably, the water-soluble polymer is a hydroxyalkylalkyl cellulose such as, for example, hydroxypropyl methyl cellulose, eg hydroxypropyl methyl cellulose 15 cps.

Other excipients such as dyes and pigments can also be added to the compositions of the invention. Dyes and pigments include titanium dioxide and food coloring. The dye or pigment is an optional ingredient in the composition of the invention, but when used, the dye may be present in an amount of up to 3.5 wt./wt.%, based on the total weight of the composition.

Perfumes are optionally used in the composition and may be selected from synthetic fragrance oils and fragrances or natural oils, extracts of plant leaves, flowers, fruits, and the like. and their combinations. They may include cinnamon oil, wintergreen oil, peppermint oil, bay oil, anise oil, eucalyptus, thyme oil. Also useful as flavorings are vanilla, citrus oil including lemon, orange, grape, lime and grapefruit, and fruit essences including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. d. The amount of perfume may depend on a number of factors, including the desired organoleptic effect. Typically, the fragrance is present in an amount of from about 0% to about 3% w/w.

Another object of the invention is to provide a process for the preparation of a pharmaceutical composition described in this application, in particular in the form of a tablet or capsule, which comprises mixing a formaldehyde scavenger, in particular meglumine, and N-(3,5-dimethoxyphenyl) -N'-(1methylethyl)-N[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, with a pharmaceutically acceptable carrier and compressing said mixture into tablets or filling capsules with said mixture.

For the preparation of pharmaceutical compositions according to the invention ,2-diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N(3,5-dimethoxyphenyl)-N-(1-methylethyl)-N[3-(1-methyl-1Hpyrazol-4-yl)quinoxalin- 6-yl]ethane-1,2-diamine base, as an active pharmaceutical ingredient, a formaldehyde scavenger, in particular meglumine, is combined to form an intimate mixture with a pharmaceutically acceptable carrier, while the carrier can take a wide variety of forms described in this application .

It is particularly preferred to formulate the above pharmaceutical compositions into unit dosage forms for ease of administration and uniform dosing. Unit dosage form as used herein refers to physically discrete units suitable as single doses, where each unit contains a predetermined amount of the active ingredient calculated to provide the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such unit dosage forms include tablets (including scored or coated tablets), capsules, pills, powder sachets, cachets, injectable solutions or suspensions, drug teaspoons, drug tablespoons, and the like, and multiples thereof. doses. Preferred forms are tablets and capsules.

In one aspect of the invention, N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol4-yl)quinoxalin-6-yl]ethan-1,2 -diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N(3,5-dimethoxyphenyl)-N-(1-methylethyl)-N[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin- 6-yl]ethane1,2-diamine base is or should be administered via the pharmaceutical compositions of the present invention in an amount sufficient to exhibit antitumor activity.

In one aspect of the invention, the pharmaceutical compositions described in this application include N-(3,5-dimethoxyphenyl)-N-( 1 -methylethyl)-N-[3-( 1 -methyl-1 H-pyrazol-4-yl) quinoxalin-6-yl]ethane-1,2-diamine base.

In one aspect of the invention, the pharmaceutical compositions described in this application include a pharmaceutically acceptable salt of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl1H-pyrazol-4-yl )quinoxalin-6-yl]ethane-1,2-diamine, in particular N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole -4-yl)quinoxalin-6-yl]ethane-1,2-diamine hydrochloride.

The invention also relates to pharmaceutical packaging suitable for commercial sale, including a container, a pharmaceutical composition described in this application, and written instructions attached to said packaging.

Containers containing the pharmaceutical composition of the present invention, such as bottles, optionally contain a desiccant. In one aspect of the invention, containers containing the pharmaceutical composition of the present invention, such as bottles, do not contain a desiccant. In one aspect of the invention, the containers are HDPE bottles.

The containers containing the pharmaceutical composition of the present invention preferably comprise or consist of a formaldehyde-free material, such as, for example, formaldehyde-free aluminum foil, such as in the case of blister packs, such as PVC blister packs with aldehyde-free aluminum foil, or Aclar® blister packs with aldehyde-free aluminum foil.

In one aspect of the invention, the container is a child-resistant container, such as a bottle with a child-resistant cap or a blister pack, a child-resistant pouch.

The term approximately, as used herein in connection with a numerical value, has its usual meaning in the context of a numerical value. If necessary, the word approximately can be replaced by a numerical value of ±10%, or ±5%, or ±2%, or ±1%.

All documents cited in this application are incorporated herein in their entirety.

Pharmaceutically acceptable salts or solvates

Salt forms of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 -diamine or 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine are typical pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al. (1977) Acceptable Salts, J. Pharm. Sc., Vol. 66, pp. 1-19.

The salts of the present invention can be synthesized from a parent compound that contains an alkali group by conventional chemical methods such as those described in

- 7 039646

Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. obtain by reacting the free base form of the compound with a suitable acid in water or in an organic solvent, or in a mixture of two such solvents; typically non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used. Salts can exist as mono- or di-salts, depending on the pKa of the acid from which the salt is formed.

Acid addition salts can be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g., L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic , butanoic, (+)camphoric, camphorsulfonic, (+)-(IS)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamon, citric, cyclamine, dodecylsulfonic, ethane-1,2disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (for example, D-glucuronone), glutamic (for example, L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic, (e.g. (+)T-lactic, (±)-DLlactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-almond, methanesulfonic, naphthalenesulfonic (naphthalene-2-sulfonic ), naphthalene-1,5-di sulfonic, 1hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, pyruvic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, sulfuric, tannic, (+ )T-tartaric, thiocyanic, toluenesulfonic (for example, p-toluenesulfonic), undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

One particular group of salts consists of salts derived from acetic, hydrochloric, hydroiodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric , acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. Another group of acid addition salts includes salts derived from acetic, adipic, ascorbic, aspartic, citric, DL-lactic, fumaric, gluconic, glucuronic, hippuric, hydrochloric, glutamic, DL-malic, methanesulfonic, sebacic, stearic, succinic, and tartaric. acids.

N-(3,5-Dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane1,2-diamine or their salts, and 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6yl]-2,3,4,5-tetrahydro- 1H-1,4-benzodiazepine, or salts thereof, may form solvates with, for example, water (ie hydrates) or common organic solvents. As used herein, the term solvate means the physical association of the compounds of the present invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are included in the crystal lattice of a crystalline solid. The term solvate is intended to encompass both solution phase solvates and recoverable solvates. Non-limiting examples of suitable solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine, and the like. The compounds of the invention can exhibit their biological effects while in solution.

Solvates are well known in pharmaceutical chemistry. They can be important for methods of obtaining a substance (for example, in connection with purification, storage of a substance (for example, its stability) and ease of handling of a substance, and are often formed as part of the isolation or purification steps of chemical synthesis. A person skilled in the art will be able to use standard and long known methods to determine the formation of a hydrate or other solvate under the isolation or purification conditions used to prepare a given compound.Examples of such methods include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), x-ray crystallography (for example, single crystal x-ray crystallography or X-ray powder diffraction) and solid-state NMR (SS-NMR, also known as magic-angle rotation NMR or MAS-NMR). Such methods are as much a part of the skilled chemist's standard analytical instrumentation as NMR, IR, HPLC, and MS. Alternatively , specialist in th region will be able to deliberately form a solvate using crystallization conditions that include the amount of solvent required for a particular solvate. Thereafter, the standard methods described above can be used to determine the formation of solvates. Any complexes (eg, inclusion complexes or clathrates with compounds such as cyclodextrins or metal complexes) of the compounds are also contemplated.

In addition, N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-8 039646

6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, or 6,8-dimethoxy-4-(1methylethyl)-1-[3-(1-methyl-1H-pyrazole-4- yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, a pharmaceutically acceptable salt or solvate thereof, may have one or more polymorphic (crystalline) or amorphous forms, and all such forms are included within the scope of the present invention.

Na(3,5-dimethoxyphenyl)-H'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane1,2-diamine, its pharmaceutical acceptable salt or solvate thereof, or 6,8-dimethoxy-4-(1-methylethyl)1-[3-(1-methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl]-2.3, 4,5-tetrahydro-1H-1,4-benzodiazepine, a pharmaceutically acceptable salt thereof, or a solvate thereof includes compounds with one or more isotopic substitutions, and reference to a particular element is intended to include all isotopes of that element. For example, reference to hydrogen includes within its scope 1H, 2H ⁽ D), and ^3H (T). Similarly, references to carbon and oxygen include ¹² C, ¹³ C, and ¹⁴ C and ¹⁶ O and ¹⁸ O, respectively. Isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds do not contain any radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.

Protein tyrosine kinase (RTK)

N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane1,2-diamine, its a pharmaceutically acceptable salt, or solvate thereof, inhibits or modulates the activity of certain tyrosine kinases, and thus the pharmaceutical compositions of the present invention will be useful for the treatment or prevention, in particular treatment, of diseases or conditions mediated by these tyrosine kinases, in particular, FGFR (receptor fibroblast growth factor).

FGFR

The protein tyrosine kinase (PTK) family of fibroblast growth factor (FGF) receptors regulates a variety of physiological functions including mitogenesis, wound healing, cell differentiation and angiogenesis, and development. Both normal and malignant cell growth and proliferation affect changes in the local concentration of FGF, extracellular signaling molecules that act as autocrine as well as paracrine factors. Autocrine FGF signaling may be particularly important in the progression of steroid-dependent cancer types to a hormone-independent state. FGFs and their receptors are expressed at elevated levels in several tissues and cell lines, and overexpression is thought to contribute to the malignant phenotype. In addition, a number of oncogenes are homologues of genes encoding growth factor receptors, and there is a possibility of aberrant activation of FGF-dependent signaling in human pancreatic cancer (Knights et al., Pharmacology and Therapeutics 2010 125:1 (105-117); Korc M. et al Current Cancer Drug Targets 2009 9:5 (639-651)).

The two prototypical members are acidic fibroblast growth factor (aFGF or FGF1) and alkaline fibroblast growth factor (bFGF or FGF2), and at least twenty separate members of the FGF family have been identified to date. The cellular response to FGFs is mediated through four types of high-affinity transmembrane protein tyrosine kinase fibroblast growth factor receptors (FGFRs), numbered 1-4 (FGFR1 - FGFR4).

Disruption of the FGFR1 pathway should affect tumor cell proliferation since this kinase is upregulated in many tumor types in addition to proliferating endothelial cells. Increased expression and activation of FGFR1 in the tumor-associated vasculature suggests a role for these molecules in tumor angiogenesis.

A recent study showed an association between FGFR1 expression and carcinogenicity in classic lobular carcinomas (CLCs). CLCs account for 10-15% of all breast cancers and typically lack p53 and Her2 expression, while retaining estrogen receptor expression. Amplification of the 8p12-p11.2 gene has been demonstrated in ~50% of CLC cases and has been shown to be associated with increased FGFR1 expression. Preliminary studies with siRNA directed against FGFR1 or a small molecule receptor inhibitor have shown that cell lines containing such amplification are particularly sensitive to the inhibition of this signaling pathway. Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma that is likely the result of abnormal proliferation and differentiation during skeletal myogenesis. FGFR1 is overexpressed in primary rhabdomyosarcoma tumors and is associated with hypomethylation of the 5'CpG island and abnormal expression of the AKT1, NOG, and BMP4 genes. FGFR1 has also been associated with squamous cell lung cancer, colorectal cancer, glioblastoma, astrocytomas, prostate cancer, small cell lung cancer, melanoma, head and neck cancer, thyroid cancer, and uterine cancer.

Fibroblast growth factor receptor 2 has a high affinity for acidic and/or alkaline fibroblast growth factors as well as keratinocyte growth factor ligands.

The fibroblast growth factor 2 receptor also mediates the strong osteogenic effects of FGF during osteoblast growth and differentiation. Mutations in fibroblast growth factor receptor 2, leading to complex functional changes, have been shown to cause abnormal ossification of cranial sutures (craniosynostosis), implying an important role for FGFR signaling in intramembranous osteogenesis. For example, in Apert syndrome (AR), characterized by premature ossification of the cranial suture, most cases are associated with point mutations that give rise to gain of function in the fibroblast growth factor receptor 2. In addition, screening for mutations in patients with syndromic craniosynostoses indicates that the number of recurrent mutations FGFR2 causes severe forms of Pfeiffer syndrome. Specific FGFR2 mutations include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R in FGFR2.

Several serious human skeletal anomalies, including Apert, Crouzon, Jackson-Weiss, Beer-Stevenson cutis gyrata, and Pfeiffer syndromes, are associated with mutations in the fibroblast growth factor receptor 2. Most, if not all, cases of Pfeiffer syndrome (PS) are also caused by de novo mutation of the fibroblast growth factor receptor 2 gene, and it has recently been shown that mutations in the fibroblast growth factor receptor 2 violate one of the basic rules governing ligand specificity. Namely, two mutant splicing forms of the fibroblast growth factor receptor FGFR2c and FGFR2b acquired the ability to bind to and be activated by atypical FGF ligands. This loss of ligand specificity leads to aberrant signaling and suggests that the severe phenotypes of these syndromes are the result of ectopic ligand-dependent activation of fibroblast growth factor receptor 2.

Genetic aberrations of the FGFR3 tyrosine kinase receptor, such as chromosomal translocations or point mutations, result in ectopically expressed or deregulated, constitutively active FGFR3 receptors. Such anomalies are associated with a subgroup of multiple myelomas and bladder carcinoma, hepatocellular, oral squamous cell carcinoma, and cervical carcinomas. Accordingly, FGFR3 inhibitors would be useful in the treatment of multiple myeloma, bladder carcinomas, and cervical carcinomas. FGFR3 is also overexpressed in bladder cancer, in particular invasive bladder cancer. FGFR3 is frequently upregulated by mutation in urothelial carcinoma (UC). Overexpression was associated with the mutation (85% of mutant tumors showed high levels of expression), but also 42% of tumors without a detectable mutation showed overexpression, including many muscle-invasive tumors. FGFR3 is also associated with endometrial and thyroid cancer.

Overexpression of FGFR4 is associated with poor prognosis in prostate and thyroid cancer. In addition, a germline polymorphism (Gly388Arg) is associated with an increase in lung, breast, colon, liver (HCC) and prostate cancers. In addition, a truncated form of FGFR4 (including the kinase domain) was found to be present in 40% of pituitary tumors, but not present in normal tissue. Overexpression of FGFR4 has been observed in liver, colon, and lung tumors. FGFR4 is associated with colorectal and hepatic cancer, where the expression of its FGF19 ligand is often upregulated. FGFR4 is also associated with astrocytomas, rhabdomyosarcoma.

Fibrotic conditions are a major medical problem caused by abnormal or excessive deposition of fibrous tissue. This occurs in many diseases, including cirrhosis of the liver, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and the natural wound healing process. The mechanisms of pathological fibrosis are not fully elucidated but are thought to result from the actions of various cytokines (including tumor necrosis factor (TNF), fibroblast growth factors (FGF), platelet growth factor (PDGF) and transforming growth factor beta (TGFe)), which are involved in proliferation of fibroblasts and deposition of extracellular matrix proteins (including collagen and fibronectin) leading to changes in tissue structure and function and subsequent pathology.

A number of preclinical studies have demonstrated upregulation of fibroblast growth factors in preclinical models of pulmonary fibrosis. TGF1 and PDGF have been reported to be involved in the fibrogenic process, and in addition, published work suggests an increase in FGF and a corresponding increase in fibroblast proliferation, possibly in response to increased TGFe1. The potential therapeutic benefit of targeting the fibrotic mechanism in conditions such as idiopathic pulmonary fibrosis (IPF) is suggested in a report on the clinical effect of the antifibrotic agent pirfenidone. Idiopathic pulmonary fibrosis (also called cryptogenic fibrosing alveolitis) is a progressive condition that results in scarring of the lungs. Gradually, the air sacs of the lungs are replaced by fibrous tissue that becomes thicker, resulting in an irreversible loss of the tissue's ability to carry oxygen into the bloodstream. Symptoms of the condition include shortness of breath, chronic dry cough, fatigue, chest pain, and loss of appetite leading to rapid weight loss. The condition is extremely serious with approximately 50% mortality after 5 years.

As such, the pharmaceutical compositions of the present invention will be useful in providing a method for preventing the growth or induction of apoptosis in tumors, in particular by inhibiting angiogenesis. Therefore, it is assumed that the pharmaceutical compositions of the present

- 10 039646 of the invention will be useful in the treatment or prevention of proliferative disorders such as cancers. In particular, tumors with activating mutants of receptor tyrosine kinases or upregulation of receptor tyrosine kinases may be particularly susceptible to inhibitors. Patients with activating mutants of any of the particular RTK isoforms discussed herein may also find treatment with the pharmaceutical compositions of the present invention particularly useful, for example, in patients with tumors, e.g., bladder or brain tumors, with FGFR3-TACC3 translocation.

Biological activity and therapeutic applications

Pharmaceutical compositions of the present invention will be useful in the prevention or treatment of diseases or conditions mediated by kinases. References to the prevention or prophylaxis or treatment of a disease or condition such as cancer are intended to alleviate the severity or reduce the incidence of cancer.

As used in this application, the term modulation, in relation to the activity of a kinase, is intended to define a change in the level of biological activity of a protein kinase. Thus, modulation encompasses physiological changes that affect the increase or decrease in the corresponding protein kinase activity. In the latter case, modulation can be described as inhibition. Modulation may occur directly or indirectly, and may be mediated by any mechanism and at any physiological level, including, for example, the level of gene expression (including, for example, transcription, translation, and/or post-translational modification), at the level of expression of genes encoding regulatory elements that act directly or indirectly on kinase activity levels. Thus, modulation can mean over/under expression or over or under expression of a kinase, including gene amplification (i.e., multiple copies of a gene) and/or increase or decrease in expression due to a transcriptional effect, as well as hyper- (or hypo-) activity and (de)activation of the protein kinase(s) (including (de)activation) by mutation(s). The terms modulated, modulating, and modulate are to be interpreted accordingly.

As used in this application, the term indirect, used, for example, in combination with a kinase, as used in this application (and applies, for example, to various physiological processes, diseases, conditions, conditions, therapies, treatments or interventions), is intended for the limited use, so that the various processes, diseases, conditions, treatments and interventions to which the term is applied refer to those in which the kinase plays a biological role. Where the term is applied to a disease, disorder, or condition, the biological role of the kinase may be direct or indirect, and may be necessary and/or sufficient for symptoms of the disease, disorder, or condition (or its etiology or progression) to manifest. Thus, kinase activity (and in particular aberrant levels of kinase activity, e.g. kinase overexpression) need not be the direct cause of the disease, disorder, or condition: rather, kinase-mediated diseases, disorders, or conditions are expected to include those have a multifactorial etiology and complex progressions in which the kinase in question is only partially involved. Where the term is applied to treatment, prevention, or intervention, the role of the kinase may be direct or indirect, and may be necessary and/or sufficient to effect the treatment, prevention, or outcome of the intervention. Thus, a disease or condition mediated by a kinase includes the development of resistance to any particular cancer drug or treatment.

Thus, for example, the pharmaceutical compositions of the present invention may be useful in alleviating the severity and incidence of cancer.

N-(3,5-dimethoxyphenyl)-M'-(1-methylethyl)-M-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane1,2-diamine, its a pharmaceutically acceptable salt or solvate thereof inhibits or modulates the activity of certain protein tyrosine kinases, in particular FGFR (fibroblast growth factor receptor). This compound is a selective inhibitor of pan-FGFR (inhibitor of FGFR1, 2, 3 and 4).

As a result of the activity of N-(3,5-dimethoxyphenyl)-N-(1-methylethyl)-M-[3-(1-methyl-N-pyrazol-4yl)quinoxalin-6-yl]ethane-1,2-diamine , a pharmaceutically acceptable salt thereof, or a solvate thereof directed at modulating or inhibiting FGFR, the pharmaceutical compositions of the present invention will be useful in providing a method for preventing the growth or inducing apoptosis of tumors, in particular by inhibiting angiogenesis. Therefore, the pharmaceutical compositions of the present invention are expected to be useful in the treatment or prevention of proliferative disorders such as cancers. In addition, the pharmaceutical compositions of the present invention may be useful in the treatment of diseases in which proliferation, apoptosis, or differentiation occurs.

Specific tumors with activating mutants or upregulation or overexpression of any of the FGFR isoforms, such as FGFR1, FGFR2, or FGFR3 or FGFR4, may be particularly susceptible to the pharmaceutical compositions of the present invention, and therefore patients, such as

- 11 039646 discussed above, with such specific tumors, treatment with the pharmaceutical compositions of the present invention may be found particularly useful. It may be preferable that the treatment be associated with or directed to a mutant form of one of the receptor tyrosine kinases discussed in this application. Tumors with such mutations can be diagnosed using methods known to those skilled in the art and described herein, such as RTPCR and FISH.

Examples of cancers that can be treated (or inhibited) include, but are not limited to, carcinoma, such as bladder, breast, colon (eg, colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung (eg, adenocarcinoma, small cell lung cancer and non-small cell lung carcinoma, squamous cell lung cancer), esophagus, head and neck, gallbladder, ovary, pancreas (eg, exocrine pancreatic carcinoma), stomach, gastrointestinal (also known as gastric) cancer (eg, gastrointestinal stromal tumors), cervix, endometrium, thyroid, prostate, or skin (eg, squamous cell carcinoma or dermatofibrosarcoma bulging); pituitary cancer, a hematopoietic tumor of the lymphoid lineage, such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (eg, diffuse large B-cell lymphoma), T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of the myeloid lineage, such as leukemias, acute and chronic myeloid leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative disorder, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia; multiple myeloma; thyroid cancer; hepatocellular carcinoma, a tumor of mesenchymal origin (eg, Ewing's sarcoma), such as fibrosarcoma or rhabdomyosarcoma; tumor of the central or peripheral nervous system, for example, astrocytoma, neuroblastoma, glioma (such as glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; pigment xeroderma; horny keratoma; thyroid cancer; or Kaposi's sarcoma. In particular, squamous cell lung cancer, breast cancer, colon cancer, glioblastoma, astrocytomas, prostate cancer, small cell lung cancer, melanoma, head and neck cancer, thyroid cancer, uterine cancer, gastric cancer, hepatocellular cancer, cervical cancer , bladder cancer, endometrial cancer, urothelial cancer, colon cancer, rhabdomyosarcoma, pituitary cancer.

Non-small cell lung cancer (NSCLC) covers progressive and refractory NSCLC.

Some types of cancer are resistant to treatment with certain drugs. This may be related to the type of tumor or may result from treatment with such a compound. In this regard, references to multiple myeloma include bortezomib-susceptible multiple myeloma or refractory multiple myeloma. Similarly, references to chronic myelogenous leukemia include neutanib-susceptible chronic myelogenous leukemia and refractory chronic myelogenous leukemia. Chronic myelogenous leukemia is also known as chronic myeloid leukemia, chronic granulocytic leukemia, or CML. Similarly, acute myelogenous leukemia is also referred to as acute myeloid leukemia, acute granulocytic leukemia, acute non-lymphocytic leukemia, or AML.

The pharmaceutical compositions of the present invention can also be used to treat hematopoietic diseases with abnormal cell proliferation, whether they are premalignant or stable, such as myeloproliferative diseases. Myeloproliferative diseases (MPD) are a group of bone marrow diseases in which an excess of cells is produced. They are associated with and may be involved in myelodysplastic syndrome. Myeloproliferative disorders include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Another hematological disorder is hypereosinophilic syndrome. T-cell lymphoproliferative diseases include diseases derived from natural killer cells.

In addition, the pharmaceutical compositions of the present invention can be used to treat cancers of the gastrointestinal tract (also known as gastric), for example, gastrointestinal stromal tumors. Gastrointestinal cancer refers to malignant conditions of the gastrointestinal tract, including the esophagus, stomach, liver, biliary system, pancreas, intestines, and anus.

Thus, in connection with the pharmaceutical compositions, uses, or methods of the present invention for the treatment of a disease or condition involving abnormal cell growth, the disease or condition involving abnormal cell growth is, in one embodiment, cancer.

Specific subgroups of cancers include multiple myeloma, carcinomas of the bladder, cervix, prostate and thyroid, lung, breast, and colon.

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Another subgroup of cancers includes multiple myeloma, bladder carcinomas, hepatocellular, oral squamous cell carcinomas, and cervical carcinomas.

Another subgroup of cancers includes hepatocellular carcinoma with amplification or overexpression of FGF19. One aspect of the invention includes a method of treating hepatocellular cancer in a patient with FGF19 amplification or overexpression, comprising administering to said patient a pharmaceutical composition according to the invention.

A subgroup of cancers includes cholangiocarcinoma, in particular cholangiocarcinoma with FGFR genomic changes (translocations, fusions and/or mutations).

A subgroup of cancers includes progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer and cholangiocarcinoma, in particular progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer and cholangiocarcinoma with FGFR genomic changes (translocations, fusions and/or mutations).

A subgroup of cancers includes metastatic or inoperable urothelial cancer, in particular, metastatic or inoperable urothelial cancer with FGFR genomic changes (translocations, fusions and/or mutations).

A subgroup of cancers includes urothelial cancer, in particular urothelial cancer with FGFR genomic changes (translocations, fusions and/or mutations).

A subgroup of cancers includes non-muscle invasive bladder cancer, in particular non-muscle invasive bladder cancer with FGFR genomic changes (translocations, fusions and/or mutations).

A subgroup of cancers includes non-small cell lung cancer (NSCLC), squamous lung cancer and non-squamous lung cancer, in particular non-small cell lung cancer (NSCLC), squamous lung cancer and non-squamous lung cancer with FGFR genomic changes (translocations, fusions and/or mutations) .

A subgroup of cancers includes sarcoma, eg rhabdomyosarcoma, in particular sarcoma, eg rhabdomyosarcoma with FGFR genomic changes (translocations, fusions and/or mutations).

The pharmaceutical compositions of the present invention may be particularly useful for the treatment or prevention of breast cancer, in particular classical lobular carcinomas (CLCs).

Since the compound in the pharmaceutical compositions of the present invention has activity against FGFR4, the pharmaceutical compositions of the present invention will also be useful in the treatment of prostate or pituitary cancer, or they will be useful in the treatment of breast cancer, lung cancer, prostate cancer, liver cancer (HCC ; hepatocellular carcinoma) or lung cancer.

In particular, the pharmaceutical compositions of the present invention are useful in the treatment of multiple myeloma, myeloproliferative disorders, endometrial cancer, prostate cancer, bladder cancer, lung cancer, ovarian cancer, breast cancer, gastric cancer, colorectal cancer, and oral squamous cell carcinoma.

Other subgroups of cancers include multiple myeloma, endometrial cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, colorectal cancer, and thyroid carcinomas.

In particular, the pharmaceutical compositions of the present invention are useful in the treatment of multiple myeloma (in particular, multiple myeloma with t(4;14) translocation or overexpression of FGFR3), prostate cancer (hormone-resistant prostate carcinomas), endometrial cancer (in particular, endometrial tumors with activating mutations in FGFR2) and breast cancer (particularly lobular breast cancer).

In particular, the pharmaceutical compositions of the present invention are useful in the treatment of lobular carcinomas such as CLCs (classic lobular carcinomas).

Since the compound in the pharmaceutical compositions of the present invention has activity against FGFR3, the pharmaceutical compositions of the present invention will be useful in the treatment of multiple myeloma and bladder cancer.

In particular, the pharmaceutical compositions of the present invention have activity against a tumor with an FGFR3-TACC3 translocation, in particular bladder or brain tumors or urothelial tumors with an FGFR3-TACC3 translocation.

In particular, the pharmaceutical compositions of the present invention are useful in the treatment of t(4;14) translocation-positive multiple myeloma.

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of sarcoma. In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of lung cancer, such as squamous cell carcinoma.

Since the compound in the pharmaceutical compositions of the present invention has activity against FGFR2, the pharmaceutical compositions of the present invention will be useful in the treatment of endometrial, ovarian, gastric, hepatocellular, uterine, cervical and colorectal cancers. FGFR2 is also overexpressed in epithelial ovarian cancer, so compositions of the invention may be particularly useful in the treatment of ovarian cancer, such as epithelial ovarian cancer.

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of lung cancer, in particular NSCLC, squamous cell carcinoma, liver cancer, kidney cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer.

In one embodiment, the pharmaceutical compositions of the present invention may be useful for the treatment of metastatic or inoperable urothelial cancer, in particular metastatic or inoperable urothelial cancer with FGFR genomic changes (translocations, fusions and/or mutations).

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of urothelial cancer, in particular urothelial cancer with FGFR genomic changes (translocations, fusions and/or mutations).

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of non-muscle invasive bladder cancer, in particular non-muscle invasive bladder cancer with FGFR genomic alterations (translocations, fusions and/or mutations).

In one embodiment, the pharmaceutical compositions of the present invention may be useful for the treatment of non-squamous lung cancer (NSCLC), squamous lung cancer and non-squamous lung cancer, in particular non-small cell lung cancer (NSCLC), squamous lung cancer and non-squamous lung cancer with FGFR genomic changes (translocations, fusions and/or mutations).

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of a sarcoma, eg rhabdomyosarcoma, in particular a sarcoma, eg rhabdomyosarcoma with FGFR genomic changes (translocations, fusions and/or mutations).

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer, and cholangiocarcinoma, in particular progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer and cholangiocarcinoma with FGFR genomic changes (translocations, fusions and/or mutations).

In one embodiment, the pharmaceutical compositions of the present invention may be useful in the treatment of cholangiocarcinoma, in particular, cholangiocarcinoma with FGFR genomic alterations (translocations, fusions and/or mutations).

The cancer may be cancer types that are susceptible to inhibition of any one or more FGFRs selected from FGFR1, FGFR2, FGFR3, FGFR4, eg one or more FGFRs selected from FGFR1, FGFR2 or FGFR3.

Whether or not a particular cancer is susceptible to inhibition of FGFR signaling can be determined using the cell growth assay described below or by the method described in the section entitled Diagnostic Methods.

The pharmaceutical compositions of the present invention may be particularly useful for the treatment or prevention of cancers of the type associated with, or characterized by, the presence of elevated levels of FGFR.

The pharmaceutical compositions of the present invention may be useful in the treatment of adult patients. The pharmaceutical compositions of the present invention may be useful in the treatment of pediatric patients. The pharmaceutical compositions of the present invention may be useful in the treatment of geriatric patients.

In one aspect of the invention, the pharmaceutical compositions are administered continuously every day, preferably once a day. Preferably, the daily dose of N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 -diamine, its pharmaceutically acceptable salt or solvate thereof is 6 to 12 mg base equivalent or 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent, or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably, the composition comprises N(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-N-pyrazol-4-yl)quinoxalin-6-yl]ethan-1, 2-dia- 14 039646 mine base. In one aspect, the daily dose administered daily is 6 mg or 8 mg of base.

Thus, one aspect of the present invention is a method for preventing cancer in a subject, in particular a human, or a method for treating cancer in a patient, in particular a human, comprising administering to the subject or patient the pharmaceutical composition described in this application daily, preferably every day once a day. Preferably, the daily dose of N(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1, 2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 to 12 mg base equivalent, or 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably, the composition comprises N-(3,5-dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-( 1-methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl]ethan- 1,2-diamine base. In one aspect, the daily dose administered continuously every day is 6 mg or 8 mg of base.

One aspect of the present invention is the use of the pharmaceutical composition described herein for the preparation of a medicament for the prevention or treatment of cancer, in particular for the treatment of cancer, wherein the medicament is administered or should be administered daily. Preferably, the daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1Hpyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 α-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 to 12 mg base equivalent, or 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent, or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably, the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 - diamine base. In one aspect, the daily dose administered continuously each day is 6 mg or 8 mg of base.

One aspect of the present invention is a pharmaceutical composition described in this application for use in the prevention or treatment of cancer, in particular for the treatment of cancer, where the composition is administered or should be administered daily. Preferably, the daily dose of N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 α-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 to 12 mg base equivalent, or 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent, or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably, the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane1,2 - diamine base. In one aspect, the daily dose administered continuously every day is 6 mg or 8 mg of base.

In one aspect of the present invention, the pharmaceutical compositions are administered using an intermittent administration schedule, preferably with the administration of the pharmaceutical compositions of the present invention daily for several consecutive days, followed by no administration of any of these compositions for several days (drug-free period). Preferably, a daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1 ,2-diamine, its pharmaceutically acceptable salt or solvate thereof is 6 to 12 mg base equivalent, or 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably, the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4yl)quinoxalin-6-yl]ethan-1,2 - diamine base.

The intermittent dosing regimen of the present invention comprises administering the pharmaceutical compositions of the present invention daily for 3 weeks (3 weeks of dosing; 21 days of consecutive drug dosing) followed by no administration of any of these compositions for 1 week (1 week no dosing; 7 consecutive days without drug administration). This cycle is then repeated. The daily dose is preferably administered once a day.

Thus, one aspect of the present invention is a method for the prevention of cancer in a subject, in particular a human, or a method for the treatment of cancer in a patient, in particular a human, comprising administering to the subject or patient the pharmaceutical composition described in this application, using the scheme intermittent injection.

One aspect of the invention includes a method for preventing cancer in a subject, in particular a human, or a method for treating cancer in a cancer patient, in particular a human, comprising administering to the subject or patient a composition of the present invention daily for 3 weeks (3 weeks of administration), with followed by 1 week without injection, and repeat this cycle 3 weeks of injection, 1 week without injection. Preferably, the daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1Hpyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 -diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 to 12 mg base equivalent, or 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent or 12 mg base equivalent. The daily dose is preferably administered once a day.

Preferably the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2- diamine base. In particular, the daily dose of N-(3,5dimethoxyphenyl)-M'-(1-methylethyl)-M-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1, 2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 mg base equivalent, more specifically 6 mg base equivalent once a day for 3 weeks, followed by 1 week without administration (no administration of N-(3,5-dimethoxyphenyl) -N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof) .

The intermittent administration regimen of the present invention comprises administering the pharmaceutical compositions of the present invention for 1 week (1 week of administration; 7 consecutive days of administration of the drug), followed by 1 week without administration of such a composition (1 week without administration; 7 consecutive days without administration of the drug ). This cycle is then repeated.

One aspect of the invention includes a method for preventing cancer in a subject or a method for treating cancer in a cancer patient, comprising administering to the subject or patient a composition of the present invention daily for 1 week (1 week of administration), followed by 1 week without administration, and repeating this cycle for 1 week injections, 1 week without injection. Preferably, the daily dose of N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 α-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 to 12 mg base equivalent, or 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably, the composition comprises N-(3,5-dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-( 1-methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl]ethan- 1, 2-diamine base. In particular, the daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1 ,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 10 mg or 12 mg base equivalent, more specifically 10 mg base equivalent once a day for 1 week, followed by 1 week without administration (no administration of N-(3, 5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2diamine, a pharmaceutically acceptable salt thereof, or solvate).

One aspect of the present invention includes the use of a pharmaceutical composition described in this application for the preparation of a medicament for the prevention or treatment of cancer, in particular for the treatment of cancer, where the drug is administered or should be administered daily for 3 weeks (3 weeks of administration), with followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 3 weeks of administration, 1 week without administration, is repeated. Preferably a daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1Hpyrazol-4-yl)quinoxalin-6-yl]ethan-1,2- diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 to 12 mg base equivalent, or is 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent, or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably, the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 - diamine base. In particular, the daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan- 1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 mg base equivalent, more specifically 6 mg base equivalent once a day for 3 weeks, followed by 1 week without administration (no administration of N-(3,5- dimethoxyphenyl)-N'-(1-methylethyl)-N[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof ).

One aspect of the present invention is a pharmaceutical composition described in this application for use in the prevention or treatment of cancer, in particular for the treatment of cancer, where the composition is administered or should be administered daily for 3 weeks (3 weeks of administration), followed by 1 week without administration (no drug administration), and where the specified cycle, including 3 weeks of administration, 1 week without administration, is repeated. Preferably, the daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan1,2 α-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 to 12 mg base equivalent, or 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably, the composition comprises N-(3,5-dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-(1-methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl]ethan- 1, 2-diamine base. In particular, the daily dose of N-(3,5-dimethoxyphenyl)N'-( 1 -methylethyl)-N-[3-( 1-methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl]ethan- 1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 mg base equivalent, more specifically 6 mg base equivalent once a day for 3 weeks, followed by 1 week without administration (no administration #(3 ,5-dimethoxyphenyl)-N-(1-methylethyl)-N[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or its solvate).

One aspect of the present invention includes the use of a pharmaceutical composition described in this application for the preparation of a medicament for the prevention or treatment of cancer, in particular for the treatment of cancer, where the drug is administered or should be administered daily for 1 week (1 week of administration), with followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated. Preferably, the daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1Hpyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 α-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 to 12 mg base equivalent, or 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably, the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 - diamine base. In particular, the daily dose of N(3,5-dimethoxyphenyl)-N-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1, 2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 10 mg or 12 mg base equivalent, more specifically 10 mg base equivalent once a day for 1 week, followed by 1 week without administration (no administration of N-(3.5 -dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof ).

One aspect of the present invention is a pharmaceutical composition described in this application for use in the prevention or treatment of cancer, in particular for the treatment of cancer, where the composition is administered or should be administered daily for 1 week (1 week of administration), followed by 1 week without administration (no drug administration), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated. Preferably a daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan1,2- diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 6 to 12 mg base equivalent, or is 6 mg base equivalent, 7 mg base equivalent, 8 mg base equivalent, 9 mg base equivalent, 10 mg base equivalent, 11 mg base equivalent, or 12 mg base equivalent. The daily dose is preferably administered once a day. Preferably the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4yl)quinoxalin-6-yl]ethan-1,2- diamine base. In particular, the daily dose of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan- 1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof is 10 mg or 12 mg base equivalent, more specifically 10 mg base equivalent once a day for 1 week, followed by 1 week without administration (no administration #(3, 5-dimethoxyphenyl)-N-(1-methylethyl)-N[3-(1-methyl-1H-pyrazol-4yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof) .

Daily dose of N-(3,5-dimethoxyphenyl)-N-(1-methylethyl)-N-[3-(1-methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 β-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof may be administered through one pharmaceutical composition according to the present invention, or through several pharmaceutical compositions according to the present invention. These several pharmaceutical compositions in accordance with the present invention can be administered separately, simultaneously or sequentially.

One aspect of the present invention includes the prevention or treatment, especially treatment, of metastatic or inoperable urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 6 mg N-(3,5-dimethoxyphenyl)-N '-(1-methylethyl)-N-[3-(1methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N -(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4yl)quinoxalin-6-yl]ethane-1,2-diamine base is introduced or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially treatment, of metastatic or inoperable urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 8 mg N-(3,5-dimethoxyphenyl)-N '-(1-methylethyl)-N-[3-(1methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N -(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base , administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially the treatment, of urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 6 mg N-(3,5-dimethoxyphenyl)- N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, in in particular, N-(3,5dimethoxyphenyl)-N-(1-methylethyl)-M-[3-(1-methyl-N-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base , administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially treatment, of urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 8 mg N-(3,5-dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N- (3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially the treatment, of non-small cell lung cancer (NSCLC), squamous lung cancer and non-squamous lung cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 6 mg N- (3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, its pharmaceutically acceptable salt or solvate thereof, in particular N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane -1,2-diamine base, administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially treatment, of non-small cell lung cancer (NSCLC), squamous lung cancer and non-squamous lung cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 8 mg N- (3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, its pharmaceutically acceptable salt or solvate thereof, in particular N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane -1,2-diamine base, administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially the treatment, of progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer, and cholangiocarcinoma, in particular with FGFR-genomic changes (translocations, fusions and/or mutations), where 9 mg N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane-1,2diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3,5-dimethoxyphenyl)N'-(1-methylethyl)-N-[3-(1- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially the treatment, of progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer, and cholangiocarcinoma, in particular with FGFR-genomic changes (translocations, fusions and/or mutations), where 6 mg N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane-1,2diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3,5-dimethoxyphenyl)N'-(1-methylethyl)-N-[3-(1- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially the treatment, of progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer, and cholangiocarcinoma, in particular with FGFR-genomic changes (translocations, fusions and/or mutations), where 8 mg N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane-1,2diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3,5-dimethoxyphenyl)N'-(1-methylethyl)-N-[3-(1- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially treatment, of cholangiocarcinoma, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 9 mg N-(3,5-dimethoxyphenyl)-N'-(1 -methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3, 5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-purazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, administered or to be administered daily , in particular once a day, in the form of one or

- 18 039646 several, in particular, several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially treatment, of cholangiocarcinoma, in particular with FGFR genomic alterations (translocations, fusions and/or mutations), where 6 mg N-(3,5-dimethoxyphenyl)-N'-(1 -methylethyl)-N-[3-(1-methyl-1H-nurαzol-4-yl)quinoxalin-6yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3, 5-dimethoxyphenyl)-N-(1-methylethyl)-M-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially treatment, of cholangiocarcinoma, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 8 mg N-(3,5-dimethoxyphenyl)-N'-(1 -methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3, 5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-purazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, administered or to be administered daily , in particular, once a day, in the form of one or more, in particular, several pharmaceutical compositions described in this application.

One aspect of the present invention includes the prevention or treatment, especially treatment, of metastatic or inoperable urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 10 mg N-(3,5-dimethoxyphenyl)-N '-(1-methylethyl)-N-[3-(1methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N -(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base , is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 1 week (1 week of administration), followed by 1 week without administration ( no drug administration), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially treatment, of metastatic or inoperable urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 12 mg N-(3,5-dimethoxyphenyl)-N '-(1-methylethyl)-N-[3-(1methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N -(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base , is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 1 week (1 week of administration), followed by 1 week without administration ( no drug administration), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially the treatment, of metastatic or inoperable urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 6 mg N-(3,5-dimethoxyphenyl)-N '-(1-methylethyl)-N-[3-(1methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt or solvate thereof, in particular N -(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base , is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 3 weeks (3 weeks of administration), followed by 1 week without administration ( no drug administration), and where the specified cycle, including 3 weeks of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially treatment, of urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 10 mg N-(3,5-dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N- (3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 1 week (1 week of administration), followed by 1 week without administration (no administration of drug means), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially treatment, of urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 12 mg N-(3,5-dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N- (3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, in

- 19 039646 for 1 week (1 week of administration), followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially treatment, of urothelial cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 6 mg N-(3,5-dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N- (3,5dimethoxyphenyl)-N-(1-methylethyl)-M-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, administered or followed administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 3 weeks (3 weeks of administration), followed by 1 week without administration (no drug administration ), and where the specified cycle, including 3 weeks of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially treatment, of non-small cell lung cancer (NSCLC), squamous lung cancer and non-squamous lung cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 10 mg N- (3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, its a pharmaceutically acceptable salt or solvate thereof, in particular N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl ]ethane-1,2-diamine base, is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 1 week (1 week of administration ), followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially treatment, of non-small cell lung cancer (NSCLC), squamous lung cancer and non-squamous lung cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 12 mg N- (3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, its pharmaceutically acceptable salt or solvate thereof, in particular N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane -1,2-diamine base, is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 1 week (1 week of administration), followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially treatment, of non-small cell lung cancer (NSCLC), squamous lung cancer and non-squamous lung cancer, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 6 mg N- (3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, its pharmaceutical a suitable salt or solvate thereof, in particular N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl] ethane-1,2-diamine base, is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 3 weeks (3 weeks of administration) , followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 3 weeks of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially the treatment, of progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer, and cholangiocarcinoma, in particular with FGFR-genomic changes (translocations, fusions and/or mutations), where 10 mg N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl -1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application for 1 week (1 week of administration) followed by 1 week without administration (no administration of the drug), and where the specified cycle, including giving 1 week of administration, 1 week without administration, repeat.

One aspect of the present invention includes the prevention or treatment, especially the treatment, of progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer, and cholangiocarcinoma, in particular with FGFR-genomic changes (translocations, fusions and/or mutations), where 12 mg N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1 -methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine

- 20 039646 bases are administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 1 week (1 week of administration) followed by 1 week without administration (no drug administration), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially the treatment, of progressive or refractory NSCLC, breast cancer, glioblastoma multiforme, urothelial cancer, ovarian cancer, head and neck cancer, esophageal cancer, gastric cancer, and cholangiocarcinoma, in particular with FGFR-genomic changes (translocations, fusions and/or mutations), where 6 mg N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane-1,2diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3,5-dimethoxyphenyl)N'-(1-methylethyl)-N-[3-(1- methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base is administered or should be administered daily, in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application for 3 weeks (3 weeks of administration) followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 3 weeks of administration, 1 week without administration, repeat.

One aspect of the present invention includes the prevention or treatment, especially treatment, of cholangiocarcinoma, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 10 mg N-(3,5-dimethoxyphenyl)-N'-(1 -methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3, 5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, administered or to be administered daily , in particular, once a day, in the form of one or more, in particular, several pharmaceutical compositions described in this application, for 1 week (1 week of administration) followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially treatment, of cholangiocarcinoma, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 12 mg N-(3,5-dimethoxyphenyl)-N'-(1 -methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3, 5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, administered or to be administered daily , in particular, once a day, in the form of one or more, in particular, several pharmaceutical compositions described in this application, for 1 week (1 week of administration) followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 1 week of administration, 1 week without administration, is repeated.

One aspect of the present invention includes the prevention or treatment, especially treatment, of cholangiocarcinoma, in particular with FGFR genomic changes (translocations, fusions and/or mutations), where 6 mg N-(3,5-dimethoxyphenyl)-N'-(1 -methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular N-(3, 5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine base, administered or to be administered daily , in particular once a day, in the form of one or more, in particular several pharmaceutical compositions described in this application, for 3 weeks (3 weeks of administration) followed by 1 week without administration (no administration of the drug), and where the specified cycle, including 3 weeks of administration, 1 week without administration, is repeated.

The pharmaceutical compositions of the present invention may be used in combination with other anticancer agents. For example, it may be useful to combine the pharmaceutical compositions of the present invention with another agent that acts by a different mechanism to regulate cell growth in order to treat various features of cancer development in this way. Examples of such combinations are given below.

The pharmaceutical compositions of the present invention may be useful in the treatment of other conditions that result from proliferation disorders such as type II or non-insulin dependent diabetes mellitus, autoimmune diseases, head trauma, stroke, epilepsy, neurodegenerative diseases such as Alzheimer's disease, motor neuron disease, progressive supranuclear palsy, corticobasal degeneration, and Pick's disease, such as autoimmune diseases and neurodegenerative diseases.

One subgroup of diseases and conditions for which the pharmaceutical compositions of the present invention may be useful consists of inflammatory diseases, cardiovascular diseases, and wound healing.

It is also known that FGFR plays a role in apoptosis, angiogenesis, proliferation, differentiation and transcription, and therefore the pharmaceutical compositions of the present invention can also be

- 21 039646 useful in the treatment of the following diseases other than cancer: chronic inflammatory diseases, eg systemic lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes mellitus, eczema, allergic reactions, asthma, chronic obstructive pulmonary disease disease, rhinitis and diseases of the upper respiratory tract; cardiovascular diseases, eg cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders such as Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndromes, ischemic-associated myocardial infarction, stroke and reperfusion injury, arrhythmias, atherosclerosis, toxin- or alcohol-induced liver diseases, hematological diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.

In addition, FGFR2 mutations are associated with several serious abnormalities in human skeletal development and therefore the pharmaceutical compositions of the present invention may be useful in the treatment of human skeletal developmental abnormalities, including abnormal ossification of the cranial sutures (craniosynostosis), Apert syndrome (AR), Crouzon syndrome, Jackson-Weiss syndrome, Beer-Stevenson cutis gyrate syndrome and Pfeiffer syndrome.

The pharmaceutical compositions of the present invention may be particularly useful in the treatment or prevention of skeletal disorders. Specific skeletal disorders are achondroplasias or thanatophoric dwarfism (also known as thanatophoric dysplasia).

The pharmaceutical compositions of the present invention may be particularly useful in the treatment or prevention of pathologies where progressive fibrosis is a symptom. Fibrotic conditions in which the pharmaceutical compositions of the present invention may be useful include diseases in which abnormal or excessive deposition of fibrous tissue occurs, such as cirrhosis of the liver, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, as well as the natural process of wound healing. In particular, the pharmaceutical compositions of the present invention may also be useful in the treatment of pulmonary fibrosis, in particular idiopathic pulmonary fibrosis.

Increased expression and activation of FGFR in the tumor-associated vasculature also suggests a role for the pharmaceutical compositions of the present invention in preventing and interrupting the initiation of tumor angiogenesis. In particular, the pharmaceutical compositions of the present invention may be useful in the treatment of cancer, metastases, leukemias such as CLL, ocular diseases such as age-related macular degeneration, in particular wet form of age-related macular degeneration, ischemic proliferative retinopathies such as retinopathy of prematurity (ROP); and diabetic retinopathy, rheumatoid arthritis, and hemangiomas.

The invention provides pharmaceutical compositions that may be useful in the prevention or treatment, especially treatment, of diseases or conditions mediated by FGFR kinases.

In one embodiment, a pharmaceutical composition is provided for use in the prevention or treatment, especially treatment, of a disease or condition mediated by FGFRkinase.

Thus, for example, the pharmaceutical compositions of the present invention may be useful in alleviating the severity and incidence of cancer. Therefore, in the following embodiment, a pharmaceutical composition described in the present application is provided for use in the prevention or treatment, especially the treatment, of cancer. In one embodiment, the pharmaceutical composition defined in this application is for use in the prevention or treatment of FGFR-dependent cancer. In one embodiment, the pharmaceutical composition defined in this application is for use in the prevention or treatment of cancer mediated by FGFR kinases.

Accordingly, the invention provides, inter alia:

a method for preventing or treating a disease or condition mediated by an FGFR kinase, which comprises administering to a subject in need thereof a pharmaceutical composition as defined herein;

a method for preventing or treating a disease or condition described in this application, which includes administering to a subject in need thereof a pharmaceutical composition defined in this application;

a method for preventing or treating cancer, which comprises administering to a subject in need thereof a pharmaceutical composition as defined herein;

a method for alleviating or reducing the incidence of a disease or condition mediated by an FGFR kinase, which comprises administering to a subject in need thereof a pharmaceutical composition as defined herein;

- 22 039646 a method of inhibiting FGFR kinase, which includes contacting the kinase with a kinase-inhibiting pharmaceutical composition defined in this application;

a method for modulating a cellular process (eg, cell division) by inhibiting FGFR kinase activity using a pharmaceutical composition as defined herein;

a pharmaceutical composition as defined herein for use in modulating a cellular process (eg, cell division) by inhibiting FGFR kinase activity;

a pharmaceutical composition as defined herein for use in the prevention or treatment of cancer, in particular the treatment of cancer;

a pharmaceutical composition as defined herein for use in modulating (eg, inhibiting) FGFR;

the use of a pharmaceutical composition as defined herein for the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by an FGFR kinase;

the use of a pharmaceutical composition defined in this application for the manufacture of a medicament for the prevention or treatment of a disease or condition described in this application;

the use of a pharmaceutical composition defined in this application for the manufacture of a medicament for the prevention or treatment, especially for the treatment, of cancer;

the use of a pharmaceutical composition as defined herein for the preparation of a medicament for modulating (eg, inhibiting) FGFR activity;

the use of a pharmaceutical composition as defined herein in the manufacture of a medicament for modulating a cellular process (eg, cell division) by inhibiting FGFR kinase activity;

the use of a pharmaceutical composition as defined herein for the manufacture of a medicament for the prevention or treatment of a disease or condition characterized by upregulation of an FGFR kinase (eg, FGFR1 or FGFR2 or FGFR3 or FGFR4);

the use of a pharmaceutical composition as defined herein for the preparation of a medicament for the prevention or treatment of cancer, wherein the cancer is one characterized by upregulation of an FGFR kinase (eg, FGFR1 or FGFR2 or FGFR3 or FGFR4);

the use of a pharmaceutical composition as defined herein for the manufacture of a medicament for the prevention or treatment of cancer in a patient selected from a subpopulation having a genetic aberration of FGFR3 kinase;

the use of a pharmaceutical composition as defined herein for the preparation of a medicament for the prevention or treatment of cancer in a patient diagnosed as being part of a subpopulation having a genetic aberration of FGFR3 kinase;

a method for preventing or treating a disease or condition characterized by upregulation of an FGFR kinase (eg, FGFR1 or FGFR2 or FGFR3 or FGFR4), comprising administering a pharmaceutical composition as defined herein;

a method for alleviating or reducing the incidence of a disease or condition characterized by upregulation of an FGFR kinase (eg, FGFR1 or FGFR2 or FGFR3 or FGFR4), comprising administering a pharmaceutical composition as defined herein;

a method for preventing or treating (or alleviating or reducing the incidence of) cancer in a patient suffering from or suspected to be suffering from cancer; which includes (i) diagnostic testing of the patient to determine whether or not the patient has a genetic aberration of the FGFR3 gene; and (ii) if the patient does have said variant, then administering to the patient a pharmaceutical composition as defined herein having an FGFR3 kinase inhibitory effect;

a method for preventing or treating (or alleviating or reducing the incidence of) a disease or condition characterized by upregulation of an FGFR kinase (eg, FGFR1 or FGFR2 or FGFR3 or FGFR4); which includes (i) diagnostic testing of the patient to determine a marker indicative of FGFR kinase upregulation (e.g., FGFR1 or FGFR2 or FGFR3 or FGFR4), and (ii) if the diagnostic test indicates FGFR kinase upregulation, then administering the pharmaceutical composition to the patient, as defined herein, having an FGFR kinase inhibitory effect;

a method for preventing or treating (or alleviating or reducing the incidence of) a disease or condition characterized by an FGFR mutation, translocation, fusion, in particular an FGFR2 or FGFR3 mutation, translocation, fusion; which includes (i) diagnostic testing of the patient to determine a marker characteristic of an FGFR mutation, translocation, fusion, in particular an FGFR2 or FGFR3 mutation, translocation, fusion, and (ii) if the diagnostic test indicates an FGFR mutation, translocation , fusion, in particular FGFR2 or FGFR3 mutation, translocation, fusion, then administering to the patient a pharmaceutical composition as defined herein having an FGFR kinase inhibitory action.

In one embodiment, the disease mediated by FGFR kinases is an oncology-associated disease (eg, cancer). In one embodiment, the disease mediated by FGFR kinases is a non-oncological disease (eg, any disease disclosed in this application, with the exception of cancer). In one embodiment, the disease mediated by FGFR kinases is a condition described in this application. In one embodiment, the FGFR kinase mediated disease is a skeletal disease as described herein. Specific human skeletal anomalies include abnormal ossification of the cranial sutures (craniosynostosis), Apert syndrome (AR), Crouzon syndrome, Jackson-Weiss syndrome, Beer-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, achondroplasias, and thanatophoric dwarfism (also known as thanatophoric dysplasia).

Mutated kinases

Mutations in kinases that cause drug resistance can occur in patient populations treated with kinase inhibitors. This occurs in part in regions of the protein that bind or interact with the specific inhibitor used in therapy. Such mutations decrease or increase the ability of the inhibitor to bind to and inhibit the kinase in question. This may occur at any of the amino acid residues that interact with the inhibitor or that are important in maintaining the binding of said inhibitor to the target. An inhibitor that binds to the target kinase without requiring interaction with the mutated amino acid residue is likely to be unaffected by the mutation and remain an effective inhibitor of the enzyme.

A study performed on samples obtained from patients with gastric cancer showed two mutations in FGFR2, Ser167Pro in exon IIIa and a 940-2A-G splice site mutation in exon IIIc. These mutations are identical to the germline activating mutations that cause craniosynotosis syndromes and were observed in 13% of primary gastric cancer tissues studied. In addition, activating mutations in FGFR3 were observed in 5% of studied patient samples, and overexpression of FGFRs correlated with poor prognosis in this group of patients.

In addition, there are chromosomal translocations or point mutations that are observed in FGFRs that lead to the acquisition of function, overexpression, or constitutively active biological states.

The pharmaceutical compositions of the present invention will therefore be of particular use in connection with cancers that express a mutated molecular target such as FGFR. Tumors with such mutations can be diagnosed using methods known to those skilled in the art and described herein, such as RTPCR and FISH.

It has been hypothesized that mutations of a conserved threonine residue at the FGFR ATP-binding site will lead to inhibitor resistance. The amino acid valine 561 mutated to methionine in FGFR1, consistent with previously described mutations found in Ab1 (T315) and EGFR (T766), which have been shown to confer resistance to selective inhibitors. The assay data for FGFR1 V561M showed that this mutation induced tyrosine kinase inhibitor resistance compared to what was observed for wild type.

Diagnostic methods

Prior to administration of the pharmaceutical composition of the present invention, a patient may be screened to determine if the disease or condition the patient is or may be suffering from is one that would be treatable with a compound having anti-FGFR activity.

For example, a biological sample taken from a patient can be analyzed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one characterized by a genetic abnormality or abnormal expression of a protein that results in upregulation of levels or activity FGFR either to sensitize the pathway to normal FGFR activity or to upregulate these growth factor signaling pathways, such as growth factor ligand levels or growth factor ligand activity, or upregulate the biochemical pathway downstream of FGFR activation.

Examples of such anomalies that result in FGFR signal activation or sensitization include loss or inhibition of apoptotic pathways, upregulation of receptors or ligands, or the presence of mutant receptor or ligand variants, such as PTK variants. Tumors with FGFR1, FGFR2 or FGFR3 or FGFR4 mutants or upregulation, in particular FGFR1 overexpression or FGFR2 or FGFR3 gain-of-function mutations, may be particularly sensitive to FGFR inhibitors.

For example, point mutations leading to the acquisition of function in FGFR2 have been identified in a number of conditions. In particular, activating mutations in FGFR2 have been identified in 10% of endometrial tumors.

- 24 039646

In addition, genetic aberrations of the FGFR3 tyrosine kinase receptor, such as chromosomal translocations or point mutations, resulting in ectopically expressed or deregulated, constitutively active FGFR3 receptors, have been identified and are associated with a subgroup of multiple myelomas, bladder carcinomas, and cervical carcinomas. A specific T674I mutation in the PDGF receptor has been identified in patients treated with imatinib. In addition, 8p12-p11.2 gene amplification has been demonstrated in ~50% of lobular breast cancer (CLC) cases and has been shown to be associated with increased FGFR1 expression. Preliminary studies with an siRNA directed against FGFR1 or a small molecule receptor inhibitor have shown that cell lines incorporating such amplification are particularly susceptible to inhibition of this signaling pathway.

Alternatively, a biological sample taken from a patient can be analyzed for loss of a negative FGFR regulator or suppressor. As used herein, the term loss includes deletion of a gene encoding a regulator or suppressor, truncation of a gene (e.g., by mutation), truncation of a transcription product of a gene, or inactivation of a transcription product (e.g., by point mutation), or sequestration by another gene product.

The term upregulation includes overexpression or overexpression, including gene amplification (i.e., multiple copies of genes) and overexpression due to the effect of transcription, as well as overactivity and activation, including activation by mutations. Thus, the patient can be subjected to diagnostic testing to detect a marker indicative of FGFR upregulation. The term diagnosis includes screening. Marker refers to genetic markers, including, for example, the measurement of DNA composition to identify FGFR mutations. The term marker also includes markers that are indicative of FGFR upregulation, including enzyme activity, enzyme levels, enzyme state (eg, phosphorylated or not), and mRNA levels of the aforementioned proteins.

Diagnostic tests and screenings are usually performed on a biological sample selected from tumor biopsy samples, blood samples (isolation and enrichment of desquamated tumor cells), stool biopsy, sputum, chromosome analysis, pleural fluid, peritoneal fluid, biopsy or urine.

Methods for identifying and analyzing mutations and upregulating proteins are known to those skilled in the art. Screening methods may include, but are not limited to, standard methods such as reverse transcriptase polymerase chain reaction (RT-PCR) or in situ hybridization such as fluorescent in situ hybridization (FISH).

Identification of a subject having a mutation in FGFR may mean that the patient will be particularly suitable for treatment with an FGFR inhibitor and therefore a pharmaceutical composition as defined herein. Tumors can preferably be screened for the presence of the FGFR variant prior to treatment. The screening process typically involves direct sequencing, microarray oligonucleotide analysis, or mutant-specific antibody. In addition, the diagnosis of tumors with such mutations can be carried out using methods known to specialists in this field and described in this application, such as RT-PCR and FISH.

In addition, mutant forms, eg FGFR, can be identified by direct sequencing of, eg, PCR tumor biopsies and PCR sequencing methods as described above. Those skilled in the art will appreciate that all such known methods for detecting overexpression, activation, or mutation of the above proteins may be applicable in this case.

In RT-PCR screening, the level of mRNA in a tumor is assessed by making a cDNA copy of the mRNA, followed by amplification of the cDNA by PCR. Methods for PCR amplification, primer selection and amplification conditions are known to those skilled in the art. Nucleic acid manipulation and PCR are performed by standard methods as described, for example, in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, MA et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acids are also described in Sambrook et al., (2001), 3rd ^Ed , Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, a commercially available RT-PCR kit (eg, Roche Molecular Biochemicals) or the methods described in US Pat. Nos. 4,666,828 can be used; 4683202; 4801531; 5192659, 5272057, 5882864 and 6218529 and included in this application by reference. An example of an in situ hybridization method for evaluating mRNA expression would be fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

Typically, in situ hybridization includes the following main steps: (1) fixing the tissue to be analyzed; (2) pre-hybridization processing of the sample to increase the availability of the target nucleic acid and to reduce non-specific binding; (3) hybridization of a mixture of nucleic acids with a nucleic acid in a biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound in hybridization, and (5) detection

- 25 039646 hybridized nucleic acid fragments. Probes used in such applications are typically labeled with, for example, radioisotopes or fluorescent reporters. Preferred probes are long enough, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to allow specific hybridization to the target nucleic acid(s) under stringent conditions. Standard methods for performing FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence in Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

Methods for profiling gene expression have been described (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA using a (dT) 24-oligomer to prime first strand cDNA synthesis, followed by second strand cDNA synthesis with randomly selected hexameric primers. The double stranded cDNA is used as a template for in vitro transcription of the cRNA using biotinylated ribonucleotides. cRNA is chemically fragmented according to the protocols described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight on Human Genome Arrays.

Alternatively, protein products expressed from mRNAs can be analyzed using immunohistochemical analysis of tumor samples, solid phase immunoassay with microtiter plates, Western blotting, 2D SDS polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art. for the detection of specific proteins. Detection methods may include the use of site-specific antibodies. Those of skill in the art will appreciate that all such well known methods for detecting FGFR upregulation or detecting FGFR variants or mutants may be applicable to the present case.

Abnormal levels of proteins such as FGFR can be measured using standard enzyme assays, such as those described herein. Activation or overexpression can also be determined in a tissue sample, such as tumor tissue. When measuring tyrosine kinase activity using an assay, for example from Chemicon International, the tyrosine kinase of interest is immunoprecipitated from a sample lysate and its activity is measured.

Alternative methods for measuring overexpression or activation of FGFR, including its isoforms, include measuring microvessel density. This, for example, can be measured using the methods described by Orre and Rogers (Int J Cancer (1999), 84(2) 101-8). Analysis methods also include the use of markers.

Therefore, all of these methods can also be used to identify tumors that are particularly suitable for treatment with the pharmaceutical compositions of the present invention.

The pharmaceutical compositions of the present invention are particularly useful for treating a patient with a mutated FGFR. The 6697C mutation in FGFR3 is observed in 62% of oral squamous cell carcinomas and causes constitutive activation of kinase activity. Activating FGFR3 mutations have also been identified in cases of bladder carcinomas. These mutations were of 6 types with different degrees of predominance: R248C, S249C, G372C, S373C, Y375C, K652Q. In addition, the Gly388Arg polymorphism in FGFR4 has been found to be associated with increased incidence and aggressiveness of prostate, colon, lung, liver (HCC) and breast cancers. The pharmaceutical compositions of the present invention are particularly useful for treating a patient having a FGFR3-TACC3 translocation.

Therefore, in a further aspect, the invention includes the use of a pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in a patient who has been screened and determined to be suffering from or at risk of developing a disease, disorder or condition that would be susceptible to treatment with a compound having activity against FGFR.

Specific mutations for which the patient is screened include the G697C, R248C, S249C, G372C, S373C, Y375C, K652Q mutations in FGFR3 and the Gly388Arg polymorphism in FGFR4.

In another aspect, the invention includes a pharmaceutical composition of the present invention for use in the prevention or treatment of cancer in a patient selected from a subpopulation having an FGFR gene variant (eg, a 6697C mutation in FGFR3 and a Gly388Arg polymorphism in FGFR4).

In one aspect of the invention, the pharmaceutical compositions described herein are useful in the treatment of cancer, particularly bladder cancer, urothelial cancer, metastatic urothelial cancer, inoperable urothelial cancer, breast cancer, glioblastoma, lung cancer, non-small cell lung cancer, squamous lung cancer, lung adenocarcinoma.

In one aspect of the invention, the pharmaceutical compositions described in this application are useful for the treatment of cancer, in particular, gastric cancer, cholangiocarcinoma, esophageal cancer, hepatocellular cancer, non-squamous lung cancer, in particular, with FGFR genomic changes (translocations, fusions and/ or mutation).

As another aspect of the present invention, a combination of a pharmaceutical composition of the present invention with another anticancer agent is provided, especially for use as a drug, more specifically for use in the treatment of cancer or related diseases described in this application. .

For the treatment of the above conditions, the pharmaceutical compositions of the invention may be advantageously used in combination with one or more other drugs, more particularly other anti-cancer agents or adjuvants in cancer therapy. Examples of anti-cancer agents or adjuvants (maintenance agents in therapy) include, but are not limited to:

platinum coordination compounds, for example cisplatin, optionally in combination with amifostine, carboplatin or oxaliplatin;

taxane compounds, eg paclitaxel, particles of protein-bound paclitaxel (Abraxane™), or docetaxel;

topoisomerase I inhibitors such as camptothecin compounds, eg irinotecan, SN-38, topotecan, topotecan hcl;

topoisomerase II inhibitors such as the antitumor epipodophyllotoxins or podophyllotoxin derivatives, for example etoposide, etoposide phosphate or teniposide;

antitumor vinca alkaloids, for example vinblastine, vincristine or vinorelbine;

antitumor nucleoside derivatives, eg 5-fluorouracil, leucovorin, gemcitabine, gemcitabine hcl, capecitabine, cladribine, fludarabine, nelarabine;

alkylating agents such as nitrogen mustard or nitrosourea, e.g. cyclophosphamide, chlorambucil, carmustine, thiotepa, mephalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide, optionally in combination with mesna, piprobroman, procarbazine, streptozocin, telozolomide , uracil;

anthracycline antineoplastic derivatives, eg daunorubicin, doxorubicin, optionally in combination with dexazoxane, doxil, idarubicin, mitoxantrone, epirubicin, epirubicin hcl, valrubicin;

molecules that target the IGF-1 receptor, such as picopodophilin;

derivatives of tetracarcin, for example, tetracarcin A;

glucocorticoid, eg prednisone;

antibodies, eg trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab, pertuzumab, bevacizumab, alumtuzumab, eculizumab, ibrttumomab tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;

estrogen receptor antagonists or selective estrogen receptor modulators or estrogen synthesis inhibitors, for example tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene or letrozole;

aromatase inhibitors such as exemestane, anastrozole, letrazole, testolactone and vorozol;

differentiating agents such as retinoids, vitamin D or retinoic acid, and agents that block the metabolism of retinoic acid (RAMBA), such as Accutane;

DNA methyltransferase inhibitors, eg azacitidine or decitabine;

antifolates, eg premetrexed disodium;

antibiotics, eg antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin;

antimetabolites, eg clofarabine, aminopterin, cytosine arabinoside or methotrexate, azacitidine, cytarabine, floxuridine, pentostatin, thioguanine;

apoptosis inducing agents and anti-angiogenic agents such as Bcl-2 inhibitors, eg YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;

tubulin-binding agents, for example combrestatin, colchicines or nocodazole;

kinase inhibitors (e.g. EGFR (Epithelial Growth Factor Receptor) inhibitors, MTKI (multiple kinase inhibitors), mTOR inhibitors, cmet inhibitors) e.g. flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib, latipinite ditosylate, sorafenib sunitinib, sunitinib maleate, temsirolimus, 6-{difluoro[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl} quinoline or a pharmaceutically acceptable salt thereof, 6-[difluoro(6-pyridin4-yl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]quinoline or a pharmaceutically acceptable salt thereof;

farnesyl transferase inhibitors, eg tipifarnib;

histone deacetylase (HDAC) inhibitors, eg sodium butyrate, hydroxamic acid suberoylanilide (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A, vorinostat;

ubiquitin-proteasome pathway inhibitors, eg PS-341, MLN.41 or bortezomib;

Yondelis-trebectin;

agents affecting the immune system associated with anticancer activity such as, but not limited to, anti-CTLA4, αntu-PD-1, anti-PDL-1, OX40, cancer vaccines;

radiation therapy in the form of external beam radiation or radioisotopes as implantable

- 27 039646 source or temporary source, or radioisotopes conjugated to other molecules;

telomerase inhibitors, eg telomestatin;

matrix metalloproteinase inhibitors, eg batimastat, marimastat, prinostat or metastat;

recombinant interleukins, eg aldesleukin, denileukin diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon alfa 2b MAPK inhibitors retinoids, eg alitretinoin, bexarotene, tretinoin arsenic trioxide asparaginase steroids, eg dromostanolone propionate, megestrol acetate, nandrolone (decanoate), ), dexamethasone gonadotropin-releasing hormone agonists or antagonists, e.g. abarelix, goserelin acetate, histrelin acetate, leuprolide acetate thalidomide, lenalidomide mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase, rasburizase BH3 mimetics, e.g. PD98059, AZD6244, CI-1040 colony stimulating factor analogs, eg filgrastim, pegfilgrastim, sarragostim; erythropoietin or its analogues (for example, darbepoetin alfa); interleukin 11; oprelvekin; zoledronate, zoledronic acid; fentanyl; bisphosphonate; palifermin a steroid inhibitor of cytochrome P450 17-alpha-hydroxylase-17,20-lyase (CYP17), e.g. abiraterone, abaraterone acetate an antibody that blocks the interaction between PD-1 (programmed cell death 1) and PDL1 (programmed death ligand 1).

In one embodiment, the present invention relates to the combination of a pharmaceutical composition according to the present invention and 6-{difluoro[6-(1-methyl-1H-pyrazol-4yl)[1,2,4]triazolo[4,3-b] pyridazin-3-yl]methyl}quinoline or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention relates to the combination of a pharmaceutical composition according to the present invention and 6-[difluoro(6-pyridin-4-yl[1,2,4]triazolo[4,3-b]pyridazin-3-yl) methyl]quinoline or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention relates to a pharmaceutical composition described in this application, further comprising 6-{difluoro[6-(1-methyl-1H-pyrazol-4yl)[1,2,4]triazolo[4,3-b ]pyridazin-3-yl]methyl}quinoline or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention relates to a pharmaceutical composition described in this application, further comprising 6-[difluoro(6-pyridin-4-yl[1,2,4]triazolo[4,3-b]pyridazin-3-yl )methyl]quinoline or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions of the present invention also have therapeutic applications in tumor cell sensitization for radiotherapy and chemotherapy.

Therefore, the pharmaceutical compositions of the present invention can be used as a radiosensitizer and/or chemosensitizer, or they can be administered in combination with another radiosensitizer and/or chemosensitizer.

As used herein, the term radiosensitizer is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to ionizing radiation and/or to promote the treatment of diseases that are treatable with ionizing radiation.

As used herein, the term chemosensitizer is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or promote the treatment of diseases that are treatable with chemotherapeutic agents.

Several mechanisms of action of radiosensitizers have been suggested in the literature, including: hypoxic cell radiosensitizers (eg, 2-nitroimidazole compounds and benzotriazine dioxide compounds) that mimic oxygen, or alternatively, they behave as bioreductive agents in hypoxia; non-hypoxic cell radioxysensitizers (eg, halogenated pyrimidines) can be DNA base analogs and preferentially integrate into cancer cell DNA and thus promote radiation-induced DNA degradation and/or prevent normal DNA repair mechanisms; and there have been hypotheses about various other potential mechanisms of action of radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently use radiosensitizers in combination with X-ray irradiation. Examples of X-ray activated radiosensitizers include, but are not limited to: metronidazole, mesonidazole, desmethylmisonidazole, pimonidazole, ethanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin and their therapeutically effective analogs and derivatives.

Photodynamic therapy (PDT) for cancer uses visible light as a radiation sensitizer activator. Examples of photodynamic radiosensitizers include, but are not limited to: hematoporphyrin derivatives, photofrin, benzoporphyrin derivatives, tin-etioporphyrin, pheopheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and their therapeutically effective analogues and derivatives.

Radiosensitizers can be administered in combination with a therapeutically effective amount of one or more other compounds, including, but not limited to: compounds that promote incorporation of radiosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients and/or oxygen to target cells; chemotherapeutic agents that act on the tumor with or without additional radiation; or other therapeutically effective compounds for the treatment of cancer or other diseases.

Chemosensitizing agents can be administered in combination with a therapeutically effective amount of one or more other compounds, including, but not limited to: compounds that promote incorporation of chemosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients and/or oxygen to target cells; chemotherapeutic agents that act on a tumor, or other therapeutically effective compounds for the treatment of cancer or other disease. Calcium antagonists, such as verapamil, can be used in combination with antitumor agents to establish chemosensitivity in tumor cells resistant to conventional chemotherapeutic agents and to increase the efficacy of such compounds in drug-responsive malignancies.

In light of their useful pharmacological properties, the components of the combinations according to the invention, ie one or more other drugs and the compound according to the present invention, can be formulated into various pharmaceutical forms for purposes of administration. The components may be formulated separately in separate pharmaceutical compositions or as a single pharmaceutical composition containing all components.

The present invention therefore also relates to the pharmaceutical composition described in this application, and further comprising one or more other drugs together with a pharmaceutical carrier.

The present invention also relates to the use of the combination according to the invention for the preparation of a pharmaceutical composition for inhibiting the growth of tumor cells.

The present invention also relates to a product containing the pharmaceutical composition described in this application, and, as an additional active ingredient, one or more anticancer agents, as a combined preparation for simultaneous, separate or sequential use for the treatment of patients suffering from cancer.

One or more other drugs and a pharmaceutical composition in accordance with the present invention can be entered simultaneously (for example, in separate or in a single composition) or sequentially in any order. In the latter case, the two or more components should be administered for such a period and in such quantity and in such a way that is sufficient to ensure that an advantageous or synergistic effect is achieved. It is understood that the preferred route and order of administration and the appropriate dosage amounts and administration schedules for each component of the combination will depend upon the particular other drug and composition of the present invention being administered, the route of administration thereof, the particular tumor being treated, and the particular host being treated. treatment. The optimal method and order of administration and the doses to be administered and the administration schedule can be easily determined by those skilled in the art using conventional methods and taking into account the information set forth in this application.

The weight ratio of the compound contained in the pharmaceutical compositions of the present invention and one or more other anticancer agents, when administered as a combination, can be determined by one skilled in the art. The specified ratio and the exact dosage and frequency of administration depend on the other anticancer agent(s) used, the specific condition being treated, the severity of the condition being treated, age, body weight, sex, diet, time of administration and general physical condition of the particular patient, method administration, as well as other drugs that the subject may take, as is well known to specialists in this field. In addition, it is obvious that the effective daily amount can be reduced or increased depending on the response of the subject receiving treatment and/or depending on the judgment of the attending physician prescribing the compositions of the present invention. Specific weight ratio for K-(3,5-dimethoxyphenyl)-K'-(1-methylethyl)-K-[3-(1-methyl1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1,2 α-diamine, a pharmaceutically acceptable salt or solvate thereof and the other anti-cancer agent may range from 1/10 to 10/1, more specifically 1/5 to 5/1, even more specifically 1/3 to 3/1.

The platinum coordination compound is preferably administered at a dose of 1-500 mg per square meter (mg/m ² ) of body surface area, for example 50-400 mg/m ² , in particular for cisplatin at a dose of about 75 mg/m ² and for carboplatin approximately 300 mg/m ² per course of treatment.

The taxane compound is preferably administered at a dose of 50-400 mg per square meter (mg/m ² ) of body surface area, for example 75-250 mg/m ² , in particular for paclitaxel at a dose of about 175-250 mg/m ² and for docetaxel approximately 75-150 mg/m ² per course of treatment.

- 29 039646

The camptothecin compound is preferably administered at a dose of 0.1-400 mg per square meter (mg/m ² ) of body surface area, for example 1-300 mg/m ² , in particular for irinotecan at a dose of about 100-350 mg/m ² and for topotecan, approximately 1-2 mg/m ² per course of treatment.

The antitumor podophyllotoxin derivative is preferably administered at a dose of 30-300 mg per square meter (mg/m ² ) of body surface area, for example 50-250 mg/m ² , in particular for etoposide at a dose of about 35-100 mg/m ² and for teniposide, approximately 50-250 mg/m ² per course of treatment.

The antitumor vinca alkaloid is preferably administered at a dose of 2-30 mg per square meter (mg/m ² ) of body surface area, in particular for vinblastine at a dose of about 3-12 mg/m ² , for vincristine at a dose of about 1-2 mg/m 2 m ² and for vinorelbine at a dose of approximately 10-30 mg/m ² per course of treatment.

The antitumor nucleoside derivative is preferably administered at a dose of 200-2500 mg per square meter (mg/m ² ) of body surface area, for example 700-1500 mg/m ² , in particular for 5-FU at a dose of 200-500 mg/m ² , for gemcitabine at a dose of approximately 800-1200 mg/m ² and for capecitabine at approximately 1000-2500 mg/m ² per course of treatment.

Alkylating agents such as nitrogen mustard or nitrosourea are preferably administered at a dose of 100-500 mg per square meter (mg/m ² ) of body surface area, for example 120-200 mg/m ² , in particular for cyclophosphamide at a dose of about 100 -500 mg/m ² , for chlorambucil at a dose of approximately 0.1-0.2 mg/kg, for carmustine at a dose of approximately 150-200 mg/m ² , and for lomustine at a dose of approximately 100-150 mg/m ² per a course of treatment.

The antitumor anthracycline derivative is preferably administered at a dose of 10-75 mg per square meter (mg/m ² ) of body surface area, for example 15-60 mg/m ² , in particular for doxorubicin at a dose of about 40-75 mg/m ² , for daunorubicin at a dose of approximately 25-45 mg/m ² and for idarubicin at a dose of approximately 10-15 mg/m ² per course of treatment.

The antiestrogen agent is preferably administered at a dose of about 1-100 mg daily, depending on the particular agent and the condition being treated. Tamoxifen is preferably administered orally at a dose of 5-50 mg, preferably 10-20 mg twice a day, continuing treatment for a sufficient time to achieve and maintain a therapeutic effect. Toremifene is preferably administered orally at a dose of approximately 60 mg once a day, continuing treatment for a sufficient time to achieve and maintain a therapeutic effect. Anastrozole is preferably administered orally at a dose of about 1 mg once a day. Droloxifene is preferably administered orally at a dose of about 20-100 mg once a day. Raloxifene is preferably administered orally at a dose of about 60 mg once a day. Exemestane is preferably administered orally at a dose of about 25 mg once a day.

Antibodies are preferably administered at a dose of about 1-5 mg per square meter (mg/m ² ) of body surface area, or as known in the art if another dose calculation method is used. Trastuzumab is preferably administered at a dose of 1-5 mg per square meter (mg/m ² ) of body surface area, specifically 2-4 mg/m ² per course of treatment.

These doses may be administered, for example, once, twice or more per course of treatment, which may be repeated, for example, every 7, 14, 21 or 28 days.

Examples

Example 1

Tablet composition 1

N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6- 3 mg yl]ethane-1,2- diamine

Meglumine

Mannitol

Microcrystalline cellulose

Croscarmellose sodium

magnesium stearate

Total tablet weight:

1.5 mg 20% to 95% w/w 20% to 95% w/w 20% to 95% w/w 0.5 to 1.5% w/w

150 mg

- 30 039646

Tablet composition 2

N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin- 4 mg

6-yl]ethane-1,2-diamine

Meglumine 2 mg

Mannitol 20% to 95% w/w

Microcrystalline cellulose 20% to 95% w/w

Croscarmellose sodium 2.5 to 5% w/w

Magnesium stearate 0.5 to 1.5% w/w

Total tablet weight: 200 mg

Tablet composition 3

N-(3,5-dimethoxyphenyl)-N ^t -(1 - methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-5 mg yl)quinoxalin-6-yl]ethan-1,2 -diamine

Meglumine 2.5 mg

Mannitol 20% to 95% w/w

Microcrystalline cellulose 20% to 95% w/w

Croscarmellose sodium 2.5 to 5% w/w

Magnesium stearate 0.5 to 1.5% w/w

Total tablet weight: 250 mg

Getting pills.

Suitable amounts of ^(3,5-dimethoxyphenyl)-Ni-(1-methylethyl)-^[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, mannitol, meglumine and croscarmellose sodium were screened together. An appropriate amount of microcrystalline cellulose was sifted through a sieve. Both fractions were mixed, crushed and mixed again. An appropriate amount of magnesium stearate was screened and added to the mixture. This mixture was compressed into tablets. The resulting tablets were film coated using Opadry® II 85F92209.

Meglumine absorption as a function of time.

In order to evaluate the stabilizing effect of meglumine in tablets of the present invention, the absorption of meglumine in tablets as a function of time was determined.

The film-coated tablets of the present invention were stored in bottles without desiccant under various conditions of temperature and relative humidity. The content of meglumine still present in the tablets was determined as a function of time by isocratic ion chromatography by conductivity detection, NMR or NIR (near infrared spectroscopy).

Formaldehyde load test.

To study the effect of meglumine on the conversion of Na(3,5-dimethoxyphenyl)-Na-(1-methylethyl)-Na[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1 ,2-diamine in 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5 -tetrahydro-1H-1,4-benzodiazepine in the presence of formaldehyde, a solid state formaldehyde load test was developed. In this test, a solid sample (eg tablet or powder mixture) was exposed to a 5% aqueous solution of formaldehyde (see Fig. 1) at a temperature of 30°C. In this loading test, the diffusion of formaldehyde originating from an external source and its interaction with N-(3,5dimethoxyphenyl)-N-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane-1,2-diamine

- 31 039646 is simulated in a controlled, reliable and reproducible way.

The following powder mixtures were tested: a powder mixture of 2 w/w% compound A, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate; a powder mixture of 2 wt./wt.% compound A, 1 wt./wt.% meglumine, mannitol, microcrystalline cellulose, croscarmellose sodium and magnesium stearate; a powder mixture of 2 wt/wt% compound A, 9 wt/wt% meglumine, mannitol, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

Aliquots of these mixtures (100±5 mg) were withdrawn at 0 h, 3 h, 8 h, 24 h, 32 h and 48 h and suspended in acetonitrile/water (1/1, 4 ml). The suspension was shaken for 20 minutes and the mixture was allowed to stand for 10 minutes. The remaining insoluble particles were removed by filtration using a syringe filter, and the filtrate was analyzed by UHPLC (UV detection at 256 nm using a PDA detector).

Column Acquity UPLC HSS T3

150 mm

Column length

Column diameter

Column temperature

Particle size

Flow rate

Injection volume

Solvent A

Solvent B

2.1mm

0°C

1.8 µm 0.35 ml/min 2 µm mM NH ₄ OAc+0, 05% AcOH

Acetonitrile

Gradient

6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl] Formation

2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (compound B) was determined based on area % versus time. % area was calculated as the peak area of 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1methyl-1 H-pyrazol-4-yl)quinoxalin-6-yl] -2.3.4, 5-tetrahydro-1H-1,4-benzodiazepine divided by the sum of the areas of all peaks above the specified threshold of 0.05%.

In carrying out this formaldehyde load test using mixtures of N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-nirazol-4-yl)quinoxalin-6-yl] ethane-1,2-diamine with different amounts of meglumine, the protective effect of meglumine could be clearly shown (see Fig. 2). Already the addition of 1 wt./wt.% meglumine significantly reduced decomposition, while it was completely inhibited in the presence of 9 wt./wt.% meglumine.

Example 2

The following capsules were obtained (filled by hand).

Composition A

N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6 mg yl]ethane-1,2-diamine

Mannitol

94.36 mg

Pregelatinized corn starch 40.44 mg

Meglumine 1.40 mg

Colloidal anhydrous silica 1.40 mg

Magnesium stearate 1.40 mg

Total weight 140 mg; loaded into a size 4 gelatin capsule

- 32 039646

Comparative composition B

N- (3,5-dimethoxyphenyl) -N' - (1-methylethyl) -N[3- (1-methyl-1H-pyrazol-4-yl)quinoxalin-6- 1 mg yl]ethane-1,2- diamine

Mannitol 95.34 mg

Pregelatinized corn starch 40.86 mg

Colloidal anhydrous silica 1.40 mg

Magnesium stearate 1.40 mg

Total weight 140 mg; loaded into a size 4 gelatin capsule

Detection of 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5tetrahydro-1H- 1,4-benzodiazepine as a function of time under different conditions.

Capsules (open; capsule shell in vial) were placed directly into a glass vial (at 60° C./50% RH, a closed capsule was also tested). One capsule was tested for each condition. The vials (opened) were placed in a dryer and the humidity was fixed using a saturated saline solution and then in an oven and the temperature was recorded.

At the appropriate time points, the opened capsules were transferred to a volumetric flask. N,N-dimethylformamide (7 ml) was added. The mixture was shaken for 60 minutes. Water/acetonitrile 1/1 (2 ml) was added and the mixture was shaken and allowed to come to room temperature. The mixture was diluted to volume (10 ml) with water/acetonitrile 1/1 and shaken vigorously. The mixture was allowed to stand for 10 min.

Standard stock and reference solutions were prepared from N-(3,5-dimethoxyphenyl)-N'-(1methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan- 1,2-diamine base.

The amount of N-(3,5-dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-( 1-methyl-1 H-pyrazol-4-yl)quinoxalin6-yl]ethane-1,2-diamine bases (compound A) and 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1Hpyrazol-4-yl)quinoxalin-6-yl] -2,3,4,5 α-tetrahydro- 1H-1,4-benzodiazepine base (compound B) was measured using the following operating conditions: ____________________________

UHPLC system Options Speaker Acquity HSS TK; 2.1 x 150 mm; 1.8 µm or equivalent * Column temperature 30°C Temperature automatic sampler 10°С Flow rate 0.35 ml/min The volume of input samples 6.5 µl The volume of sample injected can be adjusted, provided that the limits of the system (detector and injector) are not exceeded and the peak shape of the main compound is acceptable. detection UV detection at 256 nm mobile phase Preparation and composition BUT 10 mM ammonium acetate (0.771 g/l) + 0.05% v/v acetic acid in water AT Acetonitrile Gradient Solution distributor Time in minutes 0 12.5 20 22.5 23 27 %BUT 85 40 0 0 85 85 %AT fifteen 60 100 100 fifteen fifteen Analytical run time 22.5 min.

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Relative retention time tetrahydro-1H-1,4-benzodiazepine (compound B) vs. N-(3,5-dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-( 1-methyl-1 H-pyrazole-4- yl)quinoxalin-6-yl]ethane-1,2-diamine (compound

A) is 0.97. Retention time is ±7.5 min.

The following conditions have been tested:

For composition A: TO; 50°C/75% 3 days; 50°C/75% 7 days; 50°C/75% 14 days*; 60°C/50% 3 days; 60°C/50% 7 days; 60°C/50% 14 days*; 70°C/10% 3 days; 70°C/10% 7 days; 70°C/10% 14 days*; 70°C/75% 1 day; 70°C/75% 3 days; 70°C/75% 7 days; 70°C/75% 14 days*; 80°C/50% 1 day; 80°C/50% 3 days; 80°C/50% 7 days.

For composition B: TO; 50°C/75% 3 days; 50°C/75% 7 days; 60°C/50% 3 days; 60°C/50% 7 days; 70°C/10% 3 days; 70°C/10% 7 days; 70°C/75% 1 day; 70°C/75% 3 days; 70°C/75% 7 days; 80°C/50% 1 day; 80°C/50% 3 days; 80°C/50% 7 days.

*in light of the results obtained for storage conditions for 7 days, samples that were stored for 14 days were not analyzed w/w% of Compound A and Compound B were determined according to the following equation:

END . unknown (Area unknown/Area known) CONC . known where unknown is either compound A or compound B and known is a reference standard compound A with a known concentration

Results: UHPLC results for composition A

Results: UHPLC results for Comparative Composition B

Conditions %w/w connections B %w/w compound A Initial (TO) 0.05 89.9 50°C/75% 3 days 0.56 94.4 50°C/75% 7 days 0.92 95.9 60°C/50% 3 days 4.76 90.7 60°C/50% 7 days 7.50 90.3 60°C/50% 7 days-completed 0.28 99.9 70°С/10% 3 days 0.79 94.7 70°C/10% 7 days 1.33 94.5 70°C/75% 1 day 0.44 94.7 70°C/75% 3 days 0.92 93.6 70°C/75% 7 days 2.74 92.6 80°C/50% 1 day 0.71 95.4 80°C/50% 3 days 1, 63 94.1 80°C/50% 7 days 3, 15 91.8

Formation of 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]2,3,4,5-tetrahydro-1H -1,4-benzodiazepine was slowed down in composition A compared to comparative composition B.

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For most products formed as a result of the decomposition of medicinal substances, the reaction rates obey the Arrhenius kinetics. Arrhenius kinetics is a linear relationship between the natural logarithm of the reaction rate k versus the inverse logarithm of the absolute temperature T (R is the gas constant and A is the entropy of activation for the process).

Humidity can have a significant effect on drug solids or drug products; even for reactions that do not involve water themselves. The moisture-corrected Arrhenius equation [1] reflects both the influence of temperature and the influence of humidity on the kinetics of decomposition formation.

(k=reaction rate; A=activation entropy for the process; InA=collision frequency; Ea=activation energy (kcal/mol); K=gas constant; T=temperature; B=humidity response factor; RH=%relative humidity)

Determination of the moisture-corrected Arrhenius equation [1] for each individual degrader (via ASAPprime®) allows prediction of drug product behavior over time under various storage conditions. For each degradant, plan In k vs. 1/T and rel. ow. determined using the accelerated stability assessment program (ASAP) under extreme conditions (with temperatures from 40 to 70°C and relative humidity in the range of 10-75%).

The following Arrhenius parameters were used: In A=24.8; Ea=18.8; B=0.05.

Based on the approach described above, the predicted shelf life for Comparative Composition B was less than 1 month at 25°C/60% RH conditions. In light of this result, no further predictions were made.

Based on the approach described above, the predicted shelf life for Composition A was as indicated in the tables below.

Projected time for 25°C/60%RH conditions

Simulated packaging PVC blister 2.9 years Alu/Alu blister 3.25 years 100cm ³ /60 capsules HDPE bottles 5.6 years 100cm ³ /60 capsules + 2g HDPE desiccant bottle 6.4 years

Projected time for 30°C/75% RH conditions.

Simulated packaging PVC blister 1.5 years Alu/Alu blister 1.8 years 100cm ³ /60 capsules HDPE bottles 1.7 years 100cm ³ /60 capsules +2g HDPE desiccant bottle 2.0 years

CLAIM

Claims (43)

CLAIM 1. The use of meglumine in a pharmaceutical composition to improve the chemical stability of N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin- 6-yl] ethane-1,2 diamine, a pharmaceutically acceptable salt thereof or a solvate thereof contained in said composition. 2. Use according to claim 1, wherein the pharmaceutical composition is a tablet or capsule. 3. Use according to claim 1 or 2, wherein the pharmaceutical composition comprises N-(3,5-dimethoxyphenyl)N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane-1,2-diamine base. 4. Method for preventing, delaying, slowing down or reducing the conversion of N-(3,5dimethoxyphenyl)-N'-( 1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6 -yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof or a solvate thereof, contained in a pharmaceutical composition, in 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H -pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, a pharmaceutically acceptable salt or solvate thereof, comprising adding meglumine to said composition. 5. The method of claim 4, wherein the pharmaceutical composition is a tablet or capsule. 6. The method according to claim 4 or 5, where the composition comprises N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1methyl-1H-pyrazol-4-yl)quinoxalin- 6-yl]ethane-1,2-diamine base. 7. Pharmaceutical composition comprising N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethan-1 ,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof; meglumine; and a pharmaceutically acceptable carrier. - 35 039646 8. Pharmaceutical composition according to claim 7, including from about 0.1 to about 3% w/w meglumine 9. Pharmaceutical composition according to claim 7 or 8, where the composition is a tablet or capsule. 10. Pharmaceutical composition according to any one of paragraphs.7-9, where the composition includes 0-2% wt./wt. 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H1 ,4-benzodiazepine, a pharmaceutically acceptable salt thereof, or a solvate thereof. 11. Pharmaceutical composition according to claim 10, where the composition comprises from 0-0.05% wt./wt. 6,8dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H -1,4 benzodiazepine, a pharmaceutically acceptable salt thereof, or a solvate thereof. 12. Pharmaceutical composition according to any one of claims 7-11, comprising from 2 mg to 6 mg equivalent of the base N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-( 1-methyl -1 H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof. 13. Pharmaceutical composition according to claim 12, comprising 3 mg equivalent of the base N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline -6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof. 14. Pharmaceutical composition according to claim 12, comprising 4 mg equivalent of the base N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline -6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof. 15. Pharmaceutical composition according to claim 12, comprising 5 mg equivalent of the base N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline -6-yl]ethane-1,2-diamine, a pharmaceutically acceptable salt thereof, or a solvate thereof. 16. Pharmaceutical composition according to any one of paragraphs.7-15, containing from about 0.1 to about 2% wt./wt. meglumine. 17. Pharmaceutical composition according to claim 16, containing from about 0.1 to about 1.5% wt./wt. meglumine. 18. A pharmaceutical composition according to claim 17 containing from about 0.1 to about 1 w/w% meglumine. 19. A pharmaceutical composition according to any one of claims 7-15, containing from about 0.5 to about 3 w/w% meglumine. 20. Pharmaceutical composition according to claim 19, containing from about 0.5 to about 2% wt./wt. meglumine. 21. Pharmaceutical composition according to claim 20, containing from about 0.5 to about 1.5% wt./wt. meglumine. 22. A pharmaceutical composition according to claim 21 containing from about 0.5 to about 1 w/w% meglumine. 23. A pharmaceutical composition according to any one of claims 7-22, wherein the composition comprises N-(3,5dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl )quinoxalin-6-yl]ethane-1,2 diamine base. 24. Pharmaceutical composition according to claim 7, which contains a film coating, which is a water-based film coating. 25. The pharmaceutical composition of claim 24, wherein the water-based film coating is a PVA-based immediate release system, without polyethylene glycol. 26. The use of a pharmaceutical composition according to any one of claims 7 to 25 for the preparation of a medicament for the treatment of cancer. 27. A method of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition according to any one of claims 7-25. 28. A method of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition according to any one of claims 7-25 daily for 3 weeks (3 weeks of administration), followed by 1 week when the composition is not administered (1 week without administration), and repeating this cycle 3 weeks of injection, 1 week without injection. 29. A method of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition according to any one of claims 7 to 25 daily for 1 week (1 week of administration), followed by 1 week when the composition is not administered (1 week without administration), and repeating this cycle 1 week of introduction, 1 week without introduction. 30. A method of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition according to any one of claims 7 to 25, wherein the drug is administered daily. 31. A method of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition according to any one of claims 7 to 25, wherein the drug is administered once a day. 32. A method of treating cancer in a patient, comprising administering to the patient a pharmaceutical composition according to any one of claims 27 to 31, (i) where the daily dose is 6 mg base equivalent; - 36 039646 (ii) where the daily dose is 7 mg base equivalent; (iii) where the daily dose is 8 mg base equivalent or (iv) where the daily dose is 9 mg base equivalent. 33. The use of a pharmaceutical composition according to any one of claims 7-25 for the treatment of cancer. 34. Use according to claim 33, wherein the cancer is selected from the group consisting of bladder cancer, urothelial cancer, and cholangiocarcinoma. 35. The use of claim 34 wherein the cancer is selected from non-muscle invasive bladder cancer, metastatic urothelial cancer, and inoperable urothelial cancer. 36. The use of any one of 33-35, wherein the cancer is a cancer with FGFR genomic changes. 37. The use of claim 36 wherein the FGFR genomic changes are translocations, fusions and/or mutations. 38. Use according to claim 37, wherein the change is a FGFR3-TACC3 translocation. 39. Use according to claim 37, wherein the change is a mutation. 40. Use according to claim 39, wherein the mutation is R248C. 41. Use according to claim 39, wherein the mutation is S249C. 42. Use according to claim 33, where the cancer is selected from the group consisting of lung cancer, in particular progressive or refractory non-small cell lung cancer (NSCLC); breast cancer; glioblastoma multiforme; ovarian cancer; head and neck cancer; esophageal cancer; gastric cancer; multiple myeloma; myeloproliferative disorder; endometrial cancer; prostate cancer; colorectal cancer; squamous cell carcinoma of the oral cavity; hepatocellular cancer; uterine cancer and cervical cancer. 43. Use according to any one of claims 7-25 for the treatment of a disease or condition mediated by FGFR kinase.