3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione compounds as MEK inhibitors

Abstract

The present invention relates to compounds of Formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as defined herein. The present invention further relates to pharmaceutical compositions comprising such compounds and salts, and methods and uses of such compounds, salts, and compositions for treating abnormal cell growth, including cancer, in an individual in need thereof. The present invention further relates to solid forms of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.

Description

[Technical Field]

[0001] This invention relates to novel 3,4-dihydro-2,7-naphthyl-1,6(2H,7H)-dione compounds or pharmaceutically acceptable salts thereof, which are used as MEK inhibitors and can be used to treat abnormal cell growth (such as cancer) in patients. The invention also relates to pharmaceutical compositions containing said compounds and methods of using said compounds and compositions to treat abnormal cell growth (such as cancer) in individuals with this need. Furthermore, the invention relates to a solid form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyl-1,6(2H,7H)-dione, pharmaceutical compositions containing said solid form, and methods of using said solid form and compositions to treat abnormal cell growth (such as cancer) in individuals with this need. [Background Technology]

[0002] MEK kinase (mitogen-activated protein kinase kinase (MAPKK)) is a crucial component of the Ras-RAF-MEK-ERK cell survival pathway. The Ras pathway is activated by the binding of growth factors, cytokines, and hormones to their homologous receptors. However, in cancer cells, this pathway is persistently activated, leading to increased cancer cell survival, cell proliferation, angiogenesis, and metastasis. Tumors exhibiting persistent activation of this pathway include, but are not limited to, tumors of the colon, pancreas, breast, brain, ovary, lung, and skin. Activation of Ras (due to upstream signal transduction or due to point mutations in activated Ras tumor genes) leads to phosphorylation and activation of Raf kinases, which in turn phosphorylate and activate MEK1 and MEK2 (also known as MAPKK1 and MAPKK2). MEK1 and MEK2 are bispecific kinases that activate ERK1 and ERK2 by phosphorylating and activating ERK1 / 2 kinases (also known as MAP kinases), which further phosphorylate and regulate the function of proteins involved in cell survival and apoptosis, such as Mcl-1, Bim, and Bad. Therefore, activation of this phosphorylation-mediated cascade leads to enhanced cell proliferation, cell survival, and reduced cell death, all essential for initiating and maintaining a tumorigenic phenotype. Inhibition of this pathway, particularly MEK activity, is known to be beneficial for the treatment of hyperproliferative diseases. MEK inhibitors exhibit variable levels of activity in several settings, including BRAF V600-mutant melanoma, NRAS-mutant melanoma, low-grade serous ovarian cancer, neurofibromatosis plexiformis, thyroid cancer, and low-grade glioma, with more limited responses in KRAS-mutant pancreatic or lung cancer.

[0003] Cancers that frequently metastasize to the brain (e.g., melanoma and non-small cell lung cancer) are known to carry alterations in MAPK pathway activation, such as BRAF V600E and KRAS G12 mutations (Cancer Genome Atlas N., Cell 2015; 161:1681-96). Although activating mutations can occur to varying degrees in the typical pathway, all of these mutations require signal transduction via mitogen / extracellular signal-regulated kinases (MEKs) to increase proliferation and survival (Schubbert S, Shannon K, Bollag G. Nat Rev Cancer. 2007; 7:295-308). The common MAPK pathway activation in malignancies and at central and downstream locations of MEKs also makes MEK inhibitors potentially important for the treatment of intracranial tumors.

[0004] The blood-brain interface comprises the brain microvascular endothelium that forms the blood-brain barrier (BBB) ​​and the choroid plexus epithelium that forms the blood-CSF barrier (BCSFB). The BBB is a highly selective physiological, transport, and metabolic barrier that separates the central nervous system (CNS) from the blood. The BBB can prevent certain drugs from entering brain tissue and is therefore a limiting factor in the delivery of many peripherally administered drugs to the CNS. The efficacy of many molecularly targeted agents in central nervous system tumors is limited by crossing the blood-brain barrier (BBB), which is composed of a tightly junctionted monolayer of endothelial cells that acts as a physiological barrier protecting the brain. In addition, these endothelial cells express a variety of efflux transport proteins, including P-gp and breast cancer resistance protein (BCRP), which are known to exclude many anticancer agents from the brain (Ohtsuki and Terasaki, 2007, Pharm Res 24:1745-1758; Agarwal et al., 2011, Pharm Res 24:1745-1758). Similar to the blood-brain barrier, the blood-CSF barrier functions to block most blood-derived substances from entering the brain, while selectively allowing specific substances to enter the brain and promoting the translocation of brain metabolites and their products into the bloodstream.

[0005] Therefore, there is still a need for therapies to treat MEK-mediated tumors, including those that can penetrate the BBB and / or BSFFB and target tumors in the CNS. [Invention Overview]

[0007] This document provides, in part, compounds of formulas I and II and their pharmaceutically acceptable salts. These compounds inhibit MEK activity, thereby achieving their biological function and are available for use in treating individuals with MEK-related tumors. This document also provides 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyl-1,6(2H,7H)-dione in solid form. Pharmaceutical compositions and medicaments comprising compounds according to any of the formulas described herein and their pharmaceutically acceptable salts are also provided, which can be used alone or in combination with additional anticancer therapies to treat individuals with MEK-related tumors. This document also provides methods for preparing compounds, pharmaceutically acceptable salts, and pharmaceutical compositions according to any of the formulas described herein, as well as the aforementioned methods of use. An overview of this invention is provided to illustrate the inventive concept in a simplified form, which is further described in the detailed description below. This invention summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used independently as an aid in determining the scope of the claimed subject matter.

[0008] According to embodiments of the present invention, compounds of formula I are provided herein.

[0009]

[0010] Or its pharmaceutically acceptable salt, wherein:

[0011] R 1 It can be H, Br, C1-C6 alkyl or phenyl;

[0012] R 2 It can be H, halogen, or CH3-;

[0013] R 3 It is H, hydroxyC1-C6 alkyl-, hydroxyC1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)C1-C6 alkoxy-; and

[0014] R 4 It is a phenyl group that has been substituted with one, two or three independent substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

[0015] This article also provides compounds of formula II.

[0016]

[0017] Or its pharmaceutically acceptable salt, wherein:

[0018] R 1 It can be H, Br, C1-C6 alkyl or phenyl;

[0019] R 2 It can be H, halogen, or CH3-;

[0020] R 3 It is H, hydroxyC1-C6 alkyl-, hydroxyC1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)C1-C6 alkoxy-; and

[0021] R a and R b It is independently selected from halogens, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

[0022] In one embodiment, the present invention provides 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione in solid form.

[0023] In one embodiment, this document provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any of the formulas described herein, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0024] In one implementation, this document provides a treatment method and use comprising administering to an individual a compound of any of the formulas described herein or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, this document provides a method for treating abnormal cell growth (e.g., tumors, such as MEK-associated tumors) in an individual with this need, comprising administering to the individual a therapeutically effective amount of a compound according to any of the formulas described herein or a pharmaceutically acceptable salt thereof. The compound according to any of the formulas described herein may be administered as a single agent or in combination with one or more anticancer therapies.

[0026] In one embodiment, this document provides a method for treating abnormal cell growth (e.g., tumors, such as MEK-associated tumors) in an individual with this need, comprising administering to the individual a combination of a compound according to any of the formulas described herein or a pharmaceutically acceptable salt thereof with a certain amount of an additional anticancer agent, said amounts together effectively treating the abnormal cell growth.

[0027] In one embodiment, this document provides a compound or a pharmaceutically acceptable salt thereof that is used as a medicine according to any of the formulas described herein.

[0028] In one embodiment, this document provides compounds of any of the formulas described herein or pharmaceutically acceptable salts thereof for treating abnormal cell growth (e.g., tumors, such as MEK-associated tumors).

[0029] In one embodiment, this document provides the use of a compound or a pharmaceutically acceptable salt thereof according to any of the formulas described herein in the preparation of a medicament for treating an individual with abnormal cell growth (e.g., a tumor, such as a MEK-associated tumor).

[0030] In one embodiment, this document provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any of the formulas described herein and at least one pharmaceutically acceptable carrier or excipient.

[0031] Each embodiment of a compound according to any of the formulas described herein may be combined with one or more other embodiments of a compound according to any of the formulas described herein, without contradicting each other.

[0032] It should be understood that the foregoing general description and the following detailed description are merely illustrative and interpretative of the claimed invention and not limiting.

[0033] [Brief Description of the Attached Image]

[0034] Figure 1 Describe the powder X-ray diffraction pattern of crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1.

[0035] Figure 2 Powder X-ray diffraction pattern of anhydrous crystalline 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2.

[0036] Figure 3Powder X-ray diffraction pattern of crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3.

[0037] Figure 4 Describes the powder X-ray diffraction pattern of amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 4.

[0038] Figure 5 Describe the adsorption isotherm of the crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3.

[0039] [Detailed Description of the Invention]

[0040] In one aspect, the present invention provides compounds of formula I.

[0041]

[0042] Or its pharmaceutically acceptable salt, wherein:

[0043] R 1 It can be H, Br, C1-C6 alkyl or phenyl;

[0044] R 2 It can be H, halogen, or CH3-;

[0045] R 3 It is H, hydroxyC1-C6 alkyl-, hydroxyC1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)C1-C6 alkoxy-; and

[0046] R 4 It is a phenyl group that has been substituted with one, two or three independent substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

[0047] When referring to substituents, the singular forms “a,” “an,” and “the” used herein include a plural indicator unless otherwise indicated. For example, a “a” substituent includes one or more substituents.

[0048] Regarding the compound chemical names used in this article, substituents are usually named before the groups they are linked to. For example, methoxyethyl contains an ethyl backbone with methoxy substituents.

[0049] The term "halogen" refers to -F (sometimes referred to as "fluorine" or "fluorinated" in this text), -Cl, -Br, and -I.

[0050] As used herein, the term “C1-C6 alkyl” refers to a saturated straight-chain or branched monovalent hydrocarbon group with one to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0051] As used herein, the term “hydroxyl C1-C6 alkyl-” refers to a C1-C6 alkyl group as defined herein, wherein one of the hydrogen atoms is replaced by a hydroxyl group.

[0052] The term "hydroxyl group" refers to the -OH group.

[0053] The term "C3-C6 cycloalkyl" refers to a fully saturated carbon ring having 3 to 6 ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0054] As used herein, the term "fluorinated C1-C6 alkyl" refers to a C1-C6 alkyl group as defined herein, wherein one, two, or three hydrogen atoms are replaced by one, two, or three fluorine atoms, respectively. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0055] As used herein, the term “C1-C6 alkoxy” refers to a C1-C6 alkyl group as defined herein, where the single bond is attached to an oxygen atom (i.e., C1-C6-O-). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy.

[0056] As used herein, the term "fluorinated C1-C6 alkoxy" refers to a C1-C6 alkoxy group as defined herein, wherein one, two, or three hydrogen atoms are replaced by one, two, or three fluorine atoms, respectively. Examples include, but are not limited to, trifluoromethoxy.

[0057] The term “(C3-C6 cycloalkyl)C1-C6 alkoxy-” means C1-C6 alkoxy- as defined herein, wherein one of the hydrogen atoms is replaced by a C3-C6 cycloalkyl group as defined herein.

[0058] As used herein, the term “C1-C6 alkylthio” refers to a (C1-C6 alkyl)S-group, wherein the C1-C6 alkyl portion is as defined herein.

[0059] As used herein, the term “fluorinated C1-C6 alkylthio” refers to a C1-C6 alkylthio group as defined herein, wherein one, two, or three hydrogen atoms are replaced by one, two, or three fluorine atoms, respectively.

[0060] In one embodiment of Formula I, R 1 For H.

[0061] In one embodiment of Formula I, R 1 It is Br.

[0062] In one embodiment of Formula I, R 1 It is a C1-C6 alkyl group. In one embodiment of Formula I, R 1 It is a methyl group.

[0063] In one embodiment of Formula I, R 1 It is a phenyl group.

[0064] In one embodiment of Formula I, R 2 For H.

[0065] In one implementation, R 2 It is a halogen.

[0066] In one embodiment of Formula I, R 2 It is F.

[0067] In one embodiment of Formula I, R 2 It is Cl.

[0068] In one embodiment of Formula I, R 2 It is Br.

[0069] In one embodiment of Formula I, R 2 For I.

[0070] In one embodiment of Formula I, R 2 It is CH3-.

[0071] In one embodiment of Formula I, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0072] In one embodiment of Formula I, R 3 For H.

[0073] In one embodiment of Formula I, R 3 It is a hydroxyl C1-C6 alkyl-. Non-limiting examples include 2-hydroxyethyl.

[0074] In one embodiment of Formula I, R 3It is a hydroxyl C1-C6 alkoxy group. Non-limiting examples include 2-hydroxyethoxy and 2-hydroxypropoxy groups having the following structures, respectively:

[0075]

[0076] In one embodiment of Formula I, R 3 It is a C1-C6 alkoxy group. Non-limiting examples include methoxy, ethoxy, 1-methylethoxy, and 2,2-dimethylethoxy.

[0077] In one embodiment of Formula I, R 3 It is a fluorinated C1-C6 alkoxy group. Non-limiting examples include 2,2-difluoroethoxy.

[0078] In one embodiment of Formula I, R 3 It is a C3-C6 cycloalkyl group. A non-limiting example is cyclopropyl.

[0079] In one embodiment of Formula I, R 3 It is (C3-C6 cycloalkyl)C1-C6 alkoxy-. A non-limiting example is cyclopropylmethoxy.

[0080] In one embodiment of Formula I, R 4 It is a phenyl group that has been substituted with one, two or three independent substituents selected from the following: fluorine, chlorine, bromine, iodine, ethyl, propyl, isopropyl, methylthio, difluoromethylthio, trifluoromethyl, methoxy, difluoromethoxy, cyclopropyl and C1-C6 alkyl-C(=O)-.

[0081] In one embodiment of Formula I, R 4 It is a phenyl group substituted with one or two independent substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

[0082] In one embodiment of Formula I, R 4 It is a phenyl group that has been substituted with one or two independent substituents selected from the following: fluorine, chlorine, bromine, iodine, ethyl, propyl, isopropyl, methylthio, difluoromethylthio, trifluoromethyl, methoxy, difluoromethoxy, cyclopropyl and C1-C6 alkyl-C(=O)-.

[0083] In one embodiment of Formula I, R 4It is a phenyl group substituted with one of the following substituents: halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

[0084] In one embodiment of Formula I, R 4 It is a phenyl group substituted with one of the following substituents: fluorine, chlorine, bromine, iodine, ethyl, propyl, isopropyl, methylthio, difluoromethylthio, trifluoromethyl, methoxy, difluoromethoxy, cyclopropyl, and C1-C6 alkyl-C(=O)-.

[0085] In one embodiment of Formula I, R 4 Selected from the following structures:

[0086]

[0087]

[0088] In one embodiment of Formula I, R 4 for

[0089] In one embodiment of Formula I, R 4 for

[0090] In one embodiment of Formula I, R 4 Selected from the following structures:

[0091]

[0092]

[0093] In one embodiment of Formula I, R 4 Selected from the following structures:

[0094]

[0095] In one implementation, R 4 It has the following structure:

[0096]

[0097] Where R a and R b Independently selected from halogens, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl, and C1-C6 alkyl-C(=O)-. In one embodiment, wherein Ra It is a halogen. In one embodiment, R b It is a halogen, C1-C6 alkyl, C1-C6 alkylthio, or fluorinated C1-C6 alkoxy. In one embodiment, R... a It is a halogen, and R b It is a halogen, C1-C6 alkyl, C1-C6 alkylthio or fluoroC1-C6 alkoxy.

[0098] In one embodiment, compounds of formula II are provided herein:

[0099]

[0100] Or its pharmaceutically acceptable salt, wherein:

[0101] R 1 It can be H, Br, C1-C6 alkyl or phenyl;

[0102] R 2 It can be H, halogen, or CH3-;

[0103] R 3 It is H, hydroxyC1-C6 alkyl-, hydroxyC1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)C1-C6 alkoxy-; and

[0104] R a and R b It is independently selected from halogens, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

[0105] In one embodiment of Formula II, R 1 For H.

[0106] In one embodiment of Formula II, R 1 It is Br.

[0107] In one embodiment of Formula II, R 1 It is a C1-C6 alkyl group. In one embodiment of formula II, R 1 It is a methyl group.

[0108] In one embodiment of Formula II, R 1 It is a phenyl group.

[0109] In one embodiment of Formula II, R 2 For H.

[0110] In one embodiment of Formula II, R2 It is a halogen.

[0111] In one embodiment of Formula II, R 2 It is F.

[0112] In one embodiment of Formula II, R 2 It is Cl.

[0113] In one embodiment of Formula II, R 2 It is Br.

[0114] In one embodiment of Formula II, R 2 For I.

[0115] In one embodiment of Formula II, R 2 It is CH3-.

[0116] In one embodiment of Formula II, R 2 It is H or CH3-.

[0117] In one embodiment of Formula II, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 It is H or CH3-.

[0118] In one embodiment of Formula II, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0119] In one embodiment of Formula II, R 3 For H.

[0120] In one embodiment of Formula II, R 3 It is a hydroxyl C1-C6 alkyl-. Non-limiting examples include 2-hydroxyethyl.

[0121] In one embodiment of Formula II, R 3 It is a hydroxyl C1-C6 alkoxy group. Non-limiting examples include 2-hydroxyethoxy and 2-hydroxypropoxy groups having the following structures, respectively:

[0122]

[0123] In one embodiment of Formula II, R 3 It is a C1-C6 alkoxy group. Non-limiting examples include methoxy, ethoxy, 1-methylethoxy, and 2,2-dimethylethoxy.

[0124] In one embodiment of Formula II, R 3 It is a fluorinated C1-C6 alkoxy group. Non-limiting examples include 2,2-difluoroethoxy.

[0125] In one embodiment of Formula II, R 3 It is a C3-C6 cycloalkyl group. A non-limiting example is cyclopropyl.

[0126] In one embodiment of Formula II, R 3 It is (C3-C6 cycloalkyl)C1-C6 alkoxy-. A non-limiting example is cyclopropylmethoxy.

[0127] In one embodiment of Formula II, R 3 It is H or hydroxyl C1-C6 alkoxy-.

[0128] In one embodiment of Formula II, R a It is a halogen. In one embodiment of Formula II, R a It is fluorine or chlorine. In one embodiment of Formula II, R... a It is fluorine.

[0129] In one embodiment of Formula II, R b It can be fluorine, chlorine, bromine, iodine, ethyl, propyl, isopropyl, methylthio, difluoromethylthio, trifluoromethyl, methoxy, difluoromethoxy, cyclopropyl, or CH3C(=O)-.

[0130] In one embodiment of Formula II, R b It is a halogen, C1-C6 alkyl, C1-C6 alkylthio or fluoroC1-C6 alkoxy.

[0131] In one embodiment of Formula II, R b It is bromine, iodine, ethyl, methylthio, or difluoromethoxy. In one embodiment of formula II, R b It is a methylthio group.

[0132] In one embodiment of Formula II, R a It is fluorine, and R b It is a methylthio group.

[0133] In one embodiment of Formula II, R a It is a halogen, and R b It can be halogen, C1-C6 alkyl, C1-C6 alkylthio, fluorinated C1-C6 alkylthio, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, C3-C6 cycloalkyl or C1-C6 alkyl-C(=O)-.

[0134] In one embodiment of Formula II, R a It is a halogen, and R b It is a halogen, C1-C6 alkyl, C1-C6 alkylthio or fluoroC1-C6 alkoxy.

[0135] In one embodiment of Formula II, Ra It is a halogen, and R b It is a halogen. In one embodiment of Formula II, R a For halogens, R b For halogens, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0136] In one embodiment of Formula II, R a It is a halogen, and R b It is a C1-C6 alkyl group. In one embodiment of formula II, R a For halogens, R b It is a C1-C6 alkyl group, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0137] In one embodiment of Formula II, R a It is a halogen, and R b It is a C1-C6 alkylthio group. In one embodiment of formula II, R a For halogens, R b It is a C1-C6 alkylthio group, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0138] In one embodiment of Formula II, R a It is a halogen, and R b It is a fluorinated C1-C6 alkylthio group. In one embodiment of formula II, R a For halogens, R b It is a fluorinated C1-C6 alkylthio group, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0139] In one embodiment of Formula II, R a It is fluorine, R b It is methylthio, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0140] In one embodiment of Formula II, R a It is a halogen, and R b It is a fluorinated C1-C6 alkyl group. In one embodiment of formula II, R a For halogens, R b It is a fluorinated C1-C6 alkyl group, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0141] In one embodiment of Formula II, R a It is a halogen, and R bIt is a C1-C6 alkoxy group. In one embodiment of formula II, R a For halogens, R b It is a C1-C6 alkoxy group, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0142] In one embodiment of Formula II, R a It is a halogen, and R b It is a fluorinated C1-C6 alkoxy group. In one embodiment of formula II, R a For halogens, R b It is a fluorinated C1-C6 alkoxy group, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0143] In one embodiment of Formula II, R a It is a halogen, and R b It is a C3-C6 cycloalkyl group. In one embodiment of formula II, R a For halogens, R b It is a C3-C6 cycloalkyl group, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0144] In one embodiment of Formula II, R a It is a halogen, and R b It is a C1-C6 alkyl-C(=O)-. In one embodiment of formula II, R a For halogens, R b It is a C1-C6 alkyl-C(=O)-, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0145] In one embodiment of Formula II, R 1 For H, R 2 For H or CH3-, R 3 H or hydroxyl C1-C6 alkoxy-, R a It is a halogen, and R b It can be halogen, C1-C6 alkyl, C1-C6 alkylthio, fluorinated C1-C6 alkylthio, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, C3-C6 cycloalkyl or C1-C6 alkyl-C(=O)-.

[0146] In one embodiment of Formula II, R 1 For H, R 2 For H or CH3-, R 3 H or hydroxyl C1-C6 alkoxy-, R a It is a halogen, and R bIt is a halogen, C1-C6 alkyl, C1-C6 alkylthio or fluoroC1-C6 alkoxy.

[0147] In any of the above embodiments of Formula II, the group

[0148]

[0149] Selected from the following structures:

[0150]

[0151] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structure described. Compounds identified by name or structure as a particular tautomer form are intended to include other tautomer forms unless otherwise specified.

[0152] The compounds described herein may have asymmetric carbon atoms. Carbon-carbon bonds in the compounds of this invention may be represented by solid lines herein. solid wedge Or dashed wedge shape Description. Solid lines describing bonds to asymmetric carbon atoms are intended to indicate the inclusion of all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or dashed wedges describing bonds to asymmetric carbon atoms are intended to indicate the inclusion of only the stereoisomers shown. It is possible that the compounds of the present invention may contain more than one asymmetric carbon atom. In such compounds, solid lines describing bonds to asymmetric carbon atoms are intended to indicate the inclusion of all possible stereoisomers and the stereocenters at which they are bonded. For example, unless otherwise stated, it is intended that the compounds of the present invention may exist as enantiomers and diastereomers, or as racemic mixtures thereof. Solid lines describing bonds to one or more asymmetric carbon atoms in the compounds of the present invention and solid or dashed wedges describing bonds to other asymmetric carbon atoms in the same compound are intended to indicate the presence of a mixture of diastereomers.

[0153] The compounds of the present invention having a chiral center can exist as stereoisomers, such as racemates, enantiomers, or diastereomers.

[0154] Stereoisomers of the compounds described herein may include cis and trans isomers, optical isomers, such as (R) and (S) enantiomers, diastereomers, geometric isomers, rotational isomers, stenotic isomers, conformational isomers, and tautomers, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemic mixtures and diastereomer pairs).

[0155] It also includes acid addition salts or base addition salts, wherein the counterion is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine).

[0156] When any racemic compound crystallizes, there are likely two different types of crystals. The first type is the racemic compound (the true racemate) mentioned above, in which a homogeneous crystal containing two equimolar amounts of enantiomers is obtained. The second type is a racemic mixture or conglomerate, in which two equimolar amounts of crystals are obtained, each containing a single enantiomer.

[0157] Conventional techniques for preparing / isolating single enantiomers include chiral synthesis from suitable optically pure precursors, or the use of chiral high-performance liquid chromatography (HPLC) or superfluid critical chromatography (SFC) to resolve racemic mixtures (or racemic mixtures of salts or derivatives).

[0158] Alternatively, the racemic compound (or racemic precursor) can be reacted with a suitable optically active compound (e.g., an alcohol), or, if the compound contains an acidic or basic moiety, with an acid or base (such as tartaric acid or 1-phenylethylamine). The resulting mixture of diastereomers can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomers in a manner well known to those skilled in the art.

[0159] The chiral compounds (and their chiral precursors) of this invention can be obtained enantiomerically enriched by chromatography (typically HPLC) on an asymmetric resin, wherein the mobile phase consists of a hydrocarbon (typically heptane or hexane) containing 0 to 50% (typically 2 to 20%) isopropanol and 0 to 5% alkylamine (typically 0.1% diethylamine). The eluent is concentrated to obtain an enriched mixture.

[0160] Stereomeric clusters can be separated using conventional techniques known to those skilled in the art; see, for example, EL Eliel, “Stereochemistry of Organic Compounds” (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

[0161] The enantiomer purity of the compounds described herein can be described in terms of enantiomer excess (ee), which indicates the extent to which the sample contains one enantiomer in greater quantity than another. Racemic mixtures have 0% ee, while completely pure single enantiomers have 100% ee. Diastereomer purity can be similarly described in terms of diastereomer excess (de).

[0162] The compounds of this invention can exhibit tautomerism and structural isomerism. For example, the compounds can exist in several tautomer forms (including enol and imine forms and ketone and enamine forms) and geometric isomers and mixtures thereof. All such tautomer forms are included within the scope of the compounds of this invention. Tautomer systems exist in solution as mixtures of tautomer groups. In solid form, one tautomer is usually dominant. Even if one tautomer may be described, this invention includes all tautomers of the compounds of the provided formula. Compounds of formula I can exhibit tautomerism, for example, when R 3 When it is hydrogen, that is:

[0163]

[0164] Furthermore, some compounds of the present invention can form hindered transisomers (e.g., substituted biaryl groups). A hindered transisomer is a conformational stereoisomer that occurs when the rotation of a single bond surrounding the molecule is hindered or significantly slowed due to steric interactions with other parts of the molecule, and when the substituents at the ends of the single bond are asymmetrical. The interconversion of hindered transisomers is slow enough to allow separation and separation under predetermined conditions. The energy barrier to thermal racemization can be determined by the steric hindrance of the free rotation of one or more bonds forming the chiral axis.

[0165] The present invention also includes pharmaceutically acceptable isotopically labeled compounds that are identical to those described in one of the provided formulas, but in that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature.

[0166] The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or similar to those described herein, using appropriate isotopically labeled reagents instead of unlabeled reagents used in other ways.

[0167] Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to, those of other species. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 32 P, 35 S, 18 F and 36 Cl. Certain isotopically labeled compounds of the present invention (e.g., those incorporating radioactive isotopes such as...) 2 H, 3 H and14 Compounds of C can be used for drug and / or substrate tissue distribution assays. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium, i.e., 2 H) substitution can offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. Positron-emitting isotopes (such as...) 11 C 18 F, 15 O and 13 N) replaces positron emission tomography (PET) studies, which can be used to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by using isotopically labeled reagents instead of unlabeled reagents via the routes and / or methods disclosed in the examples and preparation examples below.

[0168] Pharmaceutically acceptable solvates according to the invention include those in which the solvent for crystallization can be isotopically substituted (e.g., D₂O, d). 6 -Acetone, d 6 A solvate of DMSO.

[0169] Unless otherwise indicated, all references to the compounds of the present invention herein include references to their salts, solvates, hydrates and complexes, as well as solvates, hydrates and complexes of their salts, including their polymorphs, stereoisomers and isotopically labeled forms.

[0170] The compounds of this invention may exist in pharmaceutically acceptable salt forms, such as acid addition salts and base addition salts of compounds of one of the formulas provided herein. As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological efficacy and properties of the parent compound. As used herein, the phrase "pharmaceutically acceptable salt" includes salts containing acidic or basic groups present in compounds of the formulas disclosed herein, unless otherwise indicated.

[0171] For example, the compounds of the present invention, which have basic properties, can form a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for animal administration, it is often practically desirable to initially isolate the compound of the present invention as a pharmaceutically unacceptable salt from the reaction mixture, then simply convert the pharmaceutically unacceptable salt back to the free basic compound by treating it with a basic reagent, and subsequently converting the free base of the latter into a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present invention can be prepared by treating the basic compound with substantially equal amounts of a selected inorganic or organic acid in an aqueous solvent medium or a suitable organic solvent (such as methanol or ethanol). After solvent evaporation, the desired solid salt is obtained. The desired acid salt can also be precipitated from a free basic solution in an organic solvent by adding a suitable inorganic or organic acid to the solution.

[0172] Pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are those acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochlorides, hydrobroms, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleate, gentianate, fumarate, gluconate, glucuronide, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and papoate.

[0173] Examples of salts include, but are not limited to, acetates, acrylates, benzenesulfonates, benzoates (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonates, bisulfates, bisulfites, tartrates, borates, bromides, butyn-1,4-dicitates, calcium edetate, camphorates, carbonates, chlorides, hexanoates, octanoates, clavulanates, citrates, decanoates, dihydrogen phosphates, edetates, edislyates, estolates, esylates, ethylsuccinates, formates, trans-butenedioic acid salts, gluconate, gluconate, glutamates, glycolates, glycolyllarsanilates, heptanoates, hexyn-1,6-dicitates, hexylresorcinol salts, and hypamine. (hydrabamine), hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, hydroxyethanesulfonate, lactate, lactobionate, laurate, malate, maleate, malonate, amygdalinate, methanesulfonate, metaphosphate, methanesulfonate, methyl sulfate, hydrogen phosphate, mucilage, naphthalenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetate, phenylbutyrate, phenylpropionate, phthalate, phosphate / bisphosphonate, polygalacturonate, propionate, propiolate, pyrophosphate, pyrosulfonate, salicylate, stearate, hypoacetate, octanoate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, 8-chlorotheophylline, toluenesulfonate, and valerate.

[0174] Examples of suitable salts include organic salts derived from amino acids (such as glycine and arginine), ammonia, primary amines, secondary amines and tertiary amines and cyclic amines (such as piperidine, morpholine and piperazine), as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0175] The compounds of the present invention, including basic moieties (such as amino groups), can form pharmaceutically acceptable salts with a variety of amino acids other than those described above.

[0176] Alternatively, useful compounds with acidic properties can form basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, and particularly sodium and potassium salts. All of these salts are prepared using conventional techniques. The chemical base used as a reagent to prepare the pharmaceutically acceptable basic salts of the present invention is a chemical base that forms a non-toxic basic salt with the acidic compounds described herein. These salts can be prepared by any suitable method, such as treating the free acid with an inorganic or organic base (e.g., amine (primary, secondary, or tertiary), alkali metal hydroxide, or alkaline earth metal hydroxide, etc.). These salts can also be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation and then evaporating the resulting solution to dryness (preferably under reduced pressure). Alternatively, these salts can also be prepared by mixing a low-carbon alkanol solution of the acidic compound with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as described above. In either case, stoichiometric amounts of reagents are preferably used to ensure complete reaction and the desired final product in maximum yield.

[0177] The chemical base that can be used as a reagent for preparing pharmaceutically acceptable basic salts of the compounds of the present invention having acidic properties is a chemical base that forms a non-toxic basic salt with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts (e.g., N-methylglucosamine (glucamine)) and lower alkanol ammonium salts, and other basic salts of pharmaceutically acceptable organic amines.

[0178] It can also form half-salts of acids and bases, such as half-sulfates and half-calcium salts.

[0179] For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley VCH, 2002). Methods for producing pharmaceutically acceptable salts for the compounds of the present invention are known to those skilled in the art.

[0180] The salts of the present invention can be prepared according to methods known to those skilled in the art. Pharmaceutically acceptable salts of the compounds of the present invention can be readily prepared by mixing the compounds with a solution of a suitable desired acid or base. The salts can be precipitated from the solution and collected by filtration, or recovered by evaporating the solvent. The degree of ionization of the salts can range from fully ionized to almost non-ionized.

[0181] Those skilled in the art will understand that the free base form of the compounds of the present invention, having basic functional groups, can be converted into acid addition salts by treatment with a stoichiometric excess of a suitable acid. The acid addition salts of the compounds of the present invention can be converted back into the corresponding free base by treatment with a stoichiometric excess of a suitable base (such as potassium carbonate or sodium hydroxide) in the presence of a conventional aqueous solvent and at a temperature between about 0°C and 100°C. The free base form can be separated by conventional methods, such as extraction with an organic solvent. Alternatively, the acid addition salts of the compounds of the present invention can be exchanged by utilizing the differential solubility of the salt, the volatility or acidity of the acid, or by treatment with a suitably packed ion exchange resin. For example, the exchange can be achieved by reacting the salt of the compound of the present invention with a slightly stoichiometric excess of an acid (whose pK value is lower than that of the acid component of the starting salt). This conversion is typically carried out at a temperature between about 0°C and the boiling point of the solvent used as the treatment medium. For base addition salts, similar exchange may occur, typically via an intermediate form of the free base.

[0182] The compounds of this invention can exist in both non-solventized and solvated forms. When tightly bound to a solvent or water, the complex has a well-defined stoichiometry independent of humidity. However, when weakly bound to a solvent or water (as in channel solvates and hygroscopic compounds), the water / solvent content depends on humidity and drying conditions. In these examples, non-stoichiometry is used as the standard. The term "solvent" is used herein to describe a molecular complex comprising the compounds of this invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used. Pharmaceutically acceptable solvates according to the invention include hydrates and solvates, wherein the solvent for crystallization may be isotopically substituted, for example, D2O, d6-acetone, d6-DMSO.

[0183] This invention also relates to prodrugs of compounds of the formulas provided herein. Thus, specific derivatives of the compounds of this invention, which have little or no pharmacological activity, can be converted into the compounds of this invention, for example, by hydrolysis, upon administration to a patient. These derivatives are referred to as “prodrugs.” Further information on the use of prodrugs can be found in 'Prodrugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella); Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (edited by EB Roche, American Pharmaceutical Association); Guarino, VR, Stella, VJ: Biotech Pharm. Aspects 2007 5(Pt2) 133-187; and J. Rautio et al., Nature Reviews Drug Discovery, 17, 559-587 (2018), the disclosures of which are incorporated herein by reference in their entirety.

[0184] The prodrugs according to the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with specific portions known to those skilled in the art as “pre-component portions”, as described, for example, in H. Bundgaard, “Design of Prodrugs” (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

[0185] Some non-limiting examples of prodrugs according to the present invention include:

[0186] (i) When a compound contains a carboxylic acid functional group (-COOH), its ester, for example, is replaced by a (C1-C6) alkyl group instead of hydrogen;

[0187] (ii) When the compound contains an alcohol functional group (-OH), its ether, for example, is replaced by a (C1-C6) alkanoyloxymethyl group or a phosphate ether group; and

[0188] (iii) When the compound contains a primary or secondary amino functional group (NH2 or NHR, where R is not H), its amide, for example, is replaced by a suitable metabolically unstable group (such as amide, carbamate, urea, phosphonate, sulfonate, etc.) instead of one or two hydrogens.

[0189] Further examples of substituents based on the foregoing examples and examples of other prodrug types can be found in the foregoing references.

[0190] Finally, a particular compound of the present invention can itself serve as a prodrug for other compounds of the present invention.

[0191] Metabolites of compounds of the formula described herein are also included within the scope of this invention, i.e., compounds formed in vivo after drug administration, often by oxidation or dealkylation. Examples of metabolites according to the invention include, but are not limited to, those mentioned above.

[0192] (i) In the case where the compounds of the present invention contain alkyl groups, their hydroxyalkyl derivatives (-CH>-COH);

[0193] (ii) In the case where the compounds of the present invention contain alkoxy groups, their hydroxyl derivatives (-OR->-OH);

[0194] (iii) When the compounds of the present invention contain a tertiary amino group, their secondary amino derivatives (-NRR'->-NHR or -NHR');

[0195] (iv) When the compounds of the present invention contain a secondary amino group, their primary amine derivatives (-NHR->-NH2);

[0196] (v) In the case where the compounds of the present invention contain a phenyl moiety, their phenolic derivatives (-Ph->-PhOH);

[0197] (vi) When the compounds of the present invention contain an amide group, their carboxylic acid derivatives (-CONH2->COOH); and

[0198] (vii) When a compound contains a hydroxyl or carboxylic acid group, it can undergo conjugated metabolism, for example, by forming glucuronide with glucuronic acid. Other conjugated metabolic pathways exist. These pathways are often referred to as phase II metabolism and include, for example, sulfation or acetylation. Other functional groups (such as NH groups) can also undergo conjugation.

[0199] In one embodiment, this document provides 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione in solid form. In one embodiment, the solid form is crystalline. In one embodiment, the solid form is amorphous.

[0200] As used herein, the term "crystallization" refers to molecules or outer surface planes that have a regular, repeating arrangement. A single compound can result in multiple crystal forms, each with different and distinct solid-state physical properties, such as different solubility distributions, dissolution rates, melting temperatures, fluidity, and / or different X-ray diffraction peaks. These differences in physical properties can affect pharmaceutical parameters such as storage stability, compressibility and density (which can be important in formulation and product manufacturing) and dissolution rate (which can be an important factor in bioavailability).

[0201] The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and exhibits physical properties of a solid or liquid depending on temperature. Such materials typically do not produce unique X-ray diffraction patterns and, while exhibiting solid properties, are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, characterized by a change of state, typically a second-order change ("glass transition").

[0202] Technicians in the field of solid-state chemistry can use many analytical methods to analyze solid forms. Powder X-ray diffraction may also be suitable for quantifying the amount of solid crystalline forms (or multiple crystalline forms) in a mixture. In powder X-ray diffraction, X-rays are directed onto a crystalline powder, and the intensity of the diffracted X-rays is measured as a function of the angle between the X-ray source and the beam diffracted from the sample. The intensities of these diffracted X-rays can be plotted as peaks on a graph, with the x-axis representing the angle between the X-ray source and the diffracted X-rays (called the "2θ" angle), and the y-axis representing the intensity of the diffracted X-rays. This graph is called a powder X-ray diffraction pattern or powder pattern. Different solid crystalline forms exhibit different powder patterns because the peak positions on the x-axis reflect the properties of the solid-state structure of the crystal.

[0203] Those skilled in the art will understand that, in powder diffraction patterns, the typical accuracy of the x-axis 2θ value of a peak is approximately ±0.2°2θ (±0.2°2θ). Therefore, a diffraction peak appearing, for example, at “approximately 18.0°2θ” means that the peak appears at “18.0°±0.2°2θ,” meaning that in most cases, when measured on various X-ray diffractometers, it will likely be between 17.8°2θ and 18.2°2θ. Furthermore, those skilled in the art will understand that relative peak intensities will show variability between instruments and due to crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art, and should be considered only as qualitative measurements. Therefore, the term “substantially identical” as used herein with respect to powder X-ray diffraction peak positions means that the typical variability in peak position and intensity is approximately ±0.2°2θ.

[0204] Powder X-ray diffraction is just one of several analytical techniques that can be used to characterize and / or identify solid crystal forms. Spectroscopic techniques, such as Raman (including micro Raman), infrared, and solid-state NMR spectroscopy, can also be used to characterize and / or identify solid crystal forms. These techniques can also be used to quantify the amount of one or more solid crystal forms in a mixture, and peak values ​​can be reported using the modifier "about" preceding the peak value.

[0205] As used in this article, “anhydrous” refers to a crystal form in which there is no solvent or water molecules in the crystal lattice.

[0206] The term "hydrate" refers to a solvate containing a compound and a stoichiometric or non-stoichiometric amount of water. The term "monohydrate" refers to a hydrate in which each molecule of the compound contains one molecule of water (i.e., a stoichiometric ratio of water to compound of 1:1).

[0207] In one embodiment, the present invention provides crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1.

[0208] In one embodiment, the crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1 is characterized by powder X-ray diffraction (PXRD) (2θ).

[0209] Table X provides a list of PXRD peaks in °2θ (±0.2°2θ) for crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1.

[0210] Table X

[0211]

[0212] In one embodiment, the present invention provides a PXRD pattern of crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1, having characteristic peaks at 5.0, 8.7, 9.3, 10.8, 14.5, 15.3, 18.8, and 20.5°2θ (±0.2°2θ).

[0213] In one embodiment, the present invention provides crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1, the PXRD pattern of which is substantially consistent with... Figure 1 The same 2θ value peak shown.

[0214] In one embodiment, the present invention provides crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2.

[0215] In one embodiment, the crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2 is characterized by powder X-ray diffraction (PXRD) (2θ). In one embodiment, the PXRD analysis of the crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2 was performed at 25°C and a relative humidity below 10%, as described, for example, in Example 77.

[0216] Table Y provides a list of PXRD peaks for crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2, expressed in °2θ (±0.2°2θ).

[0217] Table Y

[0218]

[0219] In one embodiment, the present invention provides crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2, having characteristic peaks at 7.1, 9.4, 12.4, 12.8, 14.3, 15.6, 16.4, 17.4, 18.5, 18.9, 19.5, 19.9, 21.1, 21.4, 23.2, 23.7, 24.8, 25.6, 27.6, 30.3, 33.2, 33.5, and 37.5°2θ (±0.2°2θ).

[0220] In one embodiment, the present invention provides crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2, the PXRD pattern of which is substantially consistent with... Figure 2 The same 2θ value peak shown.

[0221] In one embodiment, the present invention provides the crystalline monohydrate form 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione 3.

[0222] In one embodiment, the crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3 is characterized by powder X-ray diffraction (PXRD) (2θ). In one embodiment, the PXRD analysis of the crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3 was performed at 25°C and a relative humidity greater than 30%.

[0223] Table Z provides a list of PXRD peaks for the crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3, expressed in °2θ (±0.2°2θ).

[0224] Table Z

[0225]

[0226]

[0227] In one embodiment, the present invention provides a PXRD pattern of crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3, having characteristic peaks at 13.7, 18.0, and 18.3°2θ (±0.2°2θ).

[0228] In one embodiment, the present invention provides a PXRD pattern of crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3, having characteristic peaks at 6.9, 9.1, 13.7, 18.0, and 18.3°2θ (±0.2°2θ).

[0229] In one embodiment, the present invention provides a PXRD pattern of the crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3, having characteristic peaks at 6.9, 9.1, 11.8, 12.0, 13.7, 14.0, 15.2, 15.8, 18.0, 18.3, 19.0, 19.3, 20.2, 20.9, 21.6, 22.6, 23.6, 24.0, 24.9, 25.2, 25.8, 27.5, 28.1, 28.4, 29.8, 30.9, 31.7, 32.3, and 36.5°2θ (±0.2°2θ).

[0230] In one embodiment, the present invention provides a crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3, the PXRD pattern of which is substantially consistent with... Figure 3 The same 2θ value peak shown.

[0231] In one embodiment, the present invention provides an amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 4.

[0232] In one embodiment, the amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 4 is characterized by powder X-ray diffraction (PXRD) (2θ).

[0233] In one embodiment, the present invention provides an amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 4, the PXRD pattern of which is substantially consistent with... Figure 4 The same 2θ value peak shown.

[0234] The present invention further provides treatment methods and uses, including administering the compound of the present invention or a pharmaceutically acceptable salt thereof, alone or in combination with other therapeutic agents or palliative agents.

[0235] Compounds of Formula I and II and their pharmaceutically acceptable salts may be used to treat diseases and conditions that can be treated with MEK kinase inhibitors, such as MEK-related diseases and conditions, for example, for treating abnormal cell growth, such as tumors, such as MEK-related tumors. The ability of compounds of Formula I and II and their pharmaceutically acceptable salts to function as MEK inhibitors can be demonstrated by the assay described in Example A. IC 50 The values ​​are displayed in Table A.

[0236] Therefore, in one embodiment, this document provides a method of treating a tumor, comprising administering to an individual in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the tumor is a MEK-associated tumor.

[0237] As used herein, the terms “MEK kinase inhibitor” and “MEK inhibitor” are used interchangeably and refer to compounds that inhibit mitogen-activated protein kinase kinases MEK1 and / or MEK2.

[0238] The terms “MEK-associated” and “MEK-mediated” are used interchangeably and refer to a disease or condition with persistently activated MEK kinase that can be treated with MEK inhibitors. Examples include MEK-associated abnormal cell growth, such as MEK-associated tumors, e.g., MEK-associated cancers. In one embodiment, the term “MEK-associated” refers to a disease or condition with dysregulation of MEK kinase expression or activity, or dysregulation of the BRAF gene or BRAF kinase.

[0239] The phrase “MEK kinase expression or activity dysregulation” refers to gene amplification that leads to MEK protein overexpression, or autocrine activity caused by MEK gene overexpression in cells, which leads to increased pathogenicity of the activity of the kinase domains of MEK protein in cells (e.g., the constitutive activated kinase domain of MEK protein).

[0240] The phrase “BRAF gene or BRAF kinase dysregulation” refers to a gene mutation (e.g., a BRAF gene translocation resulting in fusion protein expression, a BRAF gene deletion resulting in BRAF protein expression including at least one amino acid deletion compared to wild-type BRAF protein, or a BRAF gene mutation resulting in BRAF protein expression with one or more point mutations compared to wild-type BRAF protein). As another example, dysregulation of the expression, activity, or level of the BRAF gene, BRAF protein, or either of them can be a mutation in the BRAF gene encoding the BRAF protein that is constitutively activated or has increased activity compared to a protein encoded by a BRAF gene not containing said mutation. For example, dysregulation of the expression, activity, or level of the BRAF gene, BRAF protein, or either of them can be the result of a gene or chromosomal translocation that results in the expression of a fusion protein containing a first part of BRAF, including a functional kinase domain, and a second part of a companion protein (i.e., not BRAF).

[0241] In one embodiment, the MEK-related disease or condition has an activated BRAF mutation. In one embodiment, the MEK-related disease or condition is MEK-related cancer with an activated BRAF mutation. Non-limiting examples of BRAF mutations include BRAF V600 mutations, such as V600E, V600D, V600K, V600R, and V600S. In one embodiment, the BRAF mutation is a V600E mutation. In one embodiment, the BRAF mutation is a V600K mutation.

[0242] In one implementation, the MEK-related disease or condition is a MEK-related tumor having one or more BRAF fusions that lead to constitutive kinase activation and transformation, including but not limited to KIAA11549-BRAF, MKRN1-BRAF, TRIM24-BRAF, AGAP3-BRAF, ZC3HAV1-BRAF, AKAP9-BRAF, CCDC6-BRAF, AGK-BRAF, EPS15-BRAF, NUP214-BRAF, ARMC10-BRAF, BTF3L4-BRAF, GHR-BRAF, ZC3HAV1-BRAF, and ZNF767. -BRAF, CCDC91-BRAF, DYNC112-BRAF, ZKSCAN1-BRAF, GTF2I-BRAF, MZT1-BRAF, RAD18-BRAF, CUX1-BRAF, SLC12A7-BRAF, MYRIP-BRAF, SND1 -BRAF, NUB1-BRAF, KLHL7-BRAF, TANK-BRAF, RBMS3-BRAF, STRN3-BRAF, STK35-BRAF, ETFA-BRAF, SVOPL-BRAF, JHDM1D-BRAF, or BCAP29-BRAF.

[0243] In one implementation, MEK-related disease or condition is a MEK-related tumor possessing a BRAF fusion protein, wherein the tumor is breast cancer (e.g., invasive ductal carcinoma of the breast), colorectal cancer (e.g., colonic adenocarcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), glioma (e.g., brain desmoplastic infantile ganglion glioma, brain fibrous astrocytoma, brain pleomorphic xanthoastrocytoma, spinal cord low-grade glioma (NOS), primitive oligodendroglioma, anaplastic ganglion glioma), head and neck cancer (e.g., head and neck neuroendocrine carcinoma), lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer). Cellular lung cancer (NOS), melanoma (e.g., Spitzoid cutaneous melanoma, non-Spitzoid mucosal melanoma, Spitzoid cutaneous melanoma, unknown primary melanoma, non-Spitzoid cutaneous melanoma), pancreatic cancer (e.g., adenocarcinoma, pancreatic acinar cell carcinoma), prostate cancer (e.g., prostate acinar adenocarcinoma), sarcoma (malignant solid fibroma), thyroid cancer (papillary thyroid carcinoma), unknown primary cancer (e.g., unknown primary adenocarcinoma), pleural mesothelioma, rectal adenocarcinoma, endometrial cancer (e.g., endometrial adenocarcinoma (NOS)), or ovarian serous carcinoma.

[0244] In one implementation, MEK-related cancers are selected from cancers having the BRAF fusion protein described in Table 1 (JS Ross, et al., Int. J. Cancer: 138, 881-890 (2016)).

[0245] Table 1. Illustrative BRAF fusion companions and cancers

[0246]

[0247]

[0248] In one implementation, MEK-associated tumors are BRAF wild-type tumors.

[0249] The term "wildtype" describes nucleic acids (such as the BRAF gene or BRAF mRNA) that are typically found in individuals who do not have a disease or condition associated with a reference nucleic acid or protein.

[0250] The term "wild-type BRAF" describes the BRAF nucleic acid (e.g., BRAF gene or BRAF mRNA) or BRAF protein found in individuals that do not have an activated BRAF mutation.

[0251] As used herein, “abnormal cell growth” refers to cell growth that is independent of normal regulatory mechanisms (such as loss of contact inhibition) unless otherwise indicated. Abnormal cell growth can be benign (non-cancerous) or malignant (cancerous).

[0252] The term “cancer” or “carcinoma” refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth. Cancer includes primary cancer originating at a specific site in the body, metastatic cancer that spreads from the site of origin to other parts of the body, recurrence of primary cancer after remission, and second primary cancer, which is a new primary cancer in a patient with a history of prior cancer that is a different type from the second primary cancer. Cancer includes solid tumors, blood cancers, bone marrow cancers, or lymphatic cancers named after the type of cells that form them. Solid tumors are abnormal growths or masses of tissue that typically do not contain cysts or fluid-filled areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemia (blood cancers) typically does not constitute a solid tumor (National Cancer Institute, Dictionary of Cancer Terms).

[0253] As used herein, the terms “treat” or “treatment” refer to therapeutic or austerity measures. Beneficial or desirable clinical outcomes include, but are not limited to, complete or partial relief of symptoms associated with the disease or disorder or condition, reduction of the severity of the disease, stabilization (i.e., non-deterioration) of the disease, delay or slowing of disease progression, improvement or relief (whether partial or complete) of the disease state (e.g., one or more symptoms of the disease), whether detectable or undetectable.

[0254] As used herein, “treat” or “treating” in cancer means the administration of the compounds of this invention to an individual who has cancer or has been diagnosed with cancer to achieve at least one positive therapeutic effect, such as reducing the number of cancer cells, shrinking tumor size, reducing the rate of cancer cell invasion into peripheral organs, or reducing the rate of tumor metastasis or tumor growth, reversing, alleviating, or inhibiting the progression of the condition or disease to which this term applies, or one or more symptoms of such condition or disease. As used herein, the term “treatment” refers to the act of treatment as defined above, unless otherwise indicated. The term “treating” also includes adjuvant and neoadjuvant therapy for an individual.

[0255] For the purposes of this invention, beneficial or desirable clinical outcomes include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of sarcomas or cancer cells; inhibiting metastatic or sarcoma cells; shrinking or reducing tumor size; increasing an individual's remission period (e.g., compared to one or more measures of an individual with similar cancer who has not received treatment or has received different treatments, or compared to one or more measures of the same individual before treatment); reducing cancer-related symptoms; improving the quality of life of those with cancer; reducing the dosage of other agents required to treat cancer; delaying cancer progression; curing cancer; overcoming one or more cancer resistance mechanisms; and / or prolonging the survival of cancer patients. The effectiveness of cancer treatment can be measured in many ways (see, for example, W.A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Suppl. 1: 1S-10S (2009). For example, regarding tumor growth inhibition (T / C), according to the National Cancer Institute (NCI) criteria, a T / C of less than or equal to 42% is the lowest level of antitumor activity. A T / C <10% is considered a high level of antitumor activity, where T / C (%) = median tumor volume treated / median tumor volume in the control group x 100.

[0256] In one embodiment, treatment achieved by administration of the compounds of the present invention is defined with reference to any of the following: partial response (PR), complete response (CR), overall response (OR), progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). PFS, also known as "time to tumor progression," indicates the length of time during and after treatment without cancer growth, and includes the amount of time a patient experiences CR or PR, and the amount of time a patient experiences stable disease (SD). DFS refers to the length of time a patient remains disease-free during and after treatment. OS refers to the extension of life expectancy compared to a naive or untreated individual or patient. In one embodiment, a response to treatment with the compounds of the present invention is any one of PR, CR, OR, PFS, DFS, or OS, assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria.

[0257] Treatment regimens of the compounds of the present invention, which are effective in treating cancer patients, can be modified based on factors such as the patient's disease state, age, weight, and the therapeutic capacity to elicit an anticancer response in an individual. While embodiments of any aspect of the invention may not effectively achieve a positive therapeutic effect in every individual, they should be achieved in a statistically significant number of individuals, as determined by any statistical test known in the art, such as Student's t-test, chi2 test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstrat test, and Wilcon on-test.

[0258] The terms “treatment regimen,” “dosing plan,” and “dosing schedule” are used interchangeably and refer to the dosage and timing of the administration of the compounds of the present invention, alone or in combination with another therapeutic agent.

[0259] "Improvement" means that, after treatment with the combination described herein, one or more symptoms are reduced or improved compared to when the combination was not used. "Improvement" also includes shortening or reducing the duration of symptoms.

[0260] As used herein, the term "individual" means any animal, including mammals such as humans. In one embodiment, the individual has experienced and / or exhibits at least one symptom of a disease or condition for which treatment and / or prevention are desired. In one embodiment, the individual has been identified or diagnosed with a MEK-related tumor (e.g., as determined using a regulatory authority-approved assay or kit). In one embodiment, the individual has a MEK-related tumor that is positive for a BRAF mutation (e.g., as determined using a regulatory authority-approved assay or kit). The individual may be an individual whose tumor has a MEK mutation (e.g., where the tumor was identified using a regulatory authority-approved assay or kit). In one embodiment, the individual is suspected of having a MEK-related tumor. In one embodiment, the individual has a clinical record indicating that the individual has a MEK-related tumor with a BRAF mutation (and optionally, the clinical record indicates that the individual should be treated with any of the compositions provided herein). In one embodiment, the individual is a human. In one embodiment, the human individual is a pediatric individual.

[0261] As used herein, the term “pediatric individual” refers to an individual under 21 years of age at the time of diagnosis or treatment. The term “pediatric” can be further subdivided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to a maximum of two years); children (2 years to a maximum of 12 years); and adolescents (12 to 21 years (until, but not including, their 22nd birthday)). (References: Berhman RE, Kliegman R, Arvin AM, Nelson WE, Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WBSaunders Company, 1996; Rudolph AM et al., Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.) In one implementation plan, the pediatric individual system includes the period from birth to the first 28 days of life, from 29 days to less than two years, from two years to less than 12 years, or from 12 years to 21 years (up to but not including the 22nd birthday). In another implementation plan, the pediatric individual system includes the period from birth to the first 28 days of life, from 29 days to less than 1 year, from one month to less than four months, from three months to less than seven months, from six months to less than 1 year, from 1 year to less than 2 years, from 2 years to less than 3 years, from 2 years to less than 7 years, from 3 years to less than 5 years, from 5 years to less than 10 years, from 6 years to less than 13 years, from 10 years to less than 15 years, or from 15 years to less than 22 years.

[0262] In one embodiment, this document provides a method of treating a tumor, the method comprising administering to an individual in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the tumor is a MEK-associated tumor. In one embodiment, the MEK-associated tumor has a BRAF mutation. In one embodiment, the BRAF mutation is V600E and / or V600K and / or V600D and / or V600R and / or V600S. In one embodiment, the BRAF mutation is V600E. In one embodiment, the BRAF mutation is V600K. In one embodiment, the MEK-associated tumor has a BRAF fusion, such as the BRAF fusion disclosed herein. In one embodiment, the MEK-associated tumor is a BRAF wild-type tumor.

[0263] In any embodiment of the methods of use described herein, the tumor is a solid tumor. In any embodiment of the methods disclosed herein, the solid tumor is a MEK-related tumor. In one embodiment, the tumor is intracranial. In one embodiment, the tumor is extracranial. In any embodiment of the methods of use described herein, the tumor (e.g., a MEK-related tumor) is a malignant tumor (i.e., cancer), such as MEK-related cancer. In any embodiment of the methods of use described herein, MEK-related cancers include melanoma, colon cancer, colorectal cancer, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid carcinoma, recurrent thyroid carcinoma, or refractory differentiated thyroid carcinoma), breast cancer, ovarian cancer, CNS cancer, bone cancer, anal cancer, anal canal cancer or anorectal cancer, eye cancer, bile duct cancer, ductal carcinoma in situ, liver cancer, gallbladder cancer or pleural cancer, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, nasal cancer, nasal cavity cancer or middle ear cancer, vulvar cancer, esophageal cancer, cervical cancer, and gastrointestinal carcinoid tumors. Cancers that can cause hypopharyngeal cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, melanoma, nasopharyngeal cancer, peripheral nervous system cancers (such as neuroblastoma), ovarian cancer, pancreatic cancer, peritoneal cancer, omental cancer and mesenteric cancer, pharyngeal cancer, prostate cancer, kidney cancer (such as renal cell carcinoma (RCC)), small bowel cancer, soft tissue sarcoma, gastric cancer, testicular cancer, uterine cancer, ureteral cancer or urethral bladder cancer.

[0264] In one embodiment of any of the methods of use described herein, the MEK-related cancer is an extracranial cancer (i.e., an extracranial tumor). In one embodiment, the extracranial cancer is selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, and neuroblastoma. In one embodiment, the MEK-related cancer is melanoma. In one embodiment, the MEK-related cancer is colorectal cancer. In one embodiment, the MEK-related cancer is thyroid cancer. In one embodiment, the MEK-related cancer is non-small cell lung cancer. In one embodiment, the MEK-related cancer is ovarian cancer. In one embodiment, the MEK-related cancer is neuroblastoma.

[0265] In any embodiment of the methods of use described herein, MEK-related cancer is CNS cancer.

[0266] In any implementation of the methods of use described herein, MEK-related cancer is intracranial cancer (brain cancer).

[0267] In any embodiment of the methods of use described herein, the cancer is metastatic cancer.

[0268] The term "metastasis" is a term known in the art, referring to the spread of cancer cells from their initial site of formation (primary site) to one or more other sites in an individual (one or more secondary sites). In metastasis, cancer cells escape from the original (primary) tumor, travel through the blood or lymphatic system, and form new tumors (metastatic tumors) in other organs or tissues of the body. New metastatic tumors include cancer cells that are the same as or similar to the primary tumor. At secondary sites, tumor cells may proliferate and begin to grow or colonize at this distant site, forming a secondary tumor.

[0269] As used in this article, "metastatic cancer" (also known as "secondary cancer") refers to a type of cancer that originates in one tissue type but then spreads to one or more tissues outside the (primary) cancer origin. Metastatic brain cancer refers to cancer within the brain, that is, cancer that originated in tissues outside the brain and has metastasized to the brain.

[0270] In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof and the compound of Formula II or a pharmaceutically acceptable salt thereof exhibit remarkable brain and / or CNS penetration. These compounds are able to cross the BBB and inhibit MEK kinases in the brain and / or other CNS structures. Therefore, in one embodiment, the compounds provided herein can be used to treat CNS tumors, such as CNS cancer.

[0271] In one embodiment, the MEK-related tumor is a malignant CNS tumor (i.e., MEK-related CNS carcinoma). In one embodiment, the MEK-related CNS carcinoma has a BRAF mutation. In one embodiment, the MEK-related CNS carcinoma has a BRAF V600 mutation. In one embodiment, the BRAF mutation is V600E and / or V600K and / or V600D and / or V600R and / or V600S. In one embodiment, the MEK-related CNS carcinoma has a BRAF V600E mutation. In one embodiment, the MEK-related CNS carcinoma has a BRAF V600K mutation. In one embodiment, the MEK-related tumor has a BRAF fusion. In one embodiment, the MEK-related tumor is a BRAF wild-type tumor.

[0272] As used interchangeably in this document, “CNS cancer” or “cancer of the CNS” refers to cancer of the CNS (i.e., malignant tumors), including brain cancer (also known as intracranial tumors), spinal cord cancer, and cancer of the meninges surrounding the brain and spinal cord. Brain cancer includes metastatic brain cancer (i.e., metastatic intracranial cancer) and malignant primary brain tumors.

[0273] In one embodiment, MEK-related CNS carcinoma is MEK-related metastatic brain cancer. MEK-related metastatic brain cancer can be the result of any cancer described herein, wherein the individual has developed at least one brain metastasis. In one embodiment, the metastatic brain cancer is melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, or neuroblastoma. In one embodiment, MEK-related metastatic brain cancer is metastatic melanoma, metastatic colorectal cancer, or metastatic non-small cell lung cancer. In one embodiment, MEK-related metastatic brain cancer is metastatic melanoma. In one embodiment, MEK-related metastatic brain cancer is metastatic colorectal cancer. In one embodiment, MEK-related metastatic brain cancer is metastatic non-small cell lung cancer. In one embodiment, MEK-related metastatic brain cancer is metastatic ovarian cancer. In one embodiment, metastatic brain cancer is metastatic thyroid cancer. In one embodiment, MEK-related metastatic brain cancer is renal cancer. In one embodiment, the cancer is MEK-related metastatic cancer (i.e., metastatic brain cancer) with at least one brain metastasis. In one embodiment, the cancer is MEK-related metastatic melanoma with at least one brain metastasis. In one embodiment, the cancer is MEK-related metastatic colorectal cancer with at least one brain metastasis. In one embodiment, the cancer is MEK-related metastatic non-small cell lung cancer with at least one brain metastasis. In one embodiment, the cancer is MEK-related metastatic ovarian cancer with at least one brain metastasis. In one embodiment, the cancer is MEK-related metastatic thyroid cancer with at least one brain metastasis. In one embodiment, the cancer is MEK-related neuroblastoma with at least one brain metastasis. In one embodiment of any of these MEK-related metastatic brain cancers, the cancer has a BRAF mutation. In one embodiment, the cancer has a BRAF V600 mutation. In one embodiment, the BRAF mutation is V600E and / or V600K and / or V600D and / or V600R and / or V600S. In one embodiment, the cancer has a BRAF V600E mutation. In one embodiment, the cancer has a BRAF V600K mutation. In one embodiment, the MEK-related tumor has a BRAF fusion. In one embodiment, the MEK-related tumor is a BRAF wild-type tumor.

[0274] In one implementation, MEK-related cancer is leptomeningeal metastatic carcinoma (leptomeningeal disease (LMD)). LMD refers to a subset of CNS metastases that grow in the inner lining of the brain or spinal cord and / or cerebrospinal fluid (CSF), or in the spread of leptomeningeal cancer. In mammals, the meninges are the dura mater, arachnoid mater, and pia mater. The CFS is the subarachnoid space located between the arachnoid mater and the pia mater. The arachnoid mater and pia mater are sometimes referred to together as the leptomeninges. When LMD occurs in the pia mater and / or CSF surrounding the spinal cord, it may be called “extracranial LMD.” When LMD occurs in the pia mater and / or CSF of the brain, it may be called “intracranial LMD.” Because LMD cancer cells can be suspended in the CSF, they can spread rapidly throughout the CNS. Therefore, LMD has a poor prognosis, with a survival of several months. In one implementation, the metastatic cancer is LMD. In one implementation, the metastatic cancer is MEK-related LMD. In one implementation, the metastatic cancer is MEK-related intracranial LMD. In one embodiment, the metastatic cancer is a MEK-associated extracranial LMD. In one embodiment, the MEK-associated LMD is an LMD derived from melanoma metastasis (i.e., the LMD is metastatic melanoma). In one embodiment, the MEK-associated LMD is an LMD derived from colorectal cancer metastasis (i.e., the LMD is metastatic colorectal cancer). In one embodiment, the MEK-associated LMD is an LMD derived from non-small cell lung cancer metastasis (i.e., the LMD is metastatic non-small cell lung cancer). In one embodiment of any of the MEK-associated LMDs, the LMD has a BRAF mutation. In one embodiment, the MEK-associated LMD has a BRAF V600 mutation. In one embodiment, the BRAF mutation is V600E and / or V600K and / or V600D and / or V600R and / or V600S. In one embodiment, the MEK-associated LMD has a BRAF V600E mutation. In one embodiment, the MEK-associated LMD has a BRAF V600K mutation. In one embodiment, the MEK-associated LMD has a BRAF fusion. In one implementation, MEK-associated LMD is a BRAF wild-type tumor.

[0275] In one embodiment, MEK-related tumors are cancers with a high risk of metastasis. In one embodiment, cancers with a high risk of metastasis are cancers with BRAF V600E, V600D, V600K, V600R, and / or V600S mutations. In one embodiment, cancers with a high risk of metastasis have BRAF fusions, such as any of the BRAF fusions disclosed herein. In one embodiment, cancers with a high risk of metastasis are BRAF wild-type tumors. In one embodiment, cancers with a high risk of metastasis are melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, or neuroblastoma. In one embodiment, cancers with a high risk of metastasis are melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, or neuroblastoma. In one embodiment, cancers with a high risk of metastasis are melanoma. In one embodiment, cancers with a high risk of metastasis are melanomas with BRAF V600E or BRAF V600K mutations. In one embodiment, cancers with a high risk of metastasis are colorectal cancer. In one embodiment, the cancer with a high risk of metastasis is colorectal cancer with a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the cancer with a high risk of metastasis is thyroid cancer. In one embodiment, the cancer with a high risk of metastasis is thyroid cancer with a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the cancer with a high risk of metastasis is non-small cell lung cancer. In one embodiment, the cancer with a high risk of metastasis is non-small cell lung cancer with a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the cancer with a high risk of metastasis is ovarian cancer. In one embodiment, the cancer with a high risk of metastasis is ovarian cancer with a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the cancer with a high risk of metastasis is neuroblastoma. In one embodiment, the cancer with a high risk of metastasis is neuroblastoma with a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the cancer with a high risk of metastasis has a KIAA11549-BRAF fusion.

[0276] In one implementation, a CNS tumor is a primary brain tumor. Primary brain tumors are tumors that originate in the brain or spinal cord and are collectively referred to as gliomas. The term "glioma" is used to describe a tumor originating from glial cells present in the CNS. According to the WHO classification of brain tumors, gliomas are graded based on cellular activity and aggressiveness, with grades including Grade I (benign CNS tumors) and Grades II through IV (malignant CNS tumors):

[0277] Grade I gliomas (fibrous astrocytomas): These typically occur in the cerebellum or brainstem of children and occasionally in the cerebral hemispheres, and are slow-growing. Grade I can also occur in adults. Although they are benign (WHO Grade I), the difficulty in curing this disease makes its growth behavior malignant, resulting in a high incidence (Rostami, Acta Neurochir (Wien), 2017; 159(11):2217-2221).

[0278] Grade II gliomas (low-grade gliomas): These include astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. Grade II gliomas typically occur in young adults (20 to 50 years of age) and are most commonly found in the cerebral hemispheres. Due to the invasive nature of these tumors, recurrence is possible. Some Grade II gliomas recur and evolve into more aggressive tumors (Grade III or IV).

[0279] Grade III gliomas (malignant gliomas): These include glioblastoma multiforme, primitive oligodendroglioma, and anaplastic mixed oligodendroastrocytoma. Grade III tumors are aggressive, high-grade carcinomas that invade nearby brain tissue with tentacle-like projections, making complete surgical removal more difficult.

[0280] Grade IV gliomas include glioblastoma multiforme (GBM) and gliosarcoma; GBM is a malignant glioma. GBM is the most aggressive and most common primary brain tumor. Glioblastoma multiforme usually spreads rapidly and invades other parts of the brain, with tentacle-like projections, making complete surgical resection more difficult. Gliosarcoma is a malignant carcinoma and is defined as a glioblastoma composed of glial and sarcomatous components.

[0281] In one embodiment, the primary brain tumor is a glioma. In one embodiment, the glioma is a low-grade glioma. In one embodiment, the glioma is a pediatric low-grade glioma.

[0282] In one implementation, the primary brain tumor is a benign primary brain tumor. Benign primary brain tumors can cause severe pain, permanent brain damage, and death, and in some cases become malignant. Non-limiting examples of benign primary brain tumors include grade I gliomas, papillary craniopharyngiomas, meningiomas (including rhabdoid meningiomas), atypical teratomas / rhabdoid tumors, dysembryoplastic neuroepithelial tumors (DNTs), fibrous astrocytomas, oligodendrogliomas, mixed oligodendrogliomas, glioblastomas multiforme, primitive oligodendrogliomas, anaplastic mixed oligodendrogliomas, diffuse astrocytomas, ependymomas, pleomorphic xanthoastrocytomas (PXA), ganglion gliomas, gliosarcomas, or anaplastic gangliogliomas.

[0283] In one embodiment, the cancer is a peripheral nervous system cancer. In another embodiment, the peripheral nervous system cancer is a neuroblastoma.

[0284] In one embodiment, this document provides a method of treating MEK-associated CNS tumors, comprising administering (e.g., orally) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, to an individual in need. In one embodiment, the MEK-associated CNS tumor has a BRAF V600 mutation. In one embodiment, the MEK-associated CNS tumor has BRAF V600E and / or V600K and / or V600D and / or V600R mutations and / or V600S. In one embodiment, the MEK-associated CNS tumor has a BRAF V600E mutation. In one embodiment, the MEK-associated CNS tumor has a BRAF V600K mutation. In one embodiment, the MEK-associated CNS tumor has a BRAF fusion, such as any of the BRAF fusions disclosed herein, for example, the KIAA11549-BRAF fusion. In one embodiment, the MEK-associated CNS tumor is a BRAF wild-type tumor. In one embodiment, an individual has been treated with one or more independent anticancer therapies selected from anticancer agents, surgery, and radiotherapy prior to administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, as described below. In one embodiment, a system is treated with a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, in combination with one or more independent anticancer therapies selected from one or more anticancer agents, surgery, and / or radiotherapy, as described below. In one embodiment, an individual is treated with one or more independent anticancer therapies selected from anticancer agents, surgery, and radiotherapy after administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, as described below. In one embodiment, the MEK-related tumor is a CNS tumor. In one embodiment, the MEK-related CNS tumor is a malignant CNS tumor (i.e., CNS carcinoma). In one embodiment, the malignant CNS tumor is metastatic CNS carcinoma. In one embodiment, the metastatic CNS cancer is selected from metastatic melanoma, metastatic colorectal cancer, metastatic non-small cell lung cancer, metastatic thyroid cancer, and metastatic ovarian cancer. In one embodiment, the metastatic CNS cancer is metastatic melanoma. In one embodiment, the metastatic CNS cancer is colorectal cancer. In one embodiment, the metastatic CNS cancer is metastatic non-small cell lung cancer. In one embodiment, the metastatic CNS cancer is metastatic thyroid cancer. In one embodiment, the metastatic CNS cancer is metastatic ovarian cancer. In one embodiment, MEK-associated CNS cancer is LMD. In one embodiment, the LMD is intracranial. In one embodiment, the LMD is extracranial. In one embodiment, the LMD is metastatic melanoma.In one embodiment, LMD is selected from metastatic melanoma, metastatic colorectal cancer, and metastatic non-small cell lung cancer. In one embodiment, LMD is metastatic colorectal cancer. In one embodiment, LMD is metastatic non-small cell lung cancer. In one embodiment, MEK-related CNS carcinoma is a primary brain tumor. In one embodiment, the primary brain tumor is a grade 2 glioma. In one embodiment, the primary brain tumor is a grade 3 glioma. In one embodiment, the primary brain tumor is a grade 4 glioma. In one embodiment, MEK-related CNS tumor is a benign tumor. In one embodiment, the benign CNS tumor is a mastoid craniopharyngioma, meningioma (including rhabdoid meningioma), atypical teratoma / rhabdoid tumor, or dysembryonic neuroepithelial tumor (DNT). In one embodiment, the compound is a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is selected from the compounds of Examples 1 to 69 or pharmaceutically acceptable salts thereof.

[0285] The ability of a compound to be suitable for the treatment of CNS cancer can be determined, for example, by identifying whether the compound is a substrate for efflux transport proteins and / or by measuring cell permeability and / or by measuring the ratio of free blood to free plasma, as described herein.

[0286] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof and the compound of formula II or a pharmaceutically acceptable salt thereof exhibit high cell permeability. The method for determining the permeability of the compounds of the present invention can be determined according to Example B, and the permeability coefficients are provided in Table B1.

[0287] The compounds of this invention exhibit low efflux rates. In vitro methods for assessing whether the compounds of this invention are substrates of the efflux transporter P-glycoprotein (P-gp or multidrug resistance 1 (MDR1) protein) and breast cancer resistance protein (BCRP) are described in Example B, and the efflux rates of the compounds of this invention are provided in Table B3.

[0288] In one embodiment, the compounds of the present invention exhibit a medium to high brain (unbound) / plasma (unbound) ratio (i.e., a medium to high free brain / plasma ratio). The ability of the compounds of the present invention to penetrate the BBB of an individual (e.g., a human) can be determined in a suitable animal model (e.g., a rodent, such as a mouse). For example, the ability of a particular compound to penetrate the BBB of a mouse is determined by assessing the ratio of unbound brain to unbound plasma concentration (free B / P) in the mouse, as described in Example C, and the free brain to free plasma ratio is provided in Table C2. Calculating the free brain to free plasma ratio of the compound can predict the effective concentration required to achieve therapeutic efficacy in the periphery and brain based on dose-related exposure in an animal model. These distribution data, together with associated pharmacokinetic data, can be used to model and predict the dose required to achieve therapeutic efficacy in human patients.

[0289] Therefore, in one embodiment, the method of the present invention includes a method for treating MEK-related CNS cancer in an individual with this need, comprising administering a Formula II compound or a pharmaceutically acceptable salt, wherein at least a portion of the Formula II compound penetrates the BBB, as demonstrated in suitable animal models. In one embodiment, the brain / plasma ratio of the total drug is at least about 0.3 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 0.35 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 0.4 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 0.45 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 0.5 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 0.55 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 0.6 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.65 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.7 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.75 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.8 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.85 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.9 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 0.95 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.0 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.0 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.1 after administration (e.g., oral or intravenous). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.2 after administration (e.g., oral or intravenous).In one embodiment, the brain / plasma ratio of the total drug is at least about 1.3 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 1.4 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 1.5 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 1.6 after administration (e.g., oral or intravenous) to the individual. In one embodiment, the brain / plasma ratio of the total drug is at least about 1.7 after administration (e.g., oral or intravenous) to the individual. It should be noted that the percentage of compounds penetrating the BBB is based on the area under the concentration-time curve (AUC) in the brain relative to plasma over a given time period. 0-t The percentage is used to calculate the concentration ratio. Therefore, the percentage represents the concentration ratio. That is, if the compound's (AUC) 0-24h If the concentration in the brain is 20 ng / mL and in plasma is 80 ng / mL, then the percentage of the compound that penetrates the BBB is 20% (20 ng / mL in the brain divided by the total concentration of (20 ng / mL + 80 ng / mL)) (i.e., the brain to plasma ratio is 0.20). In one embodiment, the percentage is based on the area under the concentration-time curve from t = 0 (dose administration) to the last quantifiable concentration point, i.e., (AUC). 0-最后 ) to calculate.

[0290] Cancers that frequently metastasize to the brain are known to carry alterations in the activation of the MAPK pathway, such as BRAF mutations (including the BRAF mutations revealed in this paper) or BRAF fusions (including the BRAF fusions revealed in this paper). Although the activating mutations can occur to varying degrees in the typical pathway, all of these mutations require mitogen / extracellular signal-regulated kinase (MEK) signaling to increase proliferation and survival (Schubbert S, Shannon K, Bollag G., Nat RevCancer. 2007; 7:295-308). Mutations in the BRAF gene have been identified in malignant melanoma, papillary thyroid carcinoma, colorectal cancer, non-small cell lung cancer (NSCLC), and ovarian cancer and their metastatic tumors, as well as in primary brain tumors (Davies H. et al., Nature 417(6892):949-954, 2002). For example, BRAF mutations (such as BRAF V600 mutations) have been observed in many metastatic CNS tumors, including brain metastases from melanoma (Flaherty KT et al., Nat RevCancer (2012) 12(5):349-61), brain metastases from colorectal cancer and non-small cell lung cancer (Berghoff, AS, Preusser M., Curr Opin Neurol (2014) 27(6):689-696), papillary thyroid carcinoma (Kim, WW et al., J Otolaryngol Head Neck Surg. 2018; 47:4,1-6) and ovarian cancer (Grisham RN et al., Cancer, 2013; 119:548-554).

[0291] BRAF mutations (e.g., the BRAF mutations revealed in this paper) and BRAF fusions (e.g., the BRAF fusions revealed in this paper) have also been observed in malignant primary brain tumors in pediatric and adult populations, including grade IV gliomas such as glioblastoma and gliosarcoma, glioblastoma multiforme (high-grade tumors) and WHO grade III anaplastic ganglioglioma (Berghoff, AS, Preusser M., Curr Opin Neurol (2014) 27(6):689-696); Schindler et al. (Acta Neuropathol 121(3):397-405, 2011); Behling et al. (Diagn Pathol 11(1):55, 2016); KCSchreck et al. Cancers, 2019, 11, 1262).

[0292] BRAF mutations (e.g., the BRAF mutations revealed in this paper) and BRAF fusions (e.g., the BRAF fusions revealed in this paper) have also been observed in benign primary brain tumors in pediatric and adult populations, such as in WHO grade II astrocytoma, WHO grade II pleomorphic xanthoastrocytoma (PXA), pleomorphic xanthoastrocytoma with degeneration, fibrous astrocytoma (PA), mastoid craniopharyngioma, ganglioglioma, astroblastoma, fibrous astrocytoma, atypical teratoma / rhabdoid tumor, and rhabdoid meningioma (Berghoff, AS, Preusser M. CurrOpin Neurol (2014) 27(6):689-696; Schindler et al. (Acta Neuropathol 121(3):397-405, 2011); Behling et al. (Diagn Pathol) 11(1):55,2016); (Behling et al., Diagn Pathol 11(1):55,2016; Brastianos et al., Nat Genet 46(2):161-165,2014; Dougherty et al., NeuroOncol 12(7):621-630,2010; Lehman et al., Neuro Oncol 19(1):31-42,2017; Mordechai et al., Pediatr Hematol Oncol 32(3):207-211,2015; Myung et al., Transl Oncol 5(6):430-436,2012; Schindler et al., Acta Neuropathol 121(3):397-405,2011)).

[0293] BRAF mutations have also been detected in recurrent neuroblastoma (Eleveld, TF et al., Nat Genet 47(8):864-871, 2015). Neuroblastoma is a pediatric tumor of the peripheral nervous system. Most individuals with neuroblastoma initially respond to chemotherapy, but a large proportion experience treatment-resistant relapse.

[0294] Therefore, this document also provides a method for treating an individual diagnosed or identified with MEK-related tumors (such as any of the exemplary MEK-related tumors disclosed herein), comprising administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, wherein the individual has been identified or diagnosed with a BRAF mutation having a BRAF fusion, for example by using a regulatory agency-approved (e.g., FDA-approved) test or assay to identify the BRAF mutation or fusion in the individual or a biopsy sample from the individual, or by performing any of the non-limiting examples of the assays described herein. In one embodiment, the test or assay is provided in the form of a kit. In one embodiment, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, or PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). In one embodiment, the assay is a regulatory agency-approved assay, such as an FDA-approved kit.

[0295] In one implementation, the biopsy is a tumor biopsy (e.g., a tumor sample obtained during conventional surgery or stereotactic biopsy, such as a stereotactic biopsy guided by CT or MRI scans). Tissue biopsy methods can be used to detect total tumor burden and / or BRAF mutations and / or BRAF fusions.

[0296] In one implementation, BRAF mutations or fusions can be identified using liquid biopsy (differently referred to as fluid biopsy or fluid-phase biopsy). See, for example, Karachialiou et al., “Real-time liquid biopsies become areality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or BRAF mutations. Liquid biopsy can be performed on biological samples that are relatively readily available from the individual (e.g., via a simple blood draw) and is generally less invasive than conventional methods used to detect tumor burden and / or BRAF mutations. In one implementation, liquid biopsy can be used to detect the presence of BRAF mutations at an earlier stage than conventional methods. In one implementation, biological samples used for liquid biopsy may include CSF, blood, plasma, urine, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cystic fluid, feces, ascites, and combinations thereof. In one implementation, liquid biopsy can be used to detect circulating tumor cells (CTCs). In one implementation, liquid biopsy can be used to detect cell-free DNA. In one implementation, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to detect and identify BRAF mutations or BRAF fusions.

[0297] In one embodiment, the BRAF mutation or BRAF fusion identified using liquid biopsy is also present in cancer cells, the cancer cell line present in the individual (e.g., in a tumor). In one embodiment, either the BRAF mutation or fusion type can be detected using liquid biopsy. In one embodiment, the gene mutation identified via liquid biopsy can be used to identify individuals as candidates for a specific treatment.

[0298] Also known as "tumor burden," tumor burden refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor throughout the body (including lymph nodes and bone marrow). Tumor burden can be measured by a variety of methods known in the art, such as by measuring tumor size after removal from an individual, for example using a diaphragm, or by using imaging techniques in vivo, such as magnetic resonance imaging (MRI), computed tomography (CT), multidetector CT (MDCT), positron emission tomography (PET), X-ray, ultrasound, or bone scan.

[0299] The term "tumor size" refers to the total size of a tumor, which can be measured in terms of both length and width. Tumor size can be determined by a variety of methods known in the art, such as by measuring the size of the tumor after it has been removed from an individual, for example using a diaphragm, or by using imaging techniques in vivo, such as MRI scans, bone scans, ultrasound, or CT.

[0300] Following treatment administration to an individual, liquid biopsies can be performed at multiple time points during the diagnostic, monitoring, and / or treatment processes to determine one or more clinically relevant parameters, including but not limited to disease progression or treatment efficacy. For example, a first liquid biopsy may be performed at a first time point during the diagnostic, monitoring, and / or treatment processes, and a second liquid biopsy may be performed at a second time point during those processes. In one embodiment, the first time point may be before the individual is diagnosed with a disease (e.g., when the individual is healthy), and the second time point may be after the individual has developed a disease (e.g., the second time point can be used to diagnose an individual with a disease). In one embodiment, the first time point may be before the individual is diagnosed with a disease (e.g., when the individual is healthy), after which the individual is monitored, and the second time point may be after the individual has been monitored. In one embodiment, the first time point may be after the individual is diagnosed with a disease, after which treatment is administered to the individual, and the second time point may be after the treatment is administered; in such cases, the second time point can be used to assess treatment efficacy (e.g., if the abundance of a gene mutation detected at the first time point is reduced or undetectable).

[0301] Compound of Formula I or a pharmaceutically acceptable salt thereof, or compound of Formula II or a pharmaceutically acceptable salt thereof, may be used alone or in combination with one or more different forms of treatment to treat individuals with abnormal cell growth, such as MEK-associated tumors, e.g., MEK-associated cancer.

[0302] In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, may be used in combination with one or more additional anticancer therapies, such as one or more treatments independently selected from surgery, radiotherapy, and anticancer agents acting with the same or different mechanisms of action. In one embodiment, treatment of an individual with MEK-related cancer in combination with an additional treatment of one or more, such as one or more, independently selected from surgery, radiotherapy, and anticancer agents (e.g., any of the anticancer agents described below, wherein the anticancer agent is different from a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof), may have increased therapeutic efficacy compared to treatment of the same or similar individuals with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, as a monotherapy. When using combination therapy, and one or more, such as one, two, or three, anticancer therapies independently selected from one or more anticancer agents, such as any of the anticancer agents disclosed herein, the anticancer agents may be administered simultaneously with the compounds of the present invention, or separately at variable intervals and in any order and using different dosing regimens. In one embodiment, the anticancer agent is administered to the individual prior to the administration of the compounds of the present invention. In another embodiment, the anticancer agent is administered to the individual after the administration of the compounds of the present invention. In yet another embodiment, the anticancer agent is administered to the individual concurrently with the administration of the compounds of the present invention. In one embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, is used in combination with an additional anticancer therapy, which is surgery, radiation therapy, or an anticancer agent acting with the same or different mechanisms of action.

[0303] Therefore, in one embodiment, this document provides a method for treating an individual with a MEK-related tumor (such as any of the MEK-related tumors described herein), comprising administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and one or more additional anticancer therapies. In one embodiment, the anticancer therapy is one or more anticancer agents different from a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the anticancer therapy is an anticancer agent different from a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the additional anticancer therapy is surgery. In one embodiment, the additional anticancer therapy is radiation therapy.

[0304] This document also provides for use in combination with one or more, such as one or more anticancer therapies, a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the additional anticancer therapy is independently selected from one or more treatments independently selected from surgery, radiotherapy, and / or one or more anticancer agents acting with the same or different mechanisms of action.

[0305] This document also provides for use in combination with one or more of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, for example, one or more anticancer therapies. In one embodiment, the additional anticancer therapy is independently selected from one or more treatment methods independently selected from surgery, radiotherapy, and / or one or more anticancer agents acting with the same or different mechanisms of action.

[0306] This article also provides for the use of Formula I compounds or pharmaceutically acceptable salts thereof, or Formula II compounds or pharmaceutically acceptable salts thereof, in combination with one or more, such as one or more additional anticancer therapies, for the treatment of MEK-related tumors.

[0307] This article also provides for the treatment of one or more MEK-related tumors, such as one or more additional anticancer therapies, by co-administration with a compound of Formula I or a pharmaceutically acceptable salt thereof or a compound of Formula II or a pharmaceutically acceptable salt thereof.

[0308] In one embodiment for treating an individual with MEK-related tumors, the individual is administered one or more anticancer therapies different from those of Formula I or its pharmaceutically acceptable salts, prior to administration of a compound of Formula I or its pharmaceutically acceptable salts, or a compound of Formula II or its pharmaceutically acceptable salts. In one embodiment, the one or more anticancer therapies are selected from surgery, radiotherapy, and anticancer agents acting with the same or different mechanisms of action. For example, in one embodiment, the individual in need may undergo at least partial tumor resection prior to administration of a compound of Formula I or its pharmaceutically acceptable salts, or a compound of Formula II or its pharmaceutically acceptable salts. In one embodiment, tumor size reduction (e.g., tumor burden) occurs through treatment with at least partial tumor resection prior to administration of one or more doses of a compound of Formula I or its pharmaceutically acceptable salts, or a compound of Formula II or its pharmaceutically acceptable salts. In one embodiment, the individual in need may undergo radiotherapy prior to administration of a compound of Formula I or its pharmaceutically acceptable salts, or a compound of Formula II or its pharmaceutically acceptable salts. In one implementation, prior to administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, the individual in need may have undergone treatment with one or more anticancer agents other than a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof. In one implementation, the individual has a cancer that is refractory to or intolerant of one or more previous treatments.

[0309] Therefore, in one embodiment, this document provides a method for treating an individual with MEK-related tumors, comprising (i) administering one or more, such as one or more, anticancer therapies to the individual, and (ii) after (i), administering (a) a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof as a monotherapy, or (b) a combination of a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof with one or more, such as one or more, additional anticancer therapies. In one embodiment, the additional anticancer therapies are independently selected from one or more of surgery, radiotherapy, and / or one or more anticancer agents acting with the same or different mechanisms of action. In one embodiment, the additional anticancer therapies are one or more anticancer agents acting with the same or different mechanisms of action. In one embodiment, the additional anticancer therapies are one anticancer agent acting with the same or different mechanisms of action. In one embodiment, the additional anticancer therapies are surgery. In one embodiment, the additional anticancer therapies are radiotherapy.

[0310] Non-limiting examples of additional anticancer agents that may be used in combination with any of the combination therapies described herein, in combination with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, include additional kinase inhibitors other than a compound of Formula I or a pharmaceutically acceptable salt thereof, including MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER2 and / or HER3 inhibitors, SHP2 inhibitors, Axl inhibitors, PI3K inhibitors, SOS1 inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators, cytotoxic chemotherapeutic agents, angiogenesis-targeting agents, and immune-targeting agents, including immunotherapy.

[0311] In one embodiment, an anticancer agent used in combination with any of the combination therapies described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, may be a targeted therapeutic agent. As used herein, “targeted therapeutic agent” includes, refers to, molecules that block cancer cell growth by interfering with specific target molecules required for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells (e.g., with conventional cytotoxic chemotherapy), and includes, but is not limited to, receptor tyrosine kinase-targeted therapeutic agents, signal transduction pathway inhibitors (e.g., Ras-Raf-MEK-ERK pathway inhibitors, PI3K-Akt-mTOR-S6K pathway inhibitors (“PI3K inhibitors”)), and apoptosis pathway modulators.

[0312] In one implementation, an anticancer agent that can be used in combination with any of the combination therapies described herein, together with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, is a BRAF inhibitor. Other non-limiting examples of BRAF inhibitors include encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl]-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394) and their pharmaceutically acceptable salts, published on December 30, 2020, under PCT Publication No. WO 2020 / 261156. The compounds disclosed in International Application No. PCT / IB2020 / 055992 published on A1 include, for example, compounds selected from the following:

[0313] N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)propane-1-sulfonamide;

[0314] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide;

[0315] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)propane-1-sulfonamide;

[0316] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)propane-1-sulfonamide;

[0317] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide;

[0318] N-(2-chloro-4-fluoro-3-((5-methyl-3-(methyl-d3)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide;

[0319] N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}propane-1-sulfonamide;

[0320] N-(3-chloro-4-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluoropyridin-2-yl)propane-1-sulfonamide; and

[0321] N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}-3-fluoropropane-1-sulfonamide;

[0322] Or its pharmaceutically acceptable salt;

[0323] And compounds disclosed in PCT Publication No. WO 2021 / 250521, published on December 16, 2021, including, for example, N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)phenyl)-2-azabicyclo[2.1.1]hexane-2-sulfonamide, (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)phenyl)-3-fluoropyrrolidine-1-sulfonamide and N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-4-fluorophenyl)-3-fluoroazacyclobutane-1-sulfonamide or pharmaceutically acceptable salts thereof.

[0324] In one embodiment, the BRAF inhibitor is selected from encofenib or a pharmaceutically acceptable salt thereof, N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide or a pharmaceutically acceptable salt thereof, and N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-4-fluorophenyl)-3-fluorozahexacyclobutane-1-sulfonamide or a pharmaceutically acceptable salt thereof.

[0325] In one embodiment, the BRAF inhibitor is encofenib or a pharmaceutically acceptable salt thereof. In one embodiment, the BRAF inhibitor is N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide or a pharmaceutically acceptable salt thereof. In one embodiment, the BRAF inhibitor is N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-4-fluorophenyl)-3-fluorozahexacyclobutane-1-sulfonamide or a pharmaceutically acceptable salt thereof.

[0326] Additional examples of BRAF inhibitors are known in the art.

[0327] In one embodiment, an anticancer agent that can be used in combination with any of the combination therapies described herein, together with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, is an EGFR inhibitor. Non-limiting examples of EGFR inhibitors include cetuximab. Panitumumab Osimertinib (merelectinib) ), erlotinib Gefitinib Necitumumab (Portrazza) TM ), neratinib Lapatinib Vandetanib Brigatinib And the EGFR inhibitors disclosed in PCT Publications WO 2019 / 071351 and WO 2017 / 117680. Additional examples of EGFR inhibitors are known in the art.

[0328] In one implementation, an anticancer agent that can be used in combination with any of the combination therapies described herein, together with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, is an SHP2 inhibitor. Non-limiting examples of SHP2 inhibitors include 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099), [3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol (RMC-4550), RMC-4630, TNO155, and the compounds disclosed in WO 2020 / 081848, WO2020 / 201991, WO 2015 / 107493, WO 2015 / 107494, WO 2015 / 107495, and WO 2019 / 075265. In one embodiment, the SHP2 inhibitor is a compound disclosed in WO 2020 / 201991. In another embodiment, the SHP2 inhibitor is (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine or a pharmaceutically acceptable salt thereof.

[0329] In one implementation, an anticancer agent that can be used in combination with any of the combination therapies described herein, together with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, is a PI3K inhibitor.Non-limiting examples include buparlisib (BKM120), alpelisib (BYL719), samotolisib (LY3023414), 8-[(1R)-1-[(3,5-difluorophenyl)amino]ethyl]-N,N-dimethyl-2-(morpholin-4-yl)-4-oxo-4H-chromene-6-carboxamide (AZD8186), and tenacil (…). lisib (RP6530), voxtalisib hydrochloride (SAR-245409), gedatolisib (PF-05212384), panulisib (P-7170), taselisib (GDC-0032), trans-2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4 -Methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502), duvelisib (ABBV-954), N2-[4-oxo-4-[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholin-4-onth-4-ylmethoxy]butyryl]-L-arginyl-glycyl-L-aspartyl-L-serine acetate (SF-1126), pictilis ib)(GDC-0941), 2-methyl-1-[2-methyl-3-(trifluoromethyl)benzyl]-6-(morpholin-4-yl)-1H-benzimidazole-4-carboxylic acid (GSK2636771), idelalisib (GS-1101), umbralisib toluenesulfonate (TGR-1202), picoxib (GDC-0941), copanlisib hydrochloride (BAY) 84-1236), dactolisib (BEZ-235), 1-(4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-ethyl-1H-1,2,4-triazol-3-yl]piperidin-1-yl)-3-hydroxyprop-1-one (AZD-8835), 5-[6,6-dimethyl-4-(morpholin-4-yl)-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purine-2-yl]pyrimidine-2-amine (GDC-0084), everolimus, rapamycin, perifosine, sirolimus, and temsirolimus.

[0330] In one embodiment, immunotherapy may be an anticancer agent used in combination with any of the combination therapies described herein, or a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. The term "immunotherapy" refers to an agent that modulates the immune system. In one embodiment, immunotherapy may increase the performance and / or activity of an immune system modulator. In one embodiment, immunotherapy may decrease the performance and / or activity of an immune system modulator. In one embodiment, immunotherapy may recruit and / or enhance the activity of immune cells.

[0331] In one embodiment, an immunotherapy that combines any of the combination therapies described herein with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, is an antibody therapy (e.g., a monoclonal antibody, an antibody-drug conjugate). In one embodiment, the antibody therapy is bevacizumab (Mvasti). TM , trastuzumab Rituximab (MabThera) TM , ), edrecolomab (Panorex), daratumuab olaratumab (Lartruvo) TM ofatumumab alemtuzumab cetuximab Oregomab and Pembrolizumab dinutiximab obinutuzumab tremelimumab (CP-675,206) and ramucirumab Ublituximab (TG-1101), Panitumumab Elotuzumab (Empliciti) TM Portrazza TM Cirmtuzumab (UC-961), Ibritumomab Isatuximab (SAR650984), Nimotuzumab, Fresolimumab (GC1008), Lirilumab (INN), Mogamulizumab Ficlatuzumab (AV-299) and Denosumab Ganitumab, urelumab, pidilizumab, amatuximab, blinatumomab (AMG103); Or midostaurin (Rydapt).

[0332] In one embodiment, an immunotherapy that combines any of the combination therapies described herein with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, is an immune checkpoint inhibitor. In one embodiment, the immunotherapy includes one or more, such as one or two immune checkpoint inhibitors. In one embodiment, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In one embodiment, the CTLA-4 inhibitor is ipilimumab. Alternatively, trimexumab (CP-675,206). In one implementation, the PD-1 inhibitor is pelizumab. Nivolumab And sasanlimab (RN888). In one implementation, the PD-L1 inhibitor is atezolizumab. Or durvalumab (Imfinzi) TM ).

[0333] In one embodiment, an anticancer therapy that combines any of the combination therapies described herein with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, is radiotherapy. Non-limiting examples of radiotherapy include external beam radiation therapy (e.g., external beam radiation therapy using kilovolt or megavolt X-rays) or internal radiotherapy. Internal radiotherapy (also known as proximal therapy) may include, for example, low-dose internal radiotherapy or high-dose internal radiotherapy. Low-dose internal radiotherapy includes, for example, inserting radioactive particles into or near the cancerous tissue of an individual. High-dose internal radiotherapy includes, for example, inserting a thin tube (e.g., a catheter) or implant into or near the cancerous tissue of an individual, and using a radiation machine to deliver a high dose of radiation to the thin tube or implant. Methods of performing radiotherapy on an individual with cancer are known in the art. In embodiments where the tumor is a CNS tumor, radiotherapy may include whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS), such as… Gamma or

[0334] In one embodiment, an anticancer therapy performed in combination with any of the combination therapies described herein, in combination with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof, is considered surgery. Non-limiting examples of surgery include, for example, open surgery or minimally invasive surgery. Surgery may include, for example, at least partial tumor resection, removal of the entire tumor, tumor debulking, or removal of a tumor causing pain or pressure in the individual. Methods for performing open and minimally invasive surgery on individuals with cancer are known in the art.

[0335] In one embodiment, this document provides a method of treating MEK-related tumors (such as any of the MEK-related tumors described herein), comprising administering, together or separately in any order, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and a BRAF inhibitor (such as any of the BRAF inhibitors disclosed herein). In one embodiment, the compound of formula I is a compound selected from Examples 1 to 69 or a pharmaceutically acceptable salt thereof.

[0336] In one embodiment, this document provides a method of treating MEK-related tumors (such as any of the MEK-related tumors described herein), comprising administering, together or separately in any order, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor (such as any of the EGFR inhibitors disclosed herein). In one embodiment, the compound of formula I is a compound selected from any of Examples 1 to 69 or a pharmaceutically acceptable salt thereof.

[0337] In one embodiment, this document provides a method of treating MEK-related tumors (such as any of the MEK-related tumors described herein), comprising administering, together or separately in any order, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor (such as any of the SHP2 inhibitors disclosed herein). In one embodiment, the compound of formula I is a compound selected from any of Examples 1 to 69 or a pharmaceutically acceptable salt thereof.

[0338] In one embodiment, this document provides a method of treating MEK-related tumors (such as any of the MEK-related tumors described herein), comprising administering, together or separately in any order, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor (such as the checkpoint inhibitors disclosed herein). In one embodiment, the compound of formula I is a compound selected from any of Examples 1 to 69 or a pharmaceutically acceptable salt thereof.

[0339] This document also provides a pharmaceutical combination for treating MEK-related tumors in individuals with this need, comprising (a) a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof and (b) at least one adjunct anticancer agent (e.g., any of the exemplary adjunct anticancer agents described herein or known in the art), wherein the compound of formula I or a pharmaceutically acceptable salt thereof or the compound of formula II or a pharmaceutically acceptable salt thereof and one or more, such as one or more adjunct anticancer agents, are separately formulated for simultaneous or separate treatment of the tumor, wherein the amount of the compound of formula I or a pharmaceutically acceptable salt thereof or the compound of formula II or a pharmaceutically acceptable salt thereof and the amount of the adjunct anticancer agent together effectively treat the tumor; (ii) a pharmaceutical preparation for treating the tumor using this combination; and (iii) a commercial package or product comprising this combination as a combination formulation for simultaneous, separate or sequential use; and a method of treating tumors in individuals with this need.

[0340] As used herein, the term "drug combination" refers to a non-fixed combination of active ingredients. The term "non-fixed combination" means a composition or dosage of a Formula I compound or a pharmaceutically acceptable salt thereof, or a Formula II compound or a pharmaceutically acceptable salt thereof, formulated with one or more additional anticancer agents, such that they can be administered simultaneously or separately at variable intervals and in any order to an individual in need, wherein such administration provides an effective level of two or more compounds in the individual. This also applies to cocktail therapy, such as the administration of three or more active ingredients. Similarly, when referring to the use of a Formula I compound or a pharmaceutically acceptable salt thereof, or a Formula II compound or a pharmaceutically acceptable salt thereof, in combination with one or more anticancer agents, the term "combination" refers to a non-fixed combination.

[0341] Therefore, this article also provides a method for treating MEK-related tumors, which includes administering to an individual in need a combination of drugs for treating the tumor, the combination comprising (a) a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially for treating the tumor, and (b) one or more, such as one or more additional anticancer agents, wherein the amount of the compound of formula I or a pharmaceutically acceptable salt thereof or the compound of formula II or a pharmaceutically acceptable salt thereof and the amount of the additional anticancer agent together effectively treat the tumor.

[0342] In one embodiment, this document provides a method for treating MEK-related tumors (e.g., benign, malignant, or metastatic tumors), comprising administering to an individual in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, wherein the individual has not received treatment with an anticancer therapy prior to administration of the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the anticancer therapy is selected from one or more, such as one or more anticancer therapies independently selected from surgery, radiotherapy, and anticancer agents acting with the same or different mechanisms of action. In one embodiment, the individual has not been treated with an anticancer agent prior to administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has not undergone surgical treatment prior to administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has not undergone radiotherapy prior to administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0343] In one embodiment, this document provides a method for treating an individual with MEK-related tumors (e.g., benign, malignant, or metastatic tumors), comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, wherein the individual has been treated with prior therapy or standard therapy (e.g., with one or more anticancer agents different from a compound of formula I or a pharmaceutically acceptable salt thereof and / or radiation therapy and / or surgery), wherein the MEK-related tumor has become refractory to or intolerant of the prior therapy. In one embodiment, the individual develops brain metastases during the prior therapy.

[0344] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) has previously received treatment with a BRAF inhibitor prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with a BRAF inhibitor selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide, (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)). In one embodiment, the individual has previously been treated with a BRAF inhibitor (selected from encofenib, dabrafenib, and vemurafenib). In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment period.

[0345] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic melanoma (e.g., metastatic melanoma with BRAF V600 mutation or BRAF fusion) has received treatment with BRAF inhibitors and MEK inhibitors prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one implementation, the individual had previously used a BRAF inhibitor (selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl]-2,4-difluorophenyl]propane-1-sulfonamide and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)) and a MEK inhibitor (selected from binimetinib, trametinib, cobimetinib). b) Treatment with selumetinib, pimasertib, refametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-325901), 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyridano[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733). In one embodiment, the individual has previously been treated with a BRAF inhibitor (selected from encofenib, dabrafenib, and vemurafenib) and a MEK inhibitor (selected from binitinib, trametinib, and cobimetinib). In one embodiment, the individual has previously been treated with encofenib and binitinib. In one embodiment, the individual has previously been treated with dabrafenib and trametinib. In one embodiment, the individual has previously been treated with vemurafenib and cobimetinib. In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment period.

[0346] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) has been treated with one or more, such as one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors) prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with one or more, such as one or two checkpoint inhibitors (independently selected from ipilimumab, nivolumab, and pelizumab). In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment.

[0347] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic melanoma (e.g., metastatic melanoma with BRAF V600 mutation or BRAF fusion) has received treatment with one or more, such as one or two PI3K inhibitors, prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof. In one implementation, the individual has previously been treated with one or more, such as one or two, PI3K inhibitors selected from the following: bupacicoside (BKM120), ipecoside (BYL719), sammotolicoside (LY3023414), 8-[(1R)-1-[(3,5-difluorophenyl)amino]ethyl]-N,N-dimethyl-2-(morpholin-4-yl)-4-oxo-4H-chromene-6-carboxamide (AZD8186), tranexamic acid (RP6530), votacoside hydrochloride (SAR-245409), jidacicoside (PF-05212384), panucicoside (P-7170), texicoside (GDC-0032), trans-2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methyl Pyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502), Duvexib (ABBV-954), N2-[4-oxo-4-[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholin-4-onth-4-ylmethoxy]butyryl]-L-arginyl-glycyl-L-aspartyl-L-serine acetate (SF-1) 126), Pickoxib (GDC-0941), 2-Methyl-1-[2-Methyl-3-(trifluoromethyl)benzyl]-6-(morpholin-4-yl)-1H-benzimidazole-4-carboxylic acid (GSK2636771), Adexib (GS-1101), Ubuxibu toluenesulfonate (TGR-1202), Pickoxib (GDC-0941), Cobanoxib hydrochloride (BAY) 84-1236), dapoxetine (BEZ-235), 1-(4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-ethyl-1H-1,2,4-triazol-3-yl]piperidin-1-yl)-3-hydroxyprop-1-one (AZD-8835), 5-[6,6-dimethyl-4-(morpholin-4-yl)-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purine-2-yl]pyrimidine-2-amine (GDC-0084), everolimus, rapamycin, perifoxetine, sirolimus, and tamsuloxus. In one embodiment, the individual has previously been treated with bupacoxetine or ipexicoxetine alone or in combination. In one embodiment, the individual is refractory to the previously treated condition.In one embodiment, the individual develops brain metastases during the prior treatment.

[0348] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic melanoma (e.g., metastatic melanoma with BRAF V600 mutation or BRAF fusion) has been treated with a BRAF inhibitor and one or more, such as one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors) prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with a BRAF inhibitor (selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)), and one or more, such as one or two checkpoint inhibitors (independently selected from ipilimumab, nivolumab, and pelizumab). In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment.

[0349] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic melanoma (e.g., metastatic melanoma with BRAF V600 mutation or BRAF fusion) has been treated with a BRAF inhibitor, a MEK inhibitor, and one or more, such as one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors) prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof. In one implementation, the individual had previously used a BRAF inhibitor (selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)), a MEK inhibitor (selected from binitinib, trametinib, cobimetinib, selumetinib, pimasetinib, refametinib, N-[2(R)]propane-1-sulfonamide (PLX4720) and (3R)-N-[3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)), or a MEK inhibitor (selected from binitinib, trametinib, cobimetinib, selumetinib, pimasetinib, refametinib, N-[2(R)]propane-1-sulfonamide (PLX4720) and (3R)-N-[[[5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]propane-1-sulfonamide (PLX8394)). Treatment with 3-[2(R),3-dihydroxypropyl]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-325901), 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyridano[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733), and one or more checkpoint inhibitors (such as any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors). In one embodiment, the individual has previously been treated with a BRAF inhibitor (selected from encofenib, dabrafenib, and vemurafenib), a MEK inhibitor (selected from binitinib, trametinib, and cobimetinib), and one or more, such as one or two checkpoint inhibitors (independently selected from ipilimumab, nivolumab, and pelizumab). In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment period.

[0350] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) has been treated with one or more, such as one or two, alkylating agents prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with an alkylating agent (selected from temozolomide, fotemustine, lomustine, and carmustine). In one embodiment, the individual has previously been treated with temozolomide. In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment.

[0351] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic colorectal cancer (e.g., metastatic colorectal cancer with BRAF V600 mutation or BRAF fusion) has been treated with a MEK inhibitor and one or more, such as one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors). In one implementation, the individual had previously used a MEK inhibitor (selected from binitinib, trametinib, cobimetinib, selumetinib, pimasertinib, refametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-325901), 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide). (CI-1040) and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733)) and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors). In one embodiment, the individual has previously been treated with a MEK inhibitor (selected from binitinib, trametinib, and cobimetinib) and one or more, such as one or two checkpoint inhibitors (independently selected from ipilimumab, nivolumab, and pelizumab). In one embodiment, the individual has previously been treated with a MEK inhibitor (which is binitinib) and a checkpoint inhibitor (which is nivolumab, ipilimumab, or pelizumab). In one embodiment, the individual is refractory to the previously prescribed treatment. In one implementation, the individual develops brain metastases during the prior treatment.

[0352] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF V600 mutation or BRAF fusion) has been treated with one or more, such as one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors). In one embodiment, the individual has previously been treated with one or more, such as one or two checkpoint inhibitors independently selected from ipilimumab, nivolumab, pelizumab, and sasanlimab. In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment.

[0353] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF V600 mutation or a BRAF fusion mutation) has been treated with one or more cytotoxic chemotherapeutic agents prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof or a compound of Formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has been treated with oxaliplatin, irinotecan, FOLFOXIRI (oxaliplatin, irinotecan, and fluorouracil), FOLFIRI (folate, fluorouracil, and irinotecan), or CAPEOX (capecitabine and oxaliplatin) prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment.

[0354] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic colorectal cancer (e.g., metastatic colorectal cancer with BRAF V600 mutation or BRAF fusion) has received treatment with an EGFR inhibitor, a BRAF inhibitor, and one or more cytotoxic chemotherapeutic agents prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof. In one implementation, an individual with metastatic colorectal cancer has previously been treated with an EGFR inhibitor (selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, lexiximab, neratinib, lapatinib, vandetanib, and brigatinib), a BRAF inhibitor (selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)), and one or more cytotoxic chemotherapeutic agents. In one embodiment, the individual has previously been treated with an EGFR inhibitor (selected from cetuximab and panitumumab), a BRAF inhibitor (vemurafenib), and a cytotoxic chemotherapy agent (irinotecan). In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment period.

[0355] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF V600 mutation or BRAF fusion) has previously received treatment with an EGFR inhibitor and one or more cytotoxic chemotherapeutic agents prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with an EGFR inhibitor (selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, lexicam, neratinib, lapatinib, vandetanib, and brigatinib) and one or more chemotherapeutic agents. In another embodiment, the individual has previously been treated with an EGFR inhibitor (selected from cetuximab and panitumumab) and a cytotoxic chemotherapeutic agent (irinotecan or FOLFIRI (folate, fluorouracil, and irinotecan)). In one embodiment, the individual is refractory to the previously prescribed treatment. In one implementation, the individual develops brain metastases during the prior treatment.

[0356] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual with metastatic non-small cell lung cancer (e.g., metastatic non-small cell lung cancer with a BRAF V600 mutation or BRAF fusion) has previously received treatment with one or more, such as one or two, EGFR inhibitors, prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with one or more, such as one or two, EGFR inhibitors (independently selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, lexiximab, neratinib, lapatinib, vandetanib, and brigatinib). In one embodiment, the individual has previously been treated with erlotinib. In one embodiment, the individual has previously been treated with gefitinib. In one embodiment, the individual has previously been treated with both erlotinib and gefitinib. In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment.

[0357] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, the individual with metastatic non-small cell lung cancer (e.g., metastatic non-small cell lung cancer with a BRAF mutation) had previously been treated with a BRAF inhibitor (selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-di [Fluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394)), MEK inhibitors (which are selected from (binitinib, trametinib, cobibitinib, selumetinib, pimasertinib, refametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2 2-(2-chloro-4-iodophenylamino)benzamide (PD-325901), 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733)) and EGFR inhibitors (selected from cetuximab, panitumumab, and osimertinib) The individual was previously treated with a BRAF inhibitor (selected from vemurafenib, dabrafenib, and encofenib) and an EGFR inhibitor (selected from cetuximab and panitumumab) prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the individual became refractory to the prior treatment. In one embodiment, the individual developed brain metastases during the prior treatment.

[0358] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has metastatic thyroid cancer (e.g., with BRAF) prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. Individuals with metastatic thyroid cancer due to V600 mutation or BRAF fusion have previously received treatment with BRAF inhibitors (selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl]-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)) and MEK inhibitors (selected from binitinib, trametinib, cobimetinib, selumetinib, pimasetinib, refametinib, N- [2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-325901), 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyridano[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733)), and EGFR inhibitors (selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, lexiximab, neratinib, lapatinib, vandetanib, and brigatinib) for treatment. In one embodiment, the individual has previously been treated with a BRAF inhibitor selected from vemurafenib, dabrafenib, and encofenib prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the individual becomes refractory to the prior treatment. In one embodiment, the individual develops brain metastases during the prior treatment.

[0359] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has LMD and has been previously treated with a BRAF inhibitor and one or more, such as one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors) prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with a BRAF inhibitor (selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl]-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)) and one or more, such as one or two checkpoint inhibitors (independently selected from ipilimumab, nivolumab, and pelizumab). In one embodiment, the individual becomes refractory to the previously treated BRAF.

[0360] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has LMD and has been previously treated with a BRAF inhibitor, a MEK inhibitor, and one or more, such as one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, such as a CTLA-4 inhibitor, a PD-1 inhibitor, and / or a PD-L1 inhibitor) prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof. In one implementation, the individual had previously used a BRAF inhibitor (selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl]-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)) or a MEK inhibitor (selected from binitinib, trametinib, cobibitinib, selumetinib, pimasertinib, refametinib, N-[2(R Treatment with 3-[2(R),3-dihydroxypropyl]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-325901), 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733), and checkpoint inhibitors (such as any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors). In one implementation, the individual has previously been treated with a BRAF inhibitor (selected from encofenib, dabrafenib, and vemurafenib), a MEK inhibitor (selected from binitinib, trametinib, and cobimetinib), and one or more, such as one or two checkpoint inhibitors (independently selected from ipilimumab, nivolumab, and pelizumab). In one implementation, the individual is refractory to the previously prescribed treatment.

[0361] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has LMD and has been previously treated with one or more, such as one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, such as CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors) prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has been previously treated with one or more, such as one or two checkpoint inhibitors (independently selected from ipilimumab, nivolumab, and pelizumab). In one embodiment, the individual is refractory to the previously described treatment.

[0362] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has glioma and has previously undergone surgical treatment prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual is treatment-refractory to the prior treatment. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0363] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has glioma and has previously been treated with radiation therapy (e.g., whole-brain radiation therapy or stereotactic radiosurgery) prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual is treatment-refractory to the prior treatment. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0364] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has glioma and has been previously treated with one or more cytotoxic chemotherapeutic agents prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has been previously treated with one or more cytotoxic chemotherapeutic agents independently selected from cisplatin, pemetrexed, vinorelbine, and paclitaxel. In one embodiment, the individual is treatment-refractory to the prior treatment. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0365] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related glioma and has been previously treated with an ornithine decarboxylase inhibitor prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has been previously treated with an ornithine decarboxylase inhibitor (which is eflornithine (in a racemic form or a D or L enantiomer). In one embodiment, the individual is refractory to the previously treated drug. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0366] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related glioma and has been previously treated with an alkylating agent prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has been previously treated with an alkylating agent selected from temozolomide, lomustine, and carmustine. In one embodiment, the individual is treatment-refractory to the prior treatment. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0367] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related glioma and has been previously treated with an alkylating agent and an ornithine decarboxylase inhibitor prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has been previously treated with an alkylating agent (selected from temozolomide, lomustine, and carmustine) and an ornithine decarboxylase inhibitor (eflunominoline (in racemic form or D or L enantiomer)). In one embodiment, the individual is refractory to the previously treated tumor. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0368] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related glioma and has previously been treated with radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiosurgery) and an alkylating agent prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiosurgery) and an alkylating agent (selected from temozolomide, lomustine, and carmustine). In one embodiment, the individual is treatment-refractory to the previously described method. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0369] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related glioma and has previously been treated with antibody therapy prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with antibody therapy (which is bevacizumab). In one embodiment, the individual is treatment-refractory to the prior therapy. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0370] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related glioma and has previously been treated with surgery and radiation therapy prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual is treatment-refractory to the prior treatment. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0371] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related glioma and has previously been treated with surgery, radiation therapy, and alkylating agents prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a compound of Formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has previously been treated with surgery, radiation therapy (e.g., whole-brain radiation therapy or stereotactic radiosurgery), and alkylating agents (selected from temozolomide, lomustine, and carmustine). In one embodiment, the individual is treatment-refractory to the previously described method. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0372] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related glioma and has been previously treated with a BRAF inhibitor prior to a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has been previously treated with a BRAF inhibitor selected from N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), vemurafenib, dabrafenib, encofenib, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)). In one embodiment, the individual is refractory to the previously treated BRAF. In one implementation, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0373] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related glioma and has been previously treated with a BRAF inhibitor and a MEK inhibitor prior to treatment with a compound of formula I or a pharmaceutically acceptable salt, solvate or polymorph thereof or a pharmaceutically acceptable salt, solvate or polymorph thereof or a compound of formula II or thereof. In one embodiment, the individual had previously used a BRAF inhibitor (selected from N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl]-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), vemurafenib, dabrafenib, encofenib, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)) and a MEK inhibitor (selected from binitinib, trametinib, etc.). The treatment options include nifedipine, cobimetinib, selmetinib, pimasetinib, refametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-325901), 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyridano[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733). In one embodiment, the individual has previously been treated with a BRAF inhibitor (selected from encofenib, dabrafenib, and vemurafenib) and a MEK inhibitor (selected from binitinib, trametinib, and cobimetinib). In one implementation, the individual is said to be refractory to previous treatment. In one implementation, the glioma is a grade 2, 3, or 4 glioma.

[0374] In one embodiment of the method disclosed herein for treating an individual with MEK-related tumors, the individual has MEK-related brainstem ganglion glioma and has been previously treated with a BRAF inhibitor prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the individual has been previously treated with a BRAF inhibitor selected from encofenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl]-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidin-1-sulfonamide (PLX8394)). In one implementation, the individual has previously been treated with a BRAF inhibitor (selected from encofenib, dabrafenib, and vemurafenib). In another implementation, the individual becomes refractory to the previously prescribed treatment.

[0375] Although the genetic basis of tumorigenesis may vary across different cancer types, the cellular and molecular mechanisms required for metastasis in all solid tumor types appear to be similar. During the metastatic cascade, cancer cells lose their growth-inhibiting responses, undergo changes in adhesion, and produce enzymes that degrade extracellular matrix components. This leads to tumor cells detaching from the original tumor, infiltrating the circulation through newly formed blood vessels, migrating, and extravasating at favorable distant sites where they may form communities. Many genes have been identified as promoters or repressors of metastasis.

[0376] Therefore, this document also provides a method for treating, inhibiting, preventing, assisting in the prevention of, or reducing BRAF-related cancer metastasis in individuals with such need, the method comprising administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is used in combination with one or more anticancer therapies independently selected from surgery (e.g., at least partial tumor resection), radiotherapy, and anticancer agents.

[0377] As used in this article, the term “treatment of metastases” means reducing the size, progression, and / or further spread of one or more metastases.

[0378] As used in this article, “metastasis suppression” means reducing the occurrence (or recurrence) of one or more metastases, preventing the occurrence (or recurrence) of one or more metastases, or reducing the spread of one or more metastases.

[0379] In one implementation, an individual treated according to any of the methods disclosed herein may be assessed according to one or more standard response assessment criteria known in the art, including RECIST (response assessment criteria in solid tumors, such as RECIST version 1.0, RECIST version 1.1, and the modified RECIST 1.1 (mRECIST 1.1)), RANO-BM (response assessment in neuro-oncology brain metastases), Macdonald, RANO-LMD, and NANO (neurological assessment in neuro-oncology). In one implementation of any of these criteria, the tumor is assessed using imaging studies (e.g., MRI, CT, MDCT, or PET). In one implementation, treatment response is assessed according to RECIST version 1.1, where: complete response (CR) is defined as the complete disappearance of all tumor lesions; partial response (PR) is defined as a reduction of at least 30% in the sum of tumor measurements; progressive disease (PD) is defined as an increase of at least 20% in the sum of tumor measurements (including the development of new lesions or substantial progression of non-target lesions), with an increase of at least 5 mm from baseline being assessed as PD; and stable disease (SD) is defined as neither adequately shrinking to meet the criteria for PR nor adequately increasing to meet the criteria for PD, using the smallest total diameter at the time of treatment as the reference value. In one implementation, assessments include intracranial response (assessed using gadolinium-enhanced MRI according to a modified RECIST), extracranial response, global response rate, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

[0380] As used herein, an “effective dose” or “effective amount” of a drug, compound, or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desirable biochemical, histological, and / or behavioral symptoms, including those of a disease, its complications, and intermediate pathological phenotypes present during the course of the disease. For therapeutic purposes, a “therapeutic effective amount” refers to the amount of a compound administered that reduces one or more of the symptoms of the disease to a certain degree. In the treatment of cancer, a therapeutic effective amount refers to an amount that has the following effects: (1) reducing tumor size; (2) inhibiting (i.e., slowing down, preferably stopping) tumor metastasis; (3) inhibiting tumor growth or invasion to a certain degree (i.e., slowing down, preferably stopping); (4) reducing (or preferably eliminating) one or more cancer-associated signs or symptoms; (5) reducing the dosage of other agents required to treat the disease; and / or (6) enhancing the effect of another agent; and / or (7) delaying disease progression in the patient.

[0381] The effective dose can be administered once or multiple times. For the purposes of this invention, the effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventative or therapeutic treatment. As understood in the clinical context, the effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved with another drug, compound, or pharmaceutical composition.

[0382] "Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention as active ingredients, or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs, with at least one pharmaceutically acceptable carrier or excipient. In one embodiment, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0383] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient. In one embodiment, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0384] Therefore, in one embodiment, the present invention provides a pharmaceutical composition for treating abnormal cell growth in individuals with such needs, the pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0385] As used in this article, "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the applied compound.

[0386] Pharmaceutically acceptable carriers may contain any conventional pharmaceutical carriers or excipients. The choice of carriers and / or excipients depends to a great extent on factors such as the particular administration method, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage form.

[0387] Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents (such as hydrates and solvates). If required, the pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, and the like.

[0388] This document uses the term "excipient" to refer to any component other than the compounds of this invention. The selection of excipients depends to a great extent on factors such as the mode of application, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0389] As used herein, “excipients” include any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, carriers, diluents, and the like. Examples of excipients include one or more of water, saline, phosphate-buffered saline, dextran, glycerol, ethanol, and the like, and combinations thereof, and may include isotonic agents such as sugars, sodium chloride, or polyols (such as mannitol or sorbitol) in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). When requested, pharmaceutical compositions may contain additional excipients such as flavoring agents, binders / binding agents, lubricants, disintegrants, sweeteners or flavoring agents, coloring substances or dyes, and the like. For example, tablets containing various excipients (such as citric acid) may be used orally with various disintegrants (such as starch, alginate, and certain complex silicates) and binders (such as sucrose, gelatin, and gum arabic). Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Therefore, tablets containing various excipients (such as citric acid) can be used orally with various disintegrants (such as starch, alginate, and certain complex silicates) and binders (such as sucrose, gelatin, and gum arabic). Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often used for tablet manufacturing purposes. Similar types of solid compositions can also be used in soft and hard-filled gelatin capsules. Non-limiting examples of materials therefore include lactose or milk sugar and high molecular weight polyethylene glycol. When it is desired to administer orally as an aqueous suspension or elixir, the active compound therein may be combined with various sweeteners or flavorings, coloring substances or dyes, and (if required) emulsifiers or suspending agents, together with diluents (such as water, ethanol, propylene glycol, glycerin or combinations thereof).

[0390] Examples of excipients also include pharmaceutically acceptable substances, such as wetting agents or small amounts of auxiliary substances, such as wetting agents or emulsifiers, preservatives or buffers, which enhance the shelf life or effectiveness of the compound.

[0391] Pharmaceutical compositions may be in the form of, for example, tablets, capsules, pills, powders, sustained-release formulations, suspensions, or liquid solutions (e.g., injectable or infusion-compatible solutions) suitable for oral administration; sterile solutions, suspensions, or emulsions suitable for parenteral injection; or ointments or creams, powders, liposomes, and suppositories (e.g., suppositories for rectal administration) suitable for topical application. Exemplary parenteral formulations include solutions or suspensions of the active compound in sterile aqueous solutions (e.g., aqueous propylene glycol or dextran solution). These dosage forms may be appropriately buffered if required. The dosage form depends on the intended mode of administration and therapeutic application.

[0392] The pharmaceutical composition may be in a unit dosage form suitable for precise single-dose administration.

[0393] The compounds of this invention can be administered orally. Oral administration may include swallowing, allowing the compound to enter the gastrointestinal tract, or buccal or sublingual administration, thereby allowing the compound to enter the bloodstream directly from the mouth. Suitable formulations for oral administration include solid formulations (such as tablets), capsules containing microparticles, liquids, powders, rhomboid tablets (including liquid-filled tablets), chewable tablets, multi- and nanoparticle formulations, gels, solid solutions, liposomes, films (including mucosal adhesives), ovoids, sprays, and liquid formulations. These capsules or tablets may contain controlled-release formulations. In examples of capsules, tablets, and pills, the dosage form may also contain buffers or be prepared with an enteric coating.

[0394] Liquid formulations include suspensions, solutions, syrups, and elixirs. These formulations can be used as fillers in soft or hard capsules and typically include one or more of the following: humectants, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), or flavoring agents, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oils, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by recombining solids, for example, from small capsules.

[0395] The compounds of the present invention can also be used in rapidly dissolving and rapidly disintegrating formulations, such as those described in Liang and Chen’s (2001) Expert Opinion in Therapeutic Patents, 11(6), 981 986, the disclosure of which is incorporated herein by reference in its entirety.

[0396] Regarding tablet dosage forms, the drug may constitute 1 wt% to 80 wt% of the dosage form, depending on the dosage, but more typically 5 wt% to 60 wt%. In addition to the drug, tablets usually contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone sodium carboxymethyl cellulose, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with low-carbon alkyl groups, starch, pregelatinized starch, and sodium alginate. The disintegrant typically constitutes 1 wt% to 25 wt% of the dosage form, preferably 5 wt% to 20 wt%. Binders are typically used to give the tablet formulation its binding properties. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous form, and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate. Tablets may also include surfactants (such as sodium lauryl sulfate and polysorbate 80) and lubricants (such as silica and talc) as needed. When present, the amount of surfactant is typically 0.2 wt% to 5 wt% of the tablet, and the amount of lubricant is typically 0.2 wt% to 1 wt% of the tablet. Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants are typically present in an amount of 0.25 wt% to 10 wt% of the tablet, preferably 0.5 wt% to 3 wt%. Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents. Tablet blends can be formed into tablets directly or by roller compression. Alternatively, the tablet blend or a portion thereof may be subjected to wet, dry, or melt granulation, melt freeze-drying, or extrusion prior to tablet formation. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated. Solid formulations for oral administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0397] Compositions for oral administration may be provided in tablet or capsule form containing 0.01, 0.05, 0.1, 0.25, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, or 100 mg of the active ingredient, with symptomatic dose adjustments for patients. The drug typically contains about 0.01 mg to about 100 mg of the active ingredient. In another embodiment, the formulation contains about 0.01 to 0.25 mg of the active ingredient. In another embodiment, the drug contains about 0.25, 0.5, 1.0, 5.0, 15, or 25 mg of the active ingredient.

[0398] The compounds of this invention can also be applied directly into the bloodstream, muscles, or internal organs. Suitable parenteral administration methods include intravenous, intra-arterial, intraperitoneal, intraspinal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques. Injectable formulations (e.g., sterile injectable aqueous or oily suspensions) can be formulated using one or more suitable dispersants, wetting agents, or suspending agents according to known techniques. Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably at a pH of 3 to 9), but for some applications, the formulation may be more suitable as a sterile non-aqueous solution or in a dried form for use with a suitable medium (such as sterile pyrogen-free water). The preparation of parenteral formulations under sterile conditions (e.g., by freeze-drying) can be easily accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of the present invention used in the preparation of parenteral solutions can be increased by appropriate formulation techniques, such as incorporating solubility enhancers.

[0399] Formulations intended for parenteral administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release. Therefore, the compounds of the present invention can be formulated as solid, semi-solid, or thixotropic liquids for administration to implantable receptacles to provide modified release of the active compound. Examples of such formulations include drug-coated scaffolds and PGLA microspheres.

[0400] The compounds of this invention can also be applied topically to the skin or mucous membranes, i.e., through the skin or transdermis (such as via transdermal patches or iontophoresis devices), intraocularly, or intranasally or by inhalation. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are applied via transdermal devices, the application is accomplished using reservoirs and porous membrane-type patches or solid matrix-type patches. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, powders, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oils, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated. Other methods of topical application include electroporation, iontophoresis, ultrasound transdermal delivery, ultrasound induction, and microneedle or needle-free methods (e.g., Powderject). TM Bioject TM (etc.) Injection delivery.

[0401] Formulations suitable for topical application to the eyes include, for example, eye drops, in which the compounds of the invention are dissolved or suspended in suitable excipients. Typical formulations suitable for ocular or ear application may be drops of micronized suspensions or solutions in pH-adjusted isotonic sterile saline. Other formulations suitable for ocular and ear application include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (e.g., polysiloxane) implants, powders, lenses, and microparticle or vesicle systems, such as niosomes or liposomes. Polymers (such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose) or heteropolysaccharide polymers (e.g., gelan gum) may be incorporated with preservatives (such as benzalkonium chloride). These formulations may also be delivered by iontophoresis.

[0402] Formulations intended for topical application can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0403] The compounds of this invention can also be administered intranasally or by inhalation, typically in the form of dry powder from a dry powder inhaler (alone, in a mixture, for example, with lactose, or in a mixed component particle, for example, with phospholipids (such as phosphatidylcholine), or in the form of an aerosol spray from a pressurized container, pump, nebulizer, atomizer (preferably an electrohydrodynamic atomizer) or nebulizer, with or without a suitable propellant (such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane). Powders for intranasal use may contain bioadhesives, such as glucosamine or cyclodextrin. Pressurized containers, pumps, nebulizers, atomizers, or nebulizers contain solutions or suspensions of the compounds of this invention, comprising, for example, ethanol, aqueous ethanol, or alternatives suitable for dispersing, dissolving, or prolonging the release of the active ingredient, a propellant as a solvent, and, if desired, surfactants such as sorbitol trioleate, oleic acid, or oligolactic acid. Before using dry powder or suspension formulations, drug products can be micronized to a size suitable for inhalation delivery (typically less than 5 micrometers). This can be achieved by any suitable pulverization method that forms nanoparticles (such as helical jet milling, fluidized bed jet milling, supercritical fluid processing), high-pressure homogenization, or spray drying.

[0404] Capsules (e.g., made of gelatin or HPMC), blister packs, and cartridges used in inhalers or blowpipes can be formulated into a powder mixture containing the compounds of the present invention, a suitable powder base (such as lactose or starch), and performance modifiers (such as leucine, mannitol, or magnesium stearate). Lactose can be anhydrous or in the form of lactose monohydrate, the latter being preferred. Other suitable excipients include polydextrose, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0405] Suitable flavoring agents (such as menthol and L-menthol) or sweeteners (such as saccharin or sodium saccharin) can be added to those formulations of the present invention intended for inhalation / nasal administration.

[0406] The compounds of this invention can be administered rectally or vaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is a traditional suppository base, but various alternatives can be used where appropriate.

[0407] Formulations intended for rectal / vaginal administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0408] The compounds of this invention can also be applied directly to the eyes or ears, typically in the form of micronized suspensions or solutions in pH-adjusted isotonic sterile saline drops. Other formulations suitable for eye and ear application include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., polysiloxane) implants, powders, lenses, and microparticle or vesicle systems, such as vesicles or liposomes. Polymers (such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum) can be incorporated with preservatives (such as benzalkonium chloride). These formulations can also be delivered by iontophoresis.

[0409] Formulations intended for ocular / otal application can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0410] Other excipients and administration methods known in pharmaceutical technology may also be used. The pharmaceutical compositions of this invention can be prepared using any of the well-known pharmaceutical techniques (such as efficient dispensing and administration procedures). The considerations above regarding efficient dispensing and administration procedures are well known in the art and described in standard textbooks. Drug dispensing is discussed, for example, in the following literature: Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.

[0411] Suitable excipients are non-toxic to individuals at the dosage and concentration used, and may contain one or more of the following: 1) buffers, such as phosphates, citrates, or other organic acids; 2) salts, such as sodium chloride; 3) antioxidants, such as ascorbic acid or methionine; 4) preservatives, such as octadecyl dimethylbenzamide chloride, hexamethyl quaternary ammonium chloride, benzalkonium chloride, benzyl chloride, phenol, butanol, or benzyl alcohol; 5) alkyl p-hydroxybenzoate (such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate), catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol; 6) low molecular weight peptides (less than about 10 residues); 7) proteins, such as serum albumin, gelatin, or immune... 8) Immunoglobulins; 9) Hydrophilic polymers, such as polyvinylpyrrolidone; 10) Amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 11) Monosaccharides, disaccharides, or other carbohydrates, including glucose, mannose, or dextrin; 12) Chelating agents, such as EDTA; 13) Sugars, such as sucrose, mannitol, trehalose, or sorbitol; 14) Salt-forming counterions, such as sodium, metal complexes (e.g., Zn-protein complexes); or 15) Nonionic surfactants, such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamer, or polyethylene glycol (PEG).

[0412] Liposomes containing the compounds of the present invention can be prepared by methods known in the art (see, for example, Chang, HI; Yeh, MK, Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49-60). Particularly useful liposomes can be produced by reverse-phase evaporation of a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derived phosphatidylethanolamine (PEG-PE). Liposomes can be extruded through a filter with defined pore size to produce liposomes of a desired diameter.

[0413] The compounds of this invention can also be encapsulated in microcapsules prepared, for example, by coagulation techniques or by interfacial polymerization, such as hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or coarse droplet emulsions. These techniques are disclosed in Remington's *The Science and Practice of Pharmacy*, 20th Ed., Mack Publishing (2000).

[0414] Sustained-release formulations can be used. Suitable examples of sustained-release formulations include semi-permeable matrices of solid hydrophobic polymers containing the compounds of the present invention, which are in the form of molded objects, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and 7-L-glutamic acid ethyl ester, non-degradable ethylene-vinyl acetate, degradable lacto-hydroxyacetic acid copolymers (such as those used in leuprolide acetate in reservoir suspensions (injectable microspheres composed of lacto-hydroxyacetic acid copolymers and leuprolide acetate), sucrose isobutyrate acetate, and poly-D-(-)-3-hydroxybutyric acid.

[0415] Preparations intended for intravenous administration must be sterile. This is easily achieved, for example, by filtration through a sterile filter membrane. The compounds of this invention are typically placed in containers with sterile inlets and outlets, such as intravenous solution bags or vials with stoppers that can be punctured by a hypodermic needle.

[0416] Suitable emulsions can be prepared using the following commercially available fat emulsions: such as fat emulsions containing soybean oil, fat emulsions for intravenous administration (e.g., safflower oil, soybean oil, lecithin, and glycerol contained in water), emulsions containing soybean oil and medium-chain triglycerides, and fat emulsions containing cottonseed oil. The active ingredient can be dissolved in a premixed emulsion composition, or alternatively, it can be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and mixed with phospholipids (e.g., lecithin, soybean phospholipids, or soybean lecithin) and water to form an emulsion. It should be recognized that other ingredients (e.g., glycerol or glucose) can be added to adjust the osmotic properties of the emulsion. Suitable emulsions typically contain up to 20% oil, for example, between 5% and 20%. Fat emulsions may contain fat droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and have a pH range of 5.5 to 8.0.

[0417] For example, the emulsion composition can be prepared by mixing the compound of the present invention with a lipid emulsion containing soybean oil or its components (soybean oil, lecithin, glycerol and water).

[0418] Pharmaceutical intermediates (DPIs) are partially processed materials that require further processing steps before becoming bulk drug products. The compounds of this invention can be formulated into DPIs containing active ingredients in a form with a higher free energy than the crystalline form. One reason for using DPIs is to improve oral absorption characteristics due to their low solubility, slow dissolution, improved mass transport through the mucus layer of adjacent epithelial cells, and in some cases, limitations imposed by biological barriers such as metabolic and transport proteins. Other reasons may include improved solid-state stability and downstream manufacturability. In one embodiment, the pharmaceutical intermediate comprises a separated and stable amorphous form of the compound of this invention (e.g., an amorphous solid dispersion (ASD)). Many techniques known in the art are used to manufacture ASDs, producing materials suitable for integration into drug products, such as spray-dried dispersions (SDDs), melt extrusions (commonly referred to as HMEs), coprecipitates, amorphous drug nanoparticles, and nanoadsorbents. In one embodiment, the amorphous solid dispersion comprises the compound of this invention and a polymeric excipient. Other excipients and their concentrations, as well as the concentrations of the excipients and the compounds of the present invention, are well known in the art and described in standard textbooks. See, for example, Navnit Shah et al., “Amorphous Solid Dispersions Theory and Practice”.

[0419] In another aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use as medicines, particularly for treating abnormal cell growth.

[0420] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of abnormal cell growth in an individual, such as a tumor, such as a MEK-associated tumor in an individual.

[0421] In another aspect, the present invention provides compounds of any of the formulas described herein or pharmaceutically acceptable salts thereof for treating abnormal cell growth (e.g., tumors, such as MEK-associated tumors).

[0422] The application of the compounds of the present invention can be achieved by any method capable of delivering the compounds to the site of action. Such methods include oral, duodenal, parenteral (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), local, and rectal administration.

[0423] Dosing regimens can be adjusted to provide the most suitable and desired response. For example, a single rapid bolus can be administered, several fractionated doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment. For ease of administration and dosage consistency, it is particularly advantageous to prepare parenteral compositions in unit dosage forms. As used herein, a unit dosage form refers to a physically discrete unit suitable as a single dose for use on a mammalian individual to be treated; each unit contains a predetermined amount of the active compound, calculated to combine with the desired pharmaceutical carrier to produce the desired therapeutic effect. The specifications of the unit dosage forms of the present invention may be defined by and directly depend on: (a) the unique characteristics of the compound administered and the specific therapeutic or preventative effect to be achieved, and (b) the inherent limitations in the technology of composing this active compound to treat the individual's sensitivity.

[0424] Therefore, those skilled in the art will understand from the disclosure provided herein that the dosages and administration regimens are adjusted according to methods well known in therapeutic techniques. This allows for the easy establishment of the maximum tolerated dose and the determination of the effective dose that provides detectable therapeutic benefit to the patient, as well as the determination of the time required to administer each agent to provide detectable therapeutic benefit to the patient. Therefore, while specific dosages and administration regimens are illustrated herein, these examples do not in any way limit the dosages and administration regimens available to patients for implementing the present invention.

[0425] It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that specific dosing regimens for any particular individual should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the composition, and the dosage ranges presented herein are merely illustrative and not intended to limit the scope or implementation of the proposed compositions. For example, dosage may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects, such as toxic effects and / or laboratory values. Therefore, the present invention includes dose increments for the same patient as determined by those skilled in the art. Determining appropriate dosages and dosing regimens for administering chemotherapeutic agents is well known in the relevant art, and those skilled in the art will understand the methods of determination included once provided with the teachings disclosed herein. In one embodiment, an effective dose, whether in a single or multiple dose, is typically in the range of about 0.001 to about 100 mg / kg body weight / day, and often from about 0.01 to about 35 mg / kg / day. For a 70 kg human, this dosage can total from approximately 0.07 mg / day to approximately 7000 mg / day, more commonly from approximately 10 mg / day to approximately 1000 mg / day. This dosage is sometimes approximately 10, 20, 30, 40, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 750, 800, 900, or 1000 mg / day. The dosage is sometimes about 10 mg / day to about 1000 mg / day, about 10 mg / day to about 750 mg / day, about 10 mg / day to about 600 mg / day, about 10 mg / day to about 300 mg / day, about 10 mg / day to about 150 mg / day, about 20 mg / day to about 750 mg / day, about 20 mg / day to about 600 mg / day, about 20 mg / day to about 300 mg / day, about 20 mg / day to about 150 mg / day, about 50 mg / day to about 750 mg / day, about 50 mg / day to about 600 mg / day, about 50 mg / day to about 300 mg / day, about 50 mg / day to about 150 mg / day, about 75 mg / day to about 750 mg / day, about 75 mg / day to about 600 mg / day, about 75 mg / day to about 300 mg / day, or about 75 mg / day to about 150 mg / day. In some cases, dose values ​​below the lower limit of the aforementioned range may be more appropriate, while in other cases, larger doses may still be used without causing any harmful side effects, where the larger dose is typically divided into several smaller doses administered throughout the day. In one implementation, an individual is administered approximately 50 mg / day.

[0426] Since it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a specific disease or condition, within the scope of this invention, two or more pharmaceutical compositions (at least one of which contains a compound according to the invention) can be suitably combined into a pillbox form suitable for co-administration of the composition. Therefore, the pillbox of this invention comprises two or more individual pharmaceutical compositions (at least one of which contains a compound according to the invention) and separate means for retaining the composition, such as containers, dispensing vials, or dispensing foil packs. An example of such a pillbox is the common blister pack used for packaging tablets, capsules, and the like.

[0427] The pillbox of this invention is particularly suitable for administering different dosage forms (e.g., oral and parenteral), administering individual compositions at different dose intervals, or titrating individual compositions relative to each other. To assist in adherence to medical orders, the pillbox typically includes administration instructions and may be equipped with memory aids. In some embodiments, the pillbox includes a compound or a pharmaceutical composition thereof and a diagnostic agent. In another embodiment, the pillbox includes a compound or a pharmaceutical composition thereof and one or more therapeutic agents, such as BRAF inhibitors, for example selected from the following BRAF inhibitors: N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-2,4-difluorophenyl)propane-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline)propane ... -6-yl)amino)-4,5-difluorophenyl)propane-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)propane-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide; N-(2-chloro-4-fluoro-3-((5-methyl-3-(methyl-d3)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-3-phenyl)-3 -Fluoropropane-1-sulfonamide; N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}propane-1-sulfonamide; N-(3-chloro-4-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluoropyridin-2-yl)propane-1-sulfonamide; N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}-3-fluoropropane-1-sulfonamide; N-(2-chloro-4-fluoro-3- ((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)phenyl)-2-azabicyclo[2.1.1]hexane-2-sulfonamide; (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)phenyl)-3-fluoropyrrolidine-1-sulfonamide; and N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-4-fluorophenyl)-3-fluoroazabicyclobutane-1-sulfonamide; or pharmaceutically acceptable salts thereof.

[0428] The following routes and written descriptions provide general details regarding the preparation of the compounds of this invention.

[0429] The compounds of the present invention can be prepared by any method known in the art for preparing compounds with similar structures. The compounds of the present invention can be prepared, in particular, by the procedure described with reference to the immediately following route, or by the specific method described in the examples, or by a method similar to either.

[0430] Those skilled in the art will understand that the experimental conditions presented in the following route are examples of conditions suitable for achieving the transformation shown, and that it may be necessary or desirable to change the precise conditions used to prepare compounds of Formula I and compounds falling within Formula I (e.g., compounds of Formula II) and the like.

[0431] Furthermore, those skilled in the art will understand that it may be necessary or desirable to protect one or more sensitive groups at any stage of the synthesis of the compounds of the present invention to prevent undesirable side reactions. Protection of amino or alcohol groups may be particularly necessary or desirable. Protecting groups (PGs) used in the preparation of the compounds of the present invention can be used in a conventional manner. See, for example, those described in Theodora W. Greene and Peter G. M. Wuts, third edition 'Greene's Protective Groups in Organic Synthesis' (John Wiley and Sons, 1999), particularly in sections 7 ("Protection for the Amino Group") and 2 ("Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols"), which are incorporated herein by reference, which also describe methods for removing such groups.

[0432]

[0433] Route 1 describes a general method for preparing compound 8, wherein R is a specific compound. 1 For H, R 2 For H, R 3 It is a C3-C6 cycloalkyl group, and R 4 For compounds of formula I as defined in formula I, commercially available 2,6-dichloro-4-methylnicotinic acid (compound 1) can be converted into ester analog 2 after treatment with (trimethylsilyl)diazomethane. Compound 2 can be converted into dimethylaminovinyl intermediate compound 3 after treatment with N,N-dimethylformamide dimethyl acetal. Compound 3 can be converted into aldehyde intermediate compound 4 after treatment with a suitable acid (such as hydrochloric acid) in a suitable solvent (such as ether). Cyclization of compound 4 can be achieved by using a compound having formula R 3 NH2 (of which R) 3Compound 4 is obtained by treating compound 5 with a reagent having the formula R in the presence of a reducing agent (e.g., sodium cyanoborohydride) in a suitable solvent (e.g., methanol). Compound 5 can be converted to compound 6 by treatment with trimethyliodosilane in a suitable solvent (e.g., acetonitrile). Compound 6 can be methylated by treatment with iodomethane in the presence of a suitable base (e.g., alkali metal carbonate, such as potassium carbonate) in a suitable solvent (e.g., THF) to obtain compound 7. Compound 7 can be obtained by treatment with a reagent having the formula R in the presence of a suitable base (e.g., sodium cyanoborohydride) in a suitable solvent (e.g., methanol). 4 NH2 (of which R) 4 The reagent (as defined for Formula I) undergoes aromatic nucleophilic substitution after treatment in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilazide) to provide compound 8.

[0434]

[0435] Route 2 describes a general method for preparing compound 17, wherein R is a specific compound. 1 For H, R 2 For H, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and R 4 For compounds of Formula I as defined, commercially available 4-bromo-2,6-dichloropyridine can be lithiated with a reagent (such as lithium diisopropylamine) and captured with carbon dioxide to provide carboxylic acid 10. Compound 10 can be converted to compound 11 by reflux in an aqueous base (such as 4M sodium hydroxide). Compound 11 can be methylated by treatment with iodomethane in the presence of a suitable base (such as an alkali metal carbonate, such as potassium carbonate) and in a suitable solvent (such as DMF) to provide compound 12. Compound 12 can be converted to vinyl ether intermediate 13 by reacting (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (compound (i)) with a catalyst (such as methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) and a basic base (e.g., an alkali metal carbonate, such as aqueous potassium carbonate) in a suitable solvent (such as 1,4-dioxane) using Suzuki. Compound 13 can be converted to vinyl ether intermediate 13 by reacting (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxane using formula R 3a -NH2HCl (where R) 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and P1 Compound 14 is obtained by treatment with an alcohol protecting group (such as tert-butyl, benzyl, or tert-butyldimethylsilyl), followed by heating with triethylamine and HCl in a suitable solvent (such as 1,4-dioxane) to form an oximine. Compound 14 can be reduced to an alkoxyamine intermediate 15 using a suitable reducing agent (such as sodium cyanoborohydride) in a suitable solvent (such as isopropanol). Compound 15 can be further reduced to an alkoxyamine intermediate having the formula R. 4 NH2 (of which R) 4 As defined in Formula I, a reagent undergoes aromatic nucleophilic substitution and simultaneous cyclization after treatment in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilamide). If compound 16 contains P 1 The protecting group is then optionally deprotected (using standard alcohol deprotection conditions known to those skilled in the art, such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride) to provide R 3 Compound 17 is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-.

[0436]

[0437] Route 3 describes a general method for preparing compound 20, wherein R is a specific compound. 1 For H, R 2 CH3-, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and R 4 For compounds of formula I as defined in formula I. Compound 15 prepared as described in route 2 (where R 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and P 1 It is an alcohol protecting group (such as tert-butyl, benzyl, or tert-butyldimethylsilyl), and wherein R 4 As defined for equation I, it can be expressed as having equation R. 4 NH2 (of which R) 4The reagent (as defined for Formula I) is cyclized in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilamide) to provide compound 16. Compound 16 may be iodinated with N-iodosuccinimide and p-toluenesulfonic acid in a suitable solvent (such as 1:1 MeOH:THF) to provide compound 18. Compound 18 may undergo Negishi coupling with methyl zinc chloride (II) using a catalyst (e.g., a palladium catalyst, such as bis(tri-tert-butylphosphine)palladium(O)) in a suitable solvent (such as THF), and if compound 19 contains a protecting group, may subsequently undergo deprotection (using standard alcohol deprotection conditions known to those skilled in the art, such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride) to provide wherein R 3 Compound 20 is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy compound.

[0438]

[0439] Route 4 describes a general method for preparing compound 24, wherein R is a specific compound. 1 For H, R 2 For H, R 3 Let H be the number of 'R', and R be the number of 'R'. 4 For compounds of formula I as defined in formula I. Compound 13 prepared as described in route 2 can be used in compounds having formula R. 4 NH2 (of which R) 4 As defined for Formula I, a reagent undergoes aromatic nucleophilic substitution after treatment in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilamide) to provide compound 21. Compound 21 can be hydrolyzed under acidic conditions using an acid (such as trifluoroacetic acid) in a suitable solvent (such as dichloromethane) to form aldehyde intermediate 22. Compound 22 can be further hydrolyzed in a solution having the formula P 2- NH2 (of which P) 2 After treatment with an amine protecting group (such as benzyl, p-methoxybenzyl, or 2,4-dimethoxybenzyl), cyclization is performed using a reducing agent (such as sodium triacetoxyborohydride) in a suitable solvent (such as dichloroethane) to provide compound 23. Deprotection of compound 23 can be achieved using standard deprotection conditions known to those skilled in the art, such as heating with trifluoroacetic acid or hydrochloric acid to provide compound 24.

[0440]

[0441] Route 5 describes a general method for preparing compound 27, wherein R is a specific compound. 1 For H, R 2 For H, R3 It is a hydroxyl C1-C6 alkyl group, and R 4 For compounds of formula I as defined in formula I, compound 13 prepared as described in route 2 can be hydrolyzed with a suitable acid (such as trifluoroacetic acid) to form aldehyde intermediate 25. Compound 25 can be reacted with formula P 1 O-(C1-C6 alkyl)-ONH2HCl (where P) 1 A reagent for protecting an alcohol group (such as tert-butyldimethylsilyl) is reacted with a suitable reducing agent (such as sodium triacetoxyborohydride) and acetic acid in a suitable solvent (such as dichloroethane) at 60°C to provide a cyclized deprotected compound 26. Compound 26 can be expressed in the form of formula R. 4 NH2 (of which R) 4 The reagent (as defined for Formula I) undergoes aromatic nucleophilic substitution after treatment in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilamide) to provide compound 27.

[0442]

[0443] Route 6 describes a general method for preparing an alternative to compound 17, wherein R is... 1 For H, R 2 For H, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy, and R 4 For compounds of formula I as defined in formula I. Compound 28, prepared according to a method similar to that of compound 13, can be used in compounds having formula R. 4 NH2 (of which R) 4 As defined in Formula I, a reagent undergoes aromatic nucleophilic substitution after treatment in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilamide) to provide compound 29. Compound 29 can be produced in the form of Formula R. 3a NH2 HCl (where R) 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl) C1-C6 alkoxy, and P 1 Compound 30 is obtained by treatment with an alcohol protecting group (such as tert-butyl, benzyl, or tert-butyldimethylsilyl), followed by heating with triethylamine and HCl in a suitable solvent (such as 1,4-dioxane) to undergo oxime formation. Compound 30 can be cyclized in a suitable solvent (such as isopropanol) with a suitable reducing agent (such as sodium cyanoborohydride) and acetic acid, if compound 30 contains P... 1The protecting group is then optionally deprotected (using standard alcohol deprotection conditions known to those skilled in the art, such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride) to provide R 3 Compound 17 is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy compound.

[0444]

[0445] Route 7 describes a general method for preparing an alternative to compound 17, wherein R is... 1 For H, R 2 For H, R 3 It is a hydroxyl C1-C6 alkoxy group, and R 4 For compounds of Formula I as defined in Formula I, compound 28 can undergo oxime formation by treatment with a reagent of Formula TBSO-(C1-C6 alkyl)-ONH2 HCl followed by heating with triethylamine and HCl in a suitable solvent (such as 1,4-dioxane) to provide compound 32. Compound 32 may have a suitable alcohol protecting group P. 1 Compound 14 is provided by protecting tert-butyldimethylsilyl silane and a suitable base (such as imidazole) in a suitable solvent (such as DMF). Compound 14 can be reduced to alkoxyamine intermediate 15 in a suitable solvent (such as isopropanol) using a suitable reducing agent (such as sodium cyanoborohydride). Compound 15 can be further reduced to alkoxyamine intermediate 15 by using a suitable reducing agent (such as sodium cyanoborohydride). 4 NH2 (of which R) 4 The reagent (as defined for Formula I) undergoes aromatic nucleophilic substitution after treatment in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilamide) to provide compound 16. Compound 16 may be deprotected using standard alcohol deprotection conditions known to those skilled in the art (such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride) to provide compound 17.

[0446]

[0447] Route 8 describes a general method for preparing an alternative to compound 20, wherein R is... 1 For H, R 2 CH3-, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy, and R 4 For example, for compounds of formula I as defined in formula I. Compound 28 can be in the form of formula R. 4 NH2 (of which R) 4The reagent (as defined for Formula I) undergoes aromatic nucleophilic substitution after treatment in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilamide) to provide compound 29. Compound 29 can be hydrolyzed with a suitable acid (such as trifluoroacetic acid) to aldehyde intermediate 22. Compound 22 can be reacted with formula R 3a NH2 HCl (where R) 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl) C1-C6 alkoxy, and P 1 A reagent for protecting an alcohol group, such as tert-butyl, benzyl, or tert-butyldimethylsilyl, is reacted with a suitable reducing agent (such as sodium triacetoxyborohydride) and acetic acid in a solvent (such as dichloroethane) at 60°C to provide a cyclized compound 16. Compound 16 can be iodinated with N-iodosuccinimide and p-toluenesulfonic acid in a suitable solvent (such as 1:1 MeOH:THF) to provide compound 18. Compound 18 can undergo root-lake coupling with methyl zinc(II) chloride using a catalyst (such as bis(tri-tert-butylphosphine)palladium(O)) in a suitable solvent (such as THF), if compound 18 contains P 1 The protecting group is then optionally deprotected (using standard alcohol deprotection conditions known to those skilled in the art, such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride) to provide R 3 Compound 20 is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy compound.

[0448]

[0449] Route 9 describes a general method for synthesizing compound 35, in which R is... 1 For H, R 2 For halogens, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy, and R 4 For example, for compounds of formula I as defined in formula I. Compound 12 can be in the form of formula R. 4 NH2 (of which R) 4As defined for Formula I, a reagent undergoes aromatic nucleophilic substitution after treatment with a strong base (such as lithium hexamethyldisilamide) in a suitable solvent (such as THF) to provide compound 33. Compound 33 can be converted to vinyl ether intermediate 21 via a Suzuki reaction with (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane using a catalyst (e.g., a palladium catalyst, such as methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) and a basic base (e.g., an alkali metal carbonate base, such as aqueous potassium carbonate) in a suitable solvent (such as 1,4-dioxane). Compound 21 can be converted to vinyl ether intermediate 21 via a Suzuki reaction with (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxane. 3a NH2 HCl (where R) 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl) C1-C6 alkoxy, and P 1 Compound 30 is obtained by treatment with an alcohol protecting group (such as tert-butyl, benzyl, or tert-butyldimethylsilyl), followed by heating with triethylamine and HCl in a suitable solvent (such as 1,4-dioxane) to undergo oxime formation. Compound 30 can be treated with a suitable reducing agent (such as sodium cyanoborohydride) and acetic acid in a suitable solvent (such as isopropanol) to produce a cyclized compound 31. Compound 31 can be halogenated under the following conditions: treatment with N-iodosuccinimide and p-toluenesulfonic acid in a 1:1 THF / MeOH solution, or treatment with N-bromosuccinimide in a suitable solvent (such as DMF), or treatment with N-chlorosuccinimide in a suitable solvent (such as DMF), or treatment with Selectfluor in a suitable solvent (such as acetonitrile), if compound 31 has P 1 The protecting group is then optionally deprotected (e.g., with phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride) to provide R 2 These are iodine, bromine, chlorine, or fluorine, and R. 3 Compound 35 is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy compound.

[0450]

[0451] Route 10 describes a general method for preparing an alternative to compound 17, wherein R is... 1 For H, R 2 For H, R 3It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy, and R 4 For example, for compounds of formula I as defined in formula I. Compound 12 can be in the form of formula R. 4 NH2 (of which R) 4 As defined for Formula I, a reagent undergoes aromatic nucleophilic substitution in a suitable solvent (such as THF) in the presence of a suitable base (such as potassium tert-butoxide) to provide compound 36. Compound 36 can be converted to vinyl ether intermediate 29 by a Suzuki reaction with (Z)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane using a catalyst (such as a palladium catalyst, such as methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)) and a suitable base (such as a basic base, such as an alkali metal carbonate base, such as aqueous potassium carbonate) in a solvent (such as 2-methyltetrahydrofuran). Compound 29 can be converted to vinyl ether intermediate 29 by a Suzuki reaction with formula R. 3a NH2 HCl (where R) 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl) C1-C6 alkoxy, and P 1 The reagent (such as tert-butyl, benzyl, or tert-butyldimethylsilyl) used as an alcohol protecting group reacts with triethylamine and hydrochloric acid in a suitable solvent (such as 1,4-dioxane), followed by treatment with a suitable reducing agent (such as pyridineborane) and hydrochloric acid, and heating at 60°C. If compound 29 has P 1 The protecting group is then optionally deprotected (e.g., with phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride) to provide R 3 Compound 17 is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy compound.

[0452]

[0453] Route 11 describes a method for preparing compound 43, wherein R is a specific compound. 1 It is a phenyl group, R 2 For hydrogen, R 3 It is hydrogen, and R 4For compounds of Formula I as defined in Formula I. Commercially available 2,6-dichloro-4-iodopyridine can be lithiated with a reagent (such as lithium diisopropylamine) and captured with carbon dioxide to provide compound 37. Compound 37 can be converted to compound 38 by reflux in an aqueous base (such as 4M sodium hydroxide). Compound 38 can be methylated by treatment with iodomethane in the presence of a suitable base (such as alkali metal carbonate, such as potassium carbonate) in a suitable solvent (such as DMF) to provide compound 39. Compound 39 can be converted to vinyl ether intermediate 40 by a Suzuki reaction with 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxaborane using a suitable catalyst (such as a palladium catalyst, such as Pd(dppf)Cl2) and a base (such as an alkali metal carbonate, such as aqueous potassium carbonate) in a suitable solvent (such as 1,4-dioxane). Compound 40 can be converted to vinyl ether intermediate 40 by a Suzuki reaction with 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxaborane using a suitable catalyst (such as a palladium catalyst, such as Pd(dppf)Cl2) and a base (such as an alkali metal carbonate, such as aqueous potassium carbonate) in a suitable solvent (such as 1,4-dioxane). 4 NH2 (of which R) 4 The reagent (as defined for Formula I) undergoes aromatic nucleophilic substitution after treatment in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilamide) to provide compound 41. Compound 41 can be cyclized by heating in a suitable solvent (such as toluene) with (2,4-dimethoxyphenyl)methylamine in the presence of a Lewis acid (such as trimethylaluminum) to provide compound 42. Compound 42 can be deprotected by heating with a suitable acid (such as TFA) to provide compound 43.

[0454]

[0455] Route 12 describes a method for preparing compound 51, wherein R is a specific compound. 1 It is methyl, R 2 For hydrogen, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy, and R 4For compounds of Formula I as defined in Formula I. Compound 44 can be treated with NH3, Fe(NO3)3·9H2O and NaNH2 at a low temperature, followed by treatment with iodomethane to provide compound 45. Compound 45 can be heated with benzo[d][1,3,2]dioxaborole in a suitable solvent (such as toluene) with a catalyst (such as NiCl2(dppe)) to provide compound 46. Compound 46 can be converted to compound 47 by reacting with compound 39 under Suzuki reaction conditions in a suitable solvent (such as a solvent mixture, such as toluene / THF) in the presence of a catalyst (such as a palladium catalyst, such as Pd(dppf)Cl2) and a base (such as K3PO4, K2CO3, KOtBu, Cs2CO3, NaOH or triethylamine). 3a NH2HCl (where R) 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl) C1-C6 alkoxy, and P 1 Compound 48 is obtained by treatment with an alcohol protecting group (such as tert-butyl, benzyl, or tert-butyldimethylsilyl), followed by heating with triethylamine and HCl in a suitable solvent (such as 1,4-dioxane) to undergo oxime formation. Compound 48 can be treated with a suitable reducing agent (such as sodium cyanoborohydride) and acetic acid in a suitable solvent (such as isopropanol) to produce a cyclized product 49. Compound 49 can be further processed with a solvent having the formula R... 4 NH2 (of which R) 4 As defined in Formula I, the reagent undergoes aromatic nucleophilic substitution after treatment in a suitable solvent (such as THF) in the presence of a strong base (such as lithium hexamethyldisilamide), and if compound 49 contains P 1 The protecting group is then optionally deprotected (using standard alcohol deprotection conditions known to those skilled in the art, such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride) to provide R 3 Compound 51 is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy compound.

[0456] As used herein, the term "amine protecting group" refers to a derivative of a group that is typically used to block or protect an amino group while the reaction is carried out on other functional groups of a compound. Examples of protecting groups suitable for use in any of the methods described herein include urethanes, amides, alkyl and aryl groups, imines, and many N-heteroatom derivatives that can be removed to regenerate the desired amino group. Non-limiting examples of amine protecting groups are tert-butoxycarbonyl ("Boc"), 2-trimethylsilylethoxymethyl (SEM), and p-methoxybenzyl (PMB). Further examples of these groups and other protecting groups can be found in TW Greene et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

[0457] As used herein, the term "alcohol protecting group" refers to a derivative of a group that is typically used to block the hydroxyl group while the reaction is carried out on other functional groups of a compound. Examples of protecting groups suitable for use in any of the methods described herein include benzyl, triphenylmethyl, silyl ethers, etc.

[0458] Intermediate compounds 7, 15, 18, 22, 26, 29, 30 and 31, as illustrated in the above routes, are also novel intermediates that can be used to prepare compounds of formula I and provide other embodiments of the present invention.

[0459] In one embodiment, this document provides a method for preparing a compound of formula I, comprising:

[0460] (a) For R 1 For H, R 2 For H, R 3 It is a C3-C6 cycloalkyl group, and R 4 For example, for compounds of formula I as defined in formula I, compounds of formula 7...

[0461]

[0462] With formula R 4 NH2 (of which R) 4 For example, the reagent (as defined in Formula I) reacts in the presence of a strong base; or

[0463] (b) For R 1 For H, R 2 For H, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and R 4 For example, for compounds of formula I as defined in formula I, compounds of formula 15...

[0464]

[0465] Where R 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and P 1 As an alcohol protecting group, in the presence of formula R 4 NH2 (of which R) 4 Cyclization in the presence of a reagent as defined in Formula I, in the presence of a strong base, optionally followed by removal of the alcohol protecting group (if present); or

[0466] (c) For R 1 For H, R 2 CH3-, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and R 4 For example, for compounds of formula I as defined in formula I, compounds of formula 18...

[0467]

[0468] Where R 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy, P 1 It is an alcohol protecting group, and R 4 As defined for Formula I, treatment with methyl zinc(II) chloride in the presence of a palladium catalyst, followed by removal of the alcohol protecting group (if present); or

[0469] (d) For R 1 For H, R 2 For H, R 3 Let H be the number of 'R', and R be the number of 'R'. 4 For example, for compounds of formula I as defined in formula I, compounds of formula 22...

[0470]

[0471] Where R 4 As defined for equation I, in the case of equation P 2- NH2 (of which P) 2 The reagent containing the amine protecting group undergoes cyclization, followed by removal of the amine protecting group; or

[0472] (e) For R 1 For H, R 2 For H, R 3It is a hydroxyl C1-C6 alkyl group, and R 4 For example, for compounds of formula I as defined in formula I, compounds of formula 26...

[0473]

[0474] In having formula R 4 NH2 (of which R) 4 Such as the reaction in the presence of a reagent (as defined in Formula I) or in the presence of a strong base; or

[0475] (f) For R 1 For H, R 2 For H, R 3 It is a hydroxyl C1-C6 alkyl group, and R 4 For example, for compounds of formula I as defined in formula I, compounds having formula 30

[0476]

[0477] Where P 1 It is an alcohol protecting group, and R 4 As defined for Formula I, cyclization occurs in the presence of a reducing agent, followed by removal of the alcohol protecting group; or

[0478] (g) For R 1 For H, R 2 For halogens, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and R 4 For example, for compounds of formula I as defined in formula I, halogenating compounds of formula 31

[0479]

[0480] Where R 4 As defined for equation I, R 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and P 1 The alcohol protecting group is then removed (if present); or

[0481] (h) for R 1 For H, R 2 For H, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and R 4 For example, for compounds of formula I as defined in formula I, compounds of formula 29...

[0482]

[0483] Where R 4 As defined for equation I, and equation P 1 O-(C1-C6 alkyl)-ONH2HCl (where P) 1 The reagent (with an alcohol protecting group) reacts in the presence of triethylamine and hydrochloric acid, followed by removal of the alcohol protecting group; or

[0484] (i) For R 1 It is a phenyl group, R 2 For hydrogen, R 3 It is hydrogen, and R 4 For example, for compounds of formula I as defined in formula I, compounds having formula 41

[0485]

[0486] Where R 4 As defined for Formula I, cyclization of (2,4-dimethoxyphenyl)methylamine in the presence of a Lewis acid at elevated temperature provides a compound having Formula 42:

[0487]

[0488] Compound 42 was then treated with acid; or

[0489] (j) For R 1 For methyl, R 2 For hydrogen, R 3 It is hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy, and R 4 For example, for compounds of formula I as defined in formula I, compounds having formula 49

[0490]

[0491] Where R 3a For P 1 O-C1-C6 alkoxy-, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, and P 1 It is an alcohol protecting group, and has the formula R 4 NH2 (of which R) 4 For example, if the reagent (as defined in Formula I) reacts in the presence of a strong base, and then P is removed... 1 Protecting base (if present); and

[0492] Optionally, the compound of formula I may be converted into a pharmaceutically acceptable salt.

[0493] Synthetic intermediates 3, 4, 5, 6, 7, 13, 14, 15, 16, 18, 21, 22, 23, 25, 26, 28, 29, 30, 32, 33, 36, 37, 38, 39, 40, 41, 42, 47, 48 and 49 are also considered novel and are other embodiments of the present invention.

[0494] This invention can be further understood by referring to the embodiments of the invention described in detail below and the examples included herein. It should be understood that the invention is not limited to the specific synthesis method, which can of course be modified. It should also be understood that the terminology used herein is for illustrative purposes only and is not intended to be restrictive.

[0495] E1. Compounds of formula I or their pharmaceutically acceptable salts:

[0496]

[0497] in:

[0498] R 1 It can be H, Br, C1-C6 alkyl or phenyl;

[0499] R 2 It can be H, halogen, or CH3-;

[0500] R 3 It is H, hydroxyC1-C6 alkyl-, hydroxyC1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)C1-C6 alkoxy-; and

[0501] R 4 It is a phenyl group that has been substituted with one, two or three independent substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

[0502] E2. The compound or a pharmaceutically acceptable salt thereof according to embodiment E1, wherein R 1 For H.

[0503] E3. A compound or a pharmaceutically acceptable salt thereof according to implementation scheme E1 or E2, wherein R 2 For H.

[0504] E4. A compound or a pharmaceutically acceptable salt thereof according to implementation scheme E1 or E2, wherein R 2 It is CH3-.

[0505] E5. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E1 to E4, wherein R 3 It is a hydroxyl C1-C6 alkyl-.

[0506] E6. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E1 to E5, wherein R 4 It is a phenyl group substituted with one or two independent substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

[0507] E7. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E1 to E6, wherein R 4 It is a phenyl group substituted with one or two substituents independently selected from the following: halogen and C1-C6 alkylthio group.

[0508] E8. Compounds of Formula II or their pharmaceutically acceptable salts:

[0509]

[0510] in

[0511] R 1 It can be H, Br, C1-C6 alkyl or phenyl;

[0512] R 2 It can be H, halogen, or CH3-;

[0513] R 3 It is H, hydroxyC1-C6 alkyl-, hydroxyC1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)C1-C6 alkoxy-; and

[0514] R a and R b It is independently selected from halogens, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

[0515] E9. The compound or a pharmaceutically acceptable salt thereof according to embodiment E8, wherein R 1 For H.

[0516] E10. A compound or a pharmaceutically acceptable salt thereof according to embodiment E8 or E9, wherein R 2 For H.

[0517] E11. A compound or a pharmaceutically acceptable salt thereof according to embodiment E8 or E9, wherein R 2 It is CH3-.

[0518] E12. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E8 to E11, wherein R 3 It is a hydroxyl C1-C6 alkyl-.

[0519] E13. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E8 to E11, wherein R 3 For H.

[0520] E14. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E8 to E13, wherein R a It is a halogen.

[0521] E15. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E8 to E14, wherein R b It is a halogen, C1-C6 alkyl, C1-C6 alkylthio or fluoroC1-C6 alkoxy.

[0522] E16. The compound or a pharmaceutically acceptable salt thereof according to embodiment E15, wherein R b It is a C1-C6 alkylthio group.

[0523] E17. The compound according to embodiment E1 is selected from:

[0524] 8-((4-bromo-2-fluorophenyl)amino)-2-cyclopropyl-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0525] 8-((4-bromo-2-fluorophenyl)amino)-2-(cyclopropylmethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0526] 8-((4-bromo-2-fluorophenyl)amino)-2-ethoxy-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0527] 2-Cyclopropyl-8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0528] 2-Cyclopropyl-8-((2-fluoro-4-iodophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0529] 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0530] 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0531] 8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0532] 8-((2-chloro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0533] 8-((4-bromo-2-chlorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0534] 8-((4-bromo-2,3-difluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0535] 8-((4-bromo-3-chloro-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0536] 8-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0537] 8-((4-ethyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0538] 8-((4-cyclopropyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0539] 8-((2-fluoro-4-methoxyphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0540] 8-((2-fluoro-4-((trifluoromethyl)thio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0541] 8-((2-fluoro-4-isopropylphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0542] 8-((2-chloro-4-cyclopropylphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0543] 8-((4-acetyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0544] 8-((2-chloro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0545] 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0546] 8-((2-chloro-4-ethylphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0547] 8-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0548] 8-((4-((difluoromethyl)thio)-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0549] 8-((4-bromo-2-fluorophenyl)amino)-2-isopropoxy-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0550] 8-((2-fluoro-4-iodophenyl)amino)-2-isopropoxy-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0551] 2-Ethoxy-8-((2-fluoro-4-iodophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0552] 8-((2-fluoro-4-iodophenyl)amino)-2-methoxy-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0553] 2-(tert-butoxy)-8-((2-fluoro-4-iodophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0554] (S)-8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0555] (R)-8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0556] (S)-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0557] (R)-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0558] (R)-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxypropoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0559] 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0560] 8-((4-bromo-2-fluorophenyl)amino)-5-chloro-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0561] 5-Chloro-8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0562] 8-((4-bromo-2-fluorophenyl)amino)-5-fluoro-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0563] 8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0564] 8-((2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5-iodo-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0565] 5-Bromo-8-((4-Bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0566] 4-Bromo-8-((2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0567] 8-((4-ethyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0568] 8-((4-cyclopropyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0569] 8-((4-bromo-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0570] 8-((4-bromo-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0571] 8-((2-fluoro-4-iodophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0572] 8-((4-iodo-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0573] 8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0574] 8-((4-ethyl-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0575] 8-((4-cyclopropyl-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0576] 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0577] 8-((2-fluoro-4-propylphenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidium-1,6(2H,7H)-dione;

[0578] 8-((2-fluoro-4-(methylthio)phenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0579] 8-((4-ethyl-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0580] 8-((4-cyclopropyl-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0581] 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0582] 8-((4-bromo-2-chlorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0583] 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethyl)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0584] 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0585] 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0586] 2-(2,2-difluoroethoxy)-8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0587] 8-((4-bromo-2-fluorophenyl)amino)-7-methyl-4-phenyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0588] 8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-4-phenyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0589] 8-((4-bromo-2-fluorophenyl)amino)-4,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0590] 8-((2-fluoro-4-(methylthio)phenyl)amino)-4,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0591] 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-4,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0592] 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-4,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione;

[0593] Or its pharmaceutically acceptable salt.

[0594] Compound E18, which is an 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione having the following structure:

[0595]

[0596] Or its pharmaceutically acceptable salt.

[0597] Compound E19, which is an 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione having the following structure:

[0598]

[0599] E20. Crystals containing 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione.

[0600] E21. Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1.

[0601] E22. The PXRD pattern of crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1 according to embodiment E21, having characteristic peaks at 5.0, 8.7, 9.3, 10.8, 14.5, 15.3, 18.8 and 20.5°2θ (±0.2°2θ).

[0602] E23. The anhydrous crystalline 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1 according to embodiment E21, the PXRD pattern of which is substantially consistent with... Figure 1 The same 2θ value peak shown.

[0603] E24. Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2.

[0604] E25. The PXRD pattern of crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2 according to embodiment E24, having characteristic peaks at 7.1, 9.4, 12.4, 12.8, 14.3, 15.6, 16.4, 17.4, 18.5, 18.9, 19.5, 19.9, 21.1, 21.4, 23.2, 23.7, 24.8, 25.6, 27.6, 30.3, 33.2, 33.5 and 37.5°2θ (±0.2°2θ).

[0605] E26. The anhydrous crystalline 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2 according to embodiment E24, the PXRD pattern of which is substantially the same as Figure 2 The same 2θ value peak shown.

[0606] E27. Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2 according to embodiment E25 or E26, wherein the PXRD pattern is obtained by PXRD analysis performed at 25°C and at a relative humidity below 10%.

[0607] E28. Crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3.

[0608] E29. The crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3 according to embodiment E28, having PXRD peaks at 13.7, 18.0 and 18.3°2θ (±0.2°2θ).

[0609] E30. The crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3 according to embodiment E28, having PXRD peaks at 6.9, 9.1, 13.7, 18.0 and 18.3°2θ (±0.2°2θ).

[0610] E31. The crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3 according to embodiment E28, having PXRD peaks at 6.9, 9.1, 11.8, 12.0, 13.7, 14.0, 15.2, 15.8, 18.0, 18.3, 19.0, 19.3, 20.2, 20.9, 21.6, 22.6, 23.6, 24.0, 24.9, 25.2, 25.8, 27.5, 28.1, 28.4, 29.8, 30.9, 31.7, 32.3 and 36.5°2θ (±0.2°2θ) based on 2θ.

[0611] E32. The crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3 according to embodiment E28, the PXRD pattern of which is substantially the same as Figure 3 The same 2θ value peak shown.

[0612] E33. The crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3 according to any one of embodiments E29 to E32, wherein the PXRD pattern is obtained by PXRD analysis performed at 25°C and a relative humidity greater than 35%.

[0613] E34. Amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 4.

[0614] E35. The amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 4 according to embodiment E34, the PXRD pattern of which is substantially the same as Figure 4 The same 2θ value peak shown.

[0615] E36. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E1 to E35, and at least one pharmaceutically acceptable excipient.

[0616] E37. A method for treating MEK-related tumors, comprising administering to an individual in need a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E1 to E35.

[0617] E38. The method according to implementation scheme E37, wherein the tumor has a BRAF V600 mutation selected from V600E, V600K, V600D, V600R and V600S.

[0618] E39. The method according to implementation scheme E37 or E38, wherein the tumor has a BRAF V600E mutation.

[0619] E40. The method according to any one of implementation schemes E37 to E39, wherein the tumor is an extracranial tumor.

[0620] E41. The method according to implementation plan E40, wherein the extracranial tumor is selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer and neuroblastoma.

[0621] E42. The method according to any one of implementation schemes E37 to E39, wherein the tumor is a CNS tumor.

[0622] E43. The method according to implementation plan E42, wherein the CNS tumor is an intracranial tumor.

[0623] E44. The method according to implementation plan E43, wherein the intracranial tumor is brain cancer.

[0624] E45. The method according to implementation plan E44, wherein the brain cancer is a metastatic brain cancer.

[0625] E46. The method according to implementation plan E45, wherein the metastatic brain cancer is selected from metastatic melanoma, metastatic colorectal cancer, metastatic non-small cell lung cancer, metastatic thyroid cancer, and metastatic ovarian cancer.

[0626] E47. The method according to implementation plan E42, wherein the CNS tumor is an intracranial LMD or an extracranial LMD.

[0627] E48. The method according to implementation plan E47, wherein LMD is selected from metastatic melanoma, metastatic colorectal cancer and metastatic non-small cell lung cancer.

[0628] E49. The method according to implementation plan E43, wherein the intracranial tumor is a primary tumor.

[0629] E50. The method of implementation scheme E49, wherein the primary brain tumor is a malignant tumor.

[0630] E51. The method according to implementation plan E50, wherein the primary brain tumor is a grade 2 glioma, a grade 3 glioma, or a grade 4 glioma.

[0631] E52. The method according to implementation scheme E49, wherein the primary brain tumor is a benign tumor.

[0632] E53. The method according to implementation scheme E37, wherein the tumor has BRAF fusion.

[0633] E54. The method according to embodiment E53, wherein the tumor has a composition selected from KIAA11549-BRAF, MKRN1-BRAF, TRIM24-BRAF, AGAP3-BRAF, ZC3HAV1-BRAF, AKAP9-BRAF, CCDC6-BRAF, AGK-BRAF, EPS15-BRAF, NUP214-BRAF, ARMC10-BRAF, BTF3L4-BRAF, GHR-BRAF, ZC3HAV1-BRAF, ZNF767-BRAF, CCDC91-BRAF. AF, DYNC112-BRAF, ZKSCAN1-BRAF, GTF2I-BRAF, MZT1-BRAF, RAD18-BRAF, CUX1-BRAF, SLC12A7-BRAF, MYRIP-BRAF, SND1-BRAF , BRAF fusions of NUB1-BRAF, KLHL7-BRAF, TANK-BRAF, RBMS3-BRAF, STRN3-BRAF, STK35-BRAF, ETFA-BRAF, SVOPL-BRAF and JHDM1D-BRAF.

[0634] E55. According to the method of implementation plan E54, the tumor is breast cancer (e.g., invasive ductal carcinoma of the breast), colorectal cancer (e.g., colonic adenocarcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), glioma (e.g., brain desmoplastic infantile ganglion glioma, brain fibrous astrocytoma, brain pleomorphic xanthoastrocytoma, spinal cord low-grade glioma (NOS), primitive oligodendroglioma, anaplastic ganglion glioma), head and neck cancer (e.g., head and neck neuroendocrine carcinoma), lung cancer (e.g., lung adenocarcinoma, lung non-small cell lung cancer (NOS)). S), melanoma (e.g., Spitz nevus-like cutaneous melanoma, non-Spitz nevus-like mucosal melanoma, Spitz nevus-like cutaneous melanoma, unknown primary melanoma, non-Spitz nevus-like cutaneous melanoma), pancreatic cancer (e.g., adenocarcinoma, pancreatic acinar cell carcinoma), prostate cancer (e.g., prostatic acinar adenocarcinoma), sarcoma (malignant solid fibroma), thyroid cancer (papillary thyroid carcinoma), unknown primary cancer (e.g., unknown primary adenocarcinoma), pleural mesothelioma, rectal adenocarcinoma, endometrial cancer (e.g., endometrial adenocarcinoma (NOS)), or ovarian serous carcinoma.

[0635] E56. The method according to implementation plan E37, wherein the tumor is a BRAF wild-type tumor.

[0636] E57. The method according to any one of implementation schemes E37 to E56, wherein the method further comprises administering one or more additional anticancer therapies.

[0637] E58. According to the method of implementation scheme E57, one or more additional anticancer therapies are independently selected from surgery, radiotherapy and anticancer agents.

[0638] E59. The method according to implementation plan E58, wherein the additional anticancer therapy is selected from one or more anticancer agents.

[0639] E60. The method according to implementation plan E59, wherein the anticancer agent is selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER2 and / or HER3 inhibitors, SHP2 inhibitors, Axl inhibitors, PI3K inhibitors, SOS1 inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapies, and immune-targeting agents, including immunotherapy.

[0640] E61. The method of implementing E60, wherein the anticancer agent is a BRAF inhibitor.

[0641] E62. The method of implementing E61, wherein the BRAF inhibitor is encofenib or a pharmaceutically acceptable salt thereof.

[0642] E63. The method of implementing E61, wherein the BRAF inhibitor is selected from:

[0643] N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)propane-1-sulfonamide;

[0644] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide;

[0645] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)propane-1-sulfonamide;

[0646] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)propane-1-sulfonamide;

[0647] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide;

[0648] N-(2-chloro-4-fluoro-3-((5-methyl-3-(methyl-d3)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-phenyl)-3-fluoropropane-1-sulfonamide;

[0649] N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}propane-1-sulfonamide;

[0650] N-(3-chloro-4-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluoropyridin-2-yl)propane-1-sulfonamide; and

[0651] N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}-3-fluoropropane-1-sulfonamide;

[0652] Or its pharmaceutically acceptable salt.

[0653] E64. The method of implementation scheme E63, wherein the BRAF inhibitor is N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide or a pharmaceutically acceptable salt thereof.

[0654] E65. The method of implementing E61, wherein the BRAF inhibitor is selected from:

[0655] N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-azabicyclo[2.1.1]hexane-2-sulfonamide,

[0656] (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidine-1-sulfonamide, and

[0657] N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluorozahexacyclic butane-1-sulfonamide,

[0658] Or its pharmaceutically acceptable salt.

[0659] E66. The method of implementation scheme E65, wherein the BRAF inhibitor is N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluorozahexacyclobutane-1-sulfonamide or a pharmaceutically acceptable salt thereof.

[0660] E67. The method of implementing E60, wherein the anticancer agent is an SHP2 inhibitor.

[0661] E68. The method of implementation scheme E67, wherein the SHP2 inhibitor is (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine or a pharmaceutically acceptable salt thereof.

[0662] E69. A method according to any one of embodiments E37 to E68, wherein the compound is 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione, and wherein an individual is administered 50 mg of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione once a day.

[0663] E70. A compound or a pharmaceutically acceptable salt thereof, according to any one of embodiments E1 to E35, used as a medicine.

[0664] E71. A compound or a pharmaceutically acceptable salt thereof, according to any one of embodiments E1 to E35, for the treatment of MEK-related tumors.

[0665] E72. Use of a compound or a pharmaceutically acceptable salt thereof from any of embodiments E1 to E35 in the preparation of a medicament for treating an individual with MEK-related tumors.

[0666] To better understand the present invention, the following embodiments are proposed. These embodiments are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0667] The compounds and intermediates described below are named according to the nomenclature conventions provided in ChemDraw version 20.1.1.125 (Perkin Elmer Informatics). The nomenclature conventions provided in ChemDraw version 20.1.1.125 are well known to those skilled in the art and are generally believed to conform to IUPAC (International Union for Pure and Applied Chemistry) recommendations and CAS index rules based on organic chemistry nomenclature. Unless otherwise noted, all reactants were commercially available and prepared without further purification or using methods known in the literature.

[0668] Biological Examples

[0669] Example A

[0670] Cellular phosphorylation-p44 / 42 MAPK(Erk1 / 2)(Thr202 / Tyr204) assay

[0671] Inhibition of ERK1 / 2 (Thr202 / Tyr204) phosphorylation was determined using the following cytological assay, which involved culturing cells with the compound for 1 hour and quantifying pERK signaling and normalizing it to GAPDH signaling on fixed cells using In-Cell Western blotting. The A375 cell line was obtained from ATCC and cultured with 10% fetal bovine serum, penicillin / streptomycin, ... Cells were grown in DMEM supplemented with non-essential amino acids and sodium pyruvate. Cells were seeded at 30,000 cells / well in 96-well plates and allowed to attach overnight at 37°C / 5% CO2. Cells were treated with a compound prepared in 10-point, 1:3 dilution series (range: 20 μM to 0.05 nM; maximum concentration from 20 μM to 1 μM), with a final DMSO concentration of 0.5%. Control wells contained only 0.5% DMSO (no inhibition control) or 1 μM of a highly effective control compound (complete inhibition control). After 1 hour of incubation, cells were fixed for 20 minutes at room temperature in 3.7% formaldehyde in dPBS (Dulbecco phosphate-buffered saline). Cells were then washed with dPBS and infiltrated in 100% MeOH at room temperature for 10 minutes. Following infiltration, cells were washed with dPBS and incubated in LI-COR blocking buffer (LI-COR Biosciences, catalog #927-40000) for 1 hour or longer. The discs were then incubated with antibodies specific to MEK-dependent ERK1 / 2 phosphorylation sites downstream of MEK in the MAP kinase signaling pathway, threonine 202 and tyrosine 204 (Cell Signaling Technologies; catalog #9101), and GAPDH (Millipore; catalog #MAB374). The pErk1 / 2 (Thr202 / Tyr204) antibody was diluted 1:250 in LI-COR blocking buffer containing 0.05% Tween-20; the GAPDH was diluted 1:2,500. The discs were incubated overnight at 4°C. After washing with PBS / 0.05% Tween-20, cells were cultured for 1 hour with fluorescently labeled secondary antibodies (anti-rabbit Alexa Flour680, Invitrogen catalog #A21109; anti-mouse IRDye800CW, LI-COR Biosciences catalog #926-32210, both diluted 1:1000). Cells were then washed as described above and fluorescence analysis was performed using an Odyssey CLx infrared imaging system (LI-COR Biosciences) at both 680 and 800 nm wavelengths. The phosphorylated Erk1 / 2 (Thr202 / Tyr204) signal from each well was normalized to a GAPDH signal. IC50 50 The values ​​were calculated using a 4-parameter fit from the standardized values ​​in BioAssay software and are provided in Table A.

[0672] Table A

[0673]

[0674]

[0675]

[0676] Example B

[0677] MDR1 LLC-PK1 and BCRP MDCKII Permeability Assay

[0678] Both LLC-PK1 and MDR1-transfected LLC-PK1 cells were cultured and seeded according to the manufacturer's recommendations, except that the passage medium contained only 2% fetal bovine serum in order to extend the passage time to seven days.

[0679] The BCRP-transfected MDCKII canine P-gp gene knockout cell line was cultured and inoculated according to the manufacturer's recommendations.

[0680] Positive and negative controls were used to assess the efflux function of P-gp or BCRP in the assay. Stock solutions for the control and test samples were prepared in DMSO at final test concentrations of 10 and 1 μM, respectively. The final organic concentration in the assay was 1%. All titration solutions contained 10 μM lucifer yellow to monitor the integrity of LLC-PK1 or MDCKII cell monolayers.

[0681] Add 75 μL of the test sample in transport buffer to the top of each transwell and 250 μL of bottom-side medium (without the compound or safflower roe) to each well for top-to-bottom measurements (A to B). Add 250 μL of the test sample in transport buffer to each well and 75 μL of transport buffer (without the compound or safflower roe) to each transwell for bottom-to-top measurements (B to A). All tests were performed in triplicate, testing both top-to-bottom and bottom-to-top transport of each compound. Incubate the trays on a Lab-Line Instruments TiterOrbital Shaker (VWR, West Chester, PA) at 50 rpm and 37°C with 5% CO2 for 2 hours. Remove all trays from the incubator, remove 50 μL of medium from the top and bottom portions of each well, and add it to 150 μL of 1 μM labetalol in a 2:1 acetonitrile (acetonitrile):H2O, v / v.

[0682] The disks were read using a Molecular Devices (Sunnyvale, CA) Gemini fluorometer to assess the concentration of fluorescein at excitation / emission wavelengths of 425 / 535 nm. An equivalence was considered acceptable when the top-to-bottom flux across MDR1-transfected LLC-PK1 or BCRP-transfected MDCKII cell monolayers was less than 2% and the bottom-to-top flux was less than 5%. The disks were sealed, and the contents of each well were analyzed by LC MS / MS. Compound concentrations were determined as the ratio of the peak area of ​​the compound to the internal standard (labetalol) compared to the volumetric solution.

[0683] LC-MS analysis

[0684] The LC-MS / MS system consisted of an HTS-PAL autosampler (Leap Technologies, Carrboro, NC), an HP1200 HPLC (Agilent, Palo Alto, CA), and an MDS Sciex 4000 Q Trap system (Applied Biosystems, Foster City, CA). Chromatographic separation of analytes and internal standards was performed using a C18 column at room temperature. The analyte was prepared using a 50 × 300 mm, 2.6 μm particle size (Phenomenex, Torrance, CA) and gradient conditions with mobile phases A (water containing 1% isopropanol and 0.1% formic acid) and B (0.1% formic acid in acetonitrile). The total operation time for a single injection (including reequilibration) was 1.2 minutes. Mass spectrometry of the analytes was performed using positive ion spray mode. Analytical reactions were measured using multiple reaction monitoring (MRM) of the unique transitions of each compound (m / z 329 to m / z 162 for the protonated precursor ion and selected product ion of each test item, and the internal standard labetalol).

[0685] Permeability coefficient (P) app The formula is calculated from the following formula.

[0686] P app =[((C d *V*(1x10 6 )) / (t*0.12cm 2 *C)]

[0687] Where C d V, t, and C0 represent the detection concentration (μM), volume at the titration end (mL), incubation time (s), and initial titration concentration (μM), respectively. Two copies of each were prepared. app Calculate and then average them. The permeability coefficient of compound I is provided in Table B1. In this determination, if the permeability is greater than 8 × 10⁻⁶, the permeability is considered to be greater than 8 × 10⁻⁶.-6 If the permeability is 2 × 10 cm / sec, the compound is defined as having high permeability. -6 cm / sec to 8×10 -6 If the permeability is cm / sec, the compound is defined as having medium permeability; if the permeability is less than 2 × 10 cm / sec, the compound is defined as having medium permeability. - 6 If the permeability is cm / sec, the compound is defined as having low permeability.

[0688] The efflux rate is the average P from the top to the bottom (AB). app Data and average P from bottom to top (BA) app Calculate using data:

[0689] Excretion rate = P app (BA) / P app (AB)

[0690] Table B1

[0691]

[0692]

[0693] N / A: Not obtained

[0694] The efflux rate is the average P from the top to the bottom (AB). app Data and average P from bottom to top (BA) app Calculate using data:

[0695] Excretion rate = P app (BA) / P app (AB)

[0696] Table B2 provides the efflux rates of Formula I compounds tested in this determination.

[0697] Table B2

[0698]

[0699]

[0700] N / A: Not obtained

[0701] Example C

[0702] PK (Free Brain to Free Plasma Ratio) (Mice)

[0703] The ability of a representative compound to penetrate the mouse brain blob was determined by assessing the concentration ratio of unbound brain to unbound plasma (also known as free brain to free plasma) in male CD-1 mice.

[0704] Brain compound concentrations were derived from oral pharmacokinetic (PK) studies in mice, with typical sampling times at 2, 4, 8, 12, and 24 hours after administration of 10 mg / kg via oral gavage. Brain samples were stored at -20 ± 5 °C prior to analysis. Test compound concentrations in mouse brain homogenates were determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after protein precipitation with acetonitrile. A 12-point calibration curve ranging from 0.5 to 10,000 ng / mL was prepared in duplicate. A 400 μg / mL solution of the test compound in dimethyl sulfoxide (DMSO) was serially diluted (3-fold) in 100% DMSO, and then 2.5 μL of each standard solution was added to 100 μL of untreated male CD-1 mouse brain homogenate. To simulate extraction in the standard curve, 2.5 μL of DMSO was added to all test samples. Both calibration and test brain homogenate samples were infused with 10 μL of IS (1 μg / mL structural analog). Brain homogenate was prepared by adding 0.75 mL of a 4:1 water:MeOH solution to each brain sample, followed by MPFast Prep- The sample was homogenized in a bead mill at 6 m / s for 1 minute. Proteins were precipitated from a 100 μL homogenate sample by adding 300 μL of acetonitrile. The sample was vortexed for 5 minutes and then centrifuged at approximately 1,500 x g for 15 minutes at 4 °C in an Allegra X-12R centrifuge (Beckman Coulter, Fullerton, CA; SX4750A rotor). 100 μL aliquots of each supernatant were transferred to 96-well plates via 550 μL Personal pipettes (Apricot Designs, Monrovia, CA) and diluted 1:1 with HPLC-grade water. The resulting plates were sealed in aluminum for LC-MS / MS analysis.

[0705] The brain-to-plasma ratio is calculated by dividing the concentration of a compound measured in the brain by the concentration of a compound measured in the plasma. The brain-to-plasma ratio is always generated from a single animal and at a single time point. The free brain-to-free plasma ratio is calculated using the following formula, multiplying the brain-to-plasma ratio by the free portion of the homogenized brain in vitro and dividing by the free portion of the plasma in vitro: (B / P)*(B fu / P fu ).

[0706] Table C provides the free brain to free plasma ratios of the representative compounds of Examples 6, 7, 8, 14, 22, 36 and 46 disclosed herein.

[0707] Table C

[0708] 6 0.88–1.26 7 0.62–1.06 8 1.01–16.1 14 0.57–1.58 22 0.33–2.92 36 0.83–2.09 46 3.29–6.75

[0709] Synthesis Examples

[0710] Intermediate 1

[0711]

[0712] (E)-2,6-dichloro-4-(2-(dimethylamino)vinyl)nicotinate methyl ester

[0713] Step 1. Preparation of methyl 2,6-dichloro-4-methylnicotinic acid. Trimethylsilyl)diazomethane (3.3 mL, 2 M in hexane, 6.6 mmol) was added to a solution of 2,6-dichloro-4-methylnicotinic acid (1.0 g, 4.9 mmol) in a 1:1 MeOH:dioxane (10 mL) at 0 °C. The mixture was removed from an ice bath and stirred for 10 min, then concentrated to half its volume and fractionated between water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and carefully concentrated. The residue was purified by column chromatography eluting with 0 to 15% EtOAc / petroleum ether to provide methyl 2,6-dichloro-4-methylnicotinic acid (0.81 g, 76%). 1 H NMR (400MHz, CDCl3) δ7.2 (s, 1H), 4.0 (s, 3H), 2.3 (s, 3H) ppm.

[0714] Step 2. Preparation of (E)-2,6-dichloro-4-(2-(dimethylamino)vinyl)nicotinic acid methyl ester. N,N-dimethylformamide dimethyl acetal (978 mL, 7.36 mmol) was added to a solution of 2,6-dichloro-4-methylnicotinic acid methyl ester (810 mg, 3.68 mmol) in DMF (5 mL), and the mixture was stirred at 100 °C for 16 hours. The cooled mixture was treated with water (40 mL), stirred for 10 minutes, and then the solid was collected by filtration, washed with water, and dried under vacuum to provide (E)-2,6-dichloro-4-(2-(dimethylamino)vinyl)nicotinic acid methyl ester (764 mg, 75%). 1 H NMR (400MHz, CDCl3) δ7.3(s,1H),7.1(d,1H),4.8(d,1H),3.1(s,3H),2.9(s,6H)ppm.

[0715] Intermediate 2

[0716]

[0717] methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

[0718] Step 1. Preparation of 4-bromo-2,6-dichloronicotinic acid. A solution of 4-bromo-2,6-dichloropyridine (100 g, 440.7 mmol) in THF (1000 mL) was cooled to -78 °C. LDA (2 M in THF, 242.4 mL, 484.8 mmol) was added dropwise at -78 °C with stirring for 1 hour. Solid CO2 (155.1 g, 3.53 mol) was added in portions to the reaction mixture with stirring for 2 hours at -78 °C. The reaction was quenched by adding 1 M Na2CO3 (1600 mL), followed by water (500 mL) and stirring for 10 minutes. The aqueous layer was extracted with EtOAc (300 mL). The pH of the aqueous layer was adjusted with 2 N HCl to provide a solution with pH 2. The aqueous layer was then extracted with EtOAc (3 × 300 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated to provide 4-bromo-2,6-dichloronicotinic acid (540 g, 75%). 1 H NMR (400MHz, DMSO-d6) δ15.51-12.87(m,1H),8.13(s,1H)ppm.

[0719] Step 2. Preparation of 4-bromo-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid. A NaOH solution (4 M, 1.62 L, 6.46 mol) was heated to 110 °C, and 4-bromo-2,6-dichloronicotinic acid (70 g, 258.4 mmol) was added in partial fractions. The mixture was stirred for 8 hours, then cooled to 0 °C. The reaction mixture was adjusted to pH 1 with HCl (6 M) and stirred for 30 minutes. The solid was collected by filtration and dried under vacuum to provide 4-bromo-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (assumed to be 100%).

[0720] Step 3. Preparation of methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate. Iodomethane (168.6 g, 1.19 mol, 73.98 mL) and K₂CO₃ (164.2 g, 1.19 mol) were added to a mixture of 4-bromo-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (100 g, 396 mmol) added to DMF (800 mL). The mixture was stirred at 25 °C for 3 hours, then poured into saturated NH₄Cl (1800 mL) and the aqueous phase was extracted with EtOAc (2 × 500 mL). The combined organic phases were washed with brine (400 mL), dried over Na₂SO₄, filtered, and concentrated. The combined residues (5 batches) were purified by column chromatography elution with 2 to 100% EtOAc / petroleum ether to provide methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (from 5 batches, 141.83 g, 24.7%). 1 H NMR (400MHz, CDCl3) δ6.86 (s, 1H), 3.94 (s, 3H), 3.69-3.66 (m, 3H); MS (apci, m / z) = 280.0, 282.0 (M+H).

[0721] Intermediate 3

[0722]

[0723] (Z)-2-chloro-4-(2-ethoxyvinyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester

[0724] Methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (20.0 g, 71.3 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (5.96 g, 7.13 mmol), and (Z)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (14.8 g, 74.9 mmol) were suspended in 1,4-dioxane (700 mL), and K₂CO₃ (53.5 mL, 107 mmol) (2N aqueous) was added. The mixture was stirred at 60 °C for 6 hours under an argon atmosphere, followed by stirring at ambient temperature for 12 hours. The reaction mixture was separated between water (1500 mL) and EtOAc (500 mL). The aqueous layer was extracted with EtOAc (2 × 400 mL), and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluting with 0 to 40 to 60% EtOAc / heptane to provide methyl (Z)-2-chloro-4-(2-ethoxyvinyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (13.3 g, 68%). 1 H NMR (400MHz, CDCl3) δ7.23 (s, 1H), 6.45 (d, 1H), 4.86 (d, 1H), 4.40 (q, 2H), 3.89 (s, 3H), 3.67 (s, 3H), 1.35 (t, 3H); MS (apci, m / z) = 272.0 (M+H).

[0725] Intermediate 4

[0726]

[0727] 4-(2-((2-(tert-butoxy)ethoxy)amino)ethyl)-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester

[0728] Step 1. Preparation of methyl (E / Z)-4-(2-((2-(tert-butoxy)ethoxy)imino)ethyl)-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate. Methyl (Z)-2-chloro-4-(2-ethoxyvinyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.95 g, 3.50 mmol) and O-(2-(tert-butoxy)ethyl)hydroxylamine hydrochloride (593 mg, 3.50 mmol) were combined in 1,4-dioxane (10 mL). Et3N (487 mL, 3.50 mmol) and HCl (1.75 mL, 6.99 mmol) (4N / dioxane) were added. The suspension was heated to 60 °C for 1 hour, then cooled and filtered. The filtrate was concentrated to provide methyl (E / Z)-4-(2-((2-(tert-butoxy)ethoxy)imino)ethyl)-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (assumed to be 100%) as a 1:1 isomer mixture. MS (apci, m / z) = 359.1 (M+H).

[0729] Step 2. Preparation of methyl 4-(2-((2-(tert-butoxy)ethoxy)amino)ethyl)-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate. Sodium cyanoborohydride (1.09 g, 17.4 mmol) was added to a solution of methyl (E / Z)-4-(2-((2-(tert-butoxy)ethoxy)imino)ethyl)-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.25 g, 3.48 mmol) in IPA (20 mL), followed by the addition of acetic acid (1.0 mL, 17.4 mmol). The mixture was stirred at ambient temperature for 16 hours, and then fractionally dissolved between saturated NaHCO3 (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 × 30 mL), and the combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluting with 0 to 80% EtOAc / DCM to provide methyl 4-(2-((2-(tert-butoxy)ethoxy)amino)ethyl)-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.66 g, 53%). 1 H NMR (400MHz, CDCl3) δ6.43(s,1H),3.90(s,3H),3.78(t,2H),3.68(s,3H),3.50(t, 2H), 3.10 (t, 2H), 2.71 (t, 2H), 1.20 (s, 9H) ppm; MS (apci, m / z) = 361.1, 363.1 (M+H).

[0730] Intermediate 5

[0731]

[0732] 2-Chloro-4-ethylaniline

[0733] Step 1. Preparation of N-(4-ethylphenyl)acetamide. 4-Ethylaniline (513 μL, 4.13 mmol) was dissolved in DCM (10.3 mL). After adding triethylamine (690 μL, 4.95 mmol) and cooling to 0 °C, acetic anhydride (467 μL, 4.95 mmol) was added dropwise. After 30 minutes, the reaction was quenched with saturated NaHCO3 (50 mL). The organic layers were separated, and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was wet-milled with hexane, and the solid was collected by filtration to provide N-(4-ethylphenyl)acetamide (600 mg, 89%). 1 H NMR (400MHz, CDCl3) δ7.40-7.38(d,2H),7.16-7.14(d,2H),7.07(br s,1H),2.64-2.58(q,2H),2.16(s,3H),1.23-1.20(t,3H)ppm.

[0734] Step 2. Preparation of N-(2-chloro-4-ethylphenyl)acetamide. N-(4-ethylphenyl)acetamide (50 mg, 0.31 mmol) was dissolved in DMF (613 μL). After adding N-chlorosuccinimide (65 mg, 0.49 mmol), the solution was heated to 70 °C for 6 hours, followed by cooling to ambient temperature over 16 hours. The reaction mixture was poured into 2N HCl (4 mL) and stirred for 15 minutes. The mixture was extracted with EtOAc (10 mL). The organic layer was washed with water (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography eluting with 0 to 25% EtOAc / hexane to provide N-(2-chloro-4-ethylphenyl)acetamide (36 mg, 59%). 1 H NMR (400MHz, CDCl3) δ8.23-8.21(d,1H),7.51(br s,1H),7.20-7.19(d,1H),7.11-7.08(dd,1H),2.63-2.57(q,2H),2.23(s,3H),1.23-1.20(t,3H)ppm.

[0735] Step 3. Preparation of 2-chloro-4-ethylaniline. N-(2-chloro-4-ethylphenyl)acetamide (36 mg, 0.18 mmol) was dissolved in EtOH (0.5 mL) and 12N HCl (0.5 mL, 6.0 mmol) was added. The mixture was stirred at 120 °C for 2 hours. The reaction mixture was cooled to ambient temperature, and 6N NaOH was added to bring the pH to 10, followed by extraction with MTBE (3 × 25 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to provide 2-chloro-4-ethylaniline (26 mg, 92%). 1 HNMR (400MHz, CDCl3) δ7.09-7.08(d,1H),6.91-6.88(dd,1H),6.71-6.69(d,1H),2.55-2.49(q,2H),1.20-1.16(t,3H)ppm. MS(apci,m / z)=156.1(M+H).

[0736] Intermediate 6

[0737]

[0738] 4-((difluoromethyl)thio)-2-fluoroaniline

[0739] LiBF4 (196 mg, 2.10 mmol) and LiH (17.5 mg, 2.10 mmol) were combined in DMF (8.8 mL, 1.75 mmol). 4-Amino-3-fluorothiophenol (250 mg, 1.75 mmol) was added, and the mixture was stirred at ambient temperature for 5 minutes. (Trifluoromethyl)trimethylsilane (0.644 mL, 4.37 mmol) was added rapidly, followed by stirring at the same temperature for 10 minutes. TBAF (6 mL, 1 N / THF, 6.00 mmol) was added rapidly, followed by stirring at the same temperature for 10 minutes. The reaction mixture was quenched with water (50 mL). The mixture was extracted with EtOAc (2 × 25 mL), and the combined organic layers were washed with water (3 × 50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography elution with 0 to 15% EtOAc / hexane to provide 4-((difluoromethyl)thio)-2-fluoroaniline (56 mg, 17%). 1 H NMR (400MHz, CDCl3) δ7.25-7.22(dd,1H),7.19-7.16(ddd,1H),6.86-6.58(t,1H),6.77-6.73(dd,1H),3.95(br s,1H)ppm.

[0740] Intermediate 7

[0741]

[0742] 2-Chloro-4-(methylthio)aniline

[0743] 2-Chloro-4-iodoaniline (250 mg, 0.986 mmol), NiBr2 (22 mg, 0.099 mmol), Zn powder (129 mg, 1.97 mmol), and 2,2'-bipyridine (15 mg, 0.099 mmol) were dissolved in THF (1.6 mL) under an Ar atmosphere. 1,2-Dimethyldithioethane (44 μL, 0.493 mmol) was added, the mixture was sealed, and heated to 65 °C for 16 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with concentrated NH4OH (50 mL), followed by washing with 10% citric acid solution (50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluting with 0 to 15% EtOAc / hexane to provide 2-chloro-4-(methylthio)aniline (116 mg, 68%). 1 H NMR (400MHz, CDCl3) δ7.27-7.26(m,1H),7.09-7.06(dd,1H),6.71-6.69(d,1H),4.02(br s,2H),2.41(s,3H)ppm. MS(apci,m / z)=174.0(M+H).

[0744] Intermediate 8

[0745]

[0746] (E)-2-chloro-4-(2-ethoxyvinyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester

[0747] Methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.0 g, 3.565 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.2982 g, 0.3565 mmol), and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (0.7414 g, 3.743 mmol) were suspended in 1,4-dioxane (35.65 mL), and potassium carbonate (2.674 mL, 2N aqueous, 5.35 mmol) was added. After degassing with argon, the mixture was stirred at 60 °C for 4 hours. The cooled reaction mixture was separated between water (150 mL) and EtOAc (50 mL). The aqueous layer was washed with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography eluting with 0 to 40% EtOAc / heptane to provide methyl (E)-2-chloro-4-(2-ethoxyvinyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (379 mg, 39%). 1 H NMR (400MHz, CDCl3) δ7.27(s,1H),7.03(d,1H),6.43(s,1H),5.53(d,1H),3.95-3.83(m,5H),3.67(s,3H),1.34(t,2H)ppm. MS(apci,m / z)=272.1(M+H).

[0748] Example 1

[0749]

[0750] 8-((4-bromo-2-fluorophenyl)amino)-2-cyclopropyl-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione

[0751] Step 1. Preparation of methyl 2,6-dichloro-4-(2-oxoethyl)nicotinate. A suspension of (E)-2,6-dichloro-4-(2-(dimethylamino)vinyl)nicotinate (0.797 g, 2.90 mmol) in Et₂O (30 mL) and 1N HCl (30 mL) was vigorously stirred at ambient temperature for 1 hour. The resulting solution was treated with brine (20 mL) and extracted with Et₂O (3 × 10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO₄, filtered, and carefully concentrated to provide methyl 2,6-dichloro-4-(2-oxoethyl)nicotinate (assumed to be 100%), which was used immediately.

[0752] Step 2. Preparation of 8-chloro-2-cyclopropyl-6-methoxy-3,4-dihydro-2,7-naphthidium-1(2H)-one. Cyclopropylamine (201 mL, 2.90 mmol) was added to a solution of methyl 2,6-dichloro-4-(2-oxoethyl)nicotinate (0.719 g, 2.90 mmol) in 1:1 IPA:MeOH (20 mL) at 0 °C. The mixture was stirred at ambient temperature for 10 min, followed by the addition of sodium cyanoborohydride (546 mg, 8.70 mmol) and acetic acid (498 mL, 8.70 mmol). After stirring at ambient temperature for 16 h, the mixture was fractionally dissolved between saturated NaHCO3 (50 mL) and EtOAc (20 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was dissolved in methanol (10 mL), treated with 1N NaOH (3.33 mL, 3.33 mmol), and stirred at ambient temperature for 1 hour. The mixture was concentrated to half its volume and then aliquoted between water (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2 × 10 mL), and the combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography elution from 0 to 10% (20% MeOH / DCM) / DCM to provide 8-chloro-2-cyclopropyl-6-methoxy-3,4-dihydro-2,7-naphthidium-1(2H)-one (310 mg, 42%). 1 H NMR (400MHz, CDCl3) δ6.5 (s, 1H), 4.0 (s, 3H), 3.5 (t, 2H), 2.9 (m, 3H), 0.9 (m, 2H), 0.7 (m, 2H) ppm; MS (apci, m / z) =...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in: R 1 It can be H, Br, C1-C6 alkyl or phenyl; R 2 It can be H, halogen, or CH3-; R 3 H, hydroxyC1-C6 alkyl-, hydroxyC1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)C1-C6 alkoxy-; and R 4 It is a phenyl group that has been substituted with one, two or three independent substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 For H.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 For H.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 It is CH3-.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 It is a hydroxyl C1-C6 alkyl-.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a phenyl group substituted with one or two independent substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a phenyl group substituted with one or two substituents independently selected from the following: halogen and C1-C6 alkylthio group.

8. Compounds of formula II or pharmaceutically acceptable salts thereof: in: R 1 It can be H, Br, C1-C6 alkyl or phenyl; R 2 It can be H, halogen, or CH3-; R 3 H, hydroxyC1-C6 alkyl-, hydroxyC1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)C1-C6 alkoxy-; and R a and R b It is independently selected from halogens, C1-C6 alkyl, C1-C6 alkylthio, fluoroC1-C6 alkylthio, fluoroC1-C6 alkyl, C1-C6 alkoxy, fluoroC1-C6 alkoxy, C3-C6 cycloalkyl and C1-C6 alkyl-C(=O)-.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R a It is a halogen.

10. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R b It is a halogen, C1-C6 alkyl, C1-C6 alkylthio or fluoroC1-C6 alkoxy.

11. The compound according to claim 1, wherein the compound is selected from: 8-((4-bromo-2-fluorophenyl)amino)-2-cyclopropyl-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(cyclopropylmethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-ethoxy-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 2-Cyclopropyl-8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 2-Cyclopropyl-8-((2-fluoro-4-iodophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-chloro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-chlorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2,3-difluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-3-chloro-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-ethyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-cyclopropyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-methoxyphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-((trifluoromethyl)thio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-isopropylphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-chloro-4-cyclopropylphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-acetyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-chloro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-chloro-4-ethylphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-((difluoromethyl)thio)-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-isopropoxy-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-2-isopropoxy-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 2-Ethoxy-8-((2-fluoro-4-iodophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-2-methoxy-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 2-(tert-butoxy)-8-((2-fluoro-4-iodophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; (S)-8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; (R)-8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; (S)-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; (R)-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; (R)-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxypropoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-5-chloro-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 5-Chloro-8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-5-fluoro-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5-iodo-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 5-Bromo-8-((4-Bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 4-Bromo-8-((2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-ethyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-cyclopropyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-iodo-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-ethyl-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-cyclopropyl-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-propylphenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidium-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-ethyl-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-cyclopropyl-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-chlorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethyl)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 2-(2,2-difluoroethoxy)-8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-7-methyl-4-phenyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-4-phenyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-4,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-4,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-4,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-4,7-dimethyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione; Or its pharmaceutically acceptable salt.

12. A compound having the following structure: 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione Or its pharmaceutically acceptable salt.

13. A compound having the following structure: 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione 。 14. Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 1, characterized in that... It has PXRD peaks at 5.0, 8.7, 9.3, 10.8, 14.5, 15.3, 18.8 and 20.5° 2θ (±0.2° 2θ).

15. Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 2, characterized in that... PXRD patterns with characteristic peaks at 7.1, 9.4, 12.4, 12.8, 14.3, 15.6, 16.4, 17.4, 18.5, 18.9, 19.5, 19.9, 21.1, 21.4, 23.2, 23.7, 24.8, 25.6, 27.6, 30.3, 33.2, 33.5, and 37.5° 2θ (±0.2° 2θ).

16. The crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 3, characterized in that... PXRD patterns with characteristic peaks at 6.9, 9.1, 13.7, 18.0, and 18.3° 2θ (±0.2° 2θ).

17. Amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthidine-1,6(2H,7H)-dione form 4.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

19. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 in the preparation of a medicament for treating an individual with MEK-related tumors.

20. The use according to claim 19, wherein the tumor has a BRAF V600 mutation selected from V600E, V600K, V600D, V600R and V600S.

21. The use according to claim 19, wherein the tumor has a BRAF V600E mutation.

22. The use according to claim 19, wherein the tumor is a CNS tumor.

23. The use according to claim 22, wherein the CNS tumor is an intracranial tumor.

24. The use according to claim 23, wherein the intracranial tumor is brain cancer.

25. The use according to claim 24, wherein the brain cancer is a metastatic brain cancer.

26. The use according to claim 25, wherein the metastatic brain cancer is selected from metastatic melanoma, metastatic colorectal cancer, metastatic non-small cell lung cancer, metastatic thyroid cancer, and metastatic ovarian cancer.

27. The use according to claim 22, wherein the CNS tumor is an intracranial LMD or an extracranial LMD.

28. The use according to claim 27, wherein the LMD is selected from metastatic melanoma, metastatic colorectal cancer, and metastatic non-small cell lung cancer.

29. The use according to claim 23, wherein the intracranial tumor is a primary tumor.

30. The use according to claim 29, wherein the primary brain tumor is a malignant tumor.

31. The use according to claim 30, wherein the primary brain tumor is a grade 2 glioma, a grade 3 glioma, or a grade 4 glioma.

32. The use according to claim 29, wherein the primary brain tumor is a benign tumor.

33. The use according to claim 19, wherein the tumor has BRAF fusion.

34. The use according to claim 33, wherein the tumor has BRAF fusion selected from the following: KIAA11549- BRAF, MKRN1-BRAF, TRIM24-BRAF, AGAP3-BRAF, ZC3HAV1-BRAF, AKAP9-BRAF, CCDC6-BRAF, AGK-BRAF, EPS15-BRAF, NUP214-BRAF, ARMC10-BRAF, BTF3L4-BRAF, GHR-BRAF, ZC3HAV1- BRAF, ZNF767-BRAF, CCDC91-BRAF, DYNC112-BRAF, ZKSCAN1-BRAF, GTF2I-BRAF, MZT1-BRAF, RAD18-BRAF, CUX1-BRAF, SLC12A7-BRAF, MYRIP-BRAF, SND1-BRAF, NUB1-BRAF, KLHL7-BRAF, TANK-BRAF, RBMS3-BRAF, STRN3-BRAF, STK35-BRAF, ETFA-BRAF, SVOPL-BRAF and JHDM1D-BRAF .

35. The use according to claim 34, wherein the tumor is breast cancer, colorectal cancer, esophageal cancer, glioma, head and neck cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, unknown primary cancer, pleural mesothelioma, rectal adenocarcinoma, endometrial cancer, or ovarian serous carcinoma.

36. The use according to claim 19, wherein the tumor is a BRAF wild-type tumor.

37. The use according to any one of claims 19 to 36, wherein the compound is used in combination with one or more additional anticancer therapies.

38. The use according to claim 37, wherein the additional anticancer therapy is selected from one or more anticancer agents.

39. The use according to claim 38, wherein the anticancer agent is a BRAF inhibitor.

40. The use according to claim 39, wherein the BRAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof.

41. The use according to claim 39, wherein the BRAF inhibitor is selected from: N- (3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin) - 6-yl)amino)-2,4-difluorophenyl)propane-1-sulfonamide; N- (2-Chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolino) - 6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide; N- (2-Chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolino) - 6-yl)amino)-4,5-difluorophenyl)propane-1-sulfonamide; N- (2-Chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolino) - 6-yl)amino)-4-fluorophenyl)propane-1-sulfonamide; N- (2-Chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolino) - 6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide; N- (2-Chloro-4-fluoro-3-((5-methyl-3-(methyl-d3)-4-oxo-3,4-dihydroquinazolino) - 6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide; N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}propane-1-sulfonamide; N-(3-chloro-4-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluoropyridin-2-yl)propane-1-sulfonamide; and N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}-3-fluoropropane-1-sulfonamide; Or its pharmaceutically acceptable salt.

42. The use according to claim 41, wherein the BRAF inhibitor is N- (2-Chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolino) - 6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide or a pharmaceutically acceptable salt thereof.

43. The use according to claim 39, wherein the BRAF inhibitor is selected from: N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-azabicyclo[2.1.1]hexane-2-sulfonamide, (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidine-1-sulfonamide, and N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluorozahexacyclic butane-1-sulfonamide, Or its pharmaceutically acceptable salt.

44. The use according to claim 43, wherein the BRAF inhibitor is N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluorozahexacyclobutane-1-sulfonamide or a pharmaceutically acceptable salt thereof.

45. The use according to claim 38, wherein the anticancer agent is an SHP2 inhibitor.

46. ​​The use according to claim 45, wherein the SHP2 inhibitor is (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine or a pharmaceutically acceptable salt thereof.

47. The use according to any one of claims 19 to 36, wherein the individual is a human being.

48. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, used as a medicine.

49. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, for the treatment of MEK-related tumors.

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