3,4-dihydro-2,7-naphthyrizine-1,6(2H,7H)-dione as a MEK inhibitor

Abstract

To provide a pharmaceutical composition, effective for treating tumors mediated by MEK, including therapies that can target tumors in the CNS by penetrating the blood-brain barrier (BBB) and / or blood-CSF barrier (BCSFB).SOLUTION: The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising such a compound and salt. The present invention further provides a solid form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel 3,4-dihydro-2,7-naphthirizine-1,6(2H,7H)-dione compound or a pharmaceutically acceptable salt thereof that acts as a MEK inhibitor and is useful for treating abnormal cell growth in patients, such as cancer. The present invention also relates to pharmaceutical compositions containing the compound, and to methods of using the compound and compositions in the treatment of abnormal cell growth in subjects requiring it, such as cancer. The present invention also relates to a solid form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthirizine-1,6(2H,7H)-dione, a pharmaceutical composition containing the solid form, and to methods of using the solid form and compositions in the treatment of abnormal cell growth in subjects requiring it, such as cancer. [Background technology]

[0002] MEK kinase (mitogen-activated protein kinase kinase (MAPKK)) is a key 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 constitutively activated, leading to increased cancer cell survival, proliferation, angiogenesis, and metastasis. Tumors exhibiting constitutive activation of the pathway include, but are not limited to, tumors of the colon, pancreas, breast, brain, ovaries, lungs, and skin. Activation of Ras (due to upstream signaling or as a result of activation of point mutations in the Ras oncogene) leads to phosphorylation and activation of Raf kinase, which then phosphorylates and activates 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 kinase (also known as MAP kinase), which further phosphorylates and modulates the function of proteins such as Mcl-1, Bim, and Bad, which are involved in cell survival and apoptosis. Thus, this phosphorylation-mediated cascade results in enhanced cell proliferation, cell survival, and reduced cell death, which are necessary for the initiation and maintenance of tumorigenic phenotypes. Inhibition of this pathway, particularly inhibition of MEK activity, is known to be beneficial in treating hyperproliferative diseases. MEK inhibitors have shown variable activity in several settings, including BRAF V600 mutant melanoma, NRAS mutant melanoma, low-grade serous ovarian cancer, plexiform neurofibroma, thyroid cancer, and low-grade glioma, although responses in KRAS mutant pancreatic cancer or lung cancer are more limited.

[0003] Cancers with a high frequency of brain metastasis, such as melanoma and non-small cell lung cancer, are known to have MAPK pathway activating mutations, e.g., BRAF V600E and KRAS G12 mutations (Cancer Genome Atlas N., Cell 2015;161:1681~96). Activating mutations can occur at various levels in the classical pathway, but all require mitogen / extracellular signal-regulated kinase (MEK) signaling to enhance proliferation and survival (Schubbert S, Shannon K, Bollag G., Nat Rev Cancer. 2007;7:295~308). Given the common activation of the MAPK pathway in malignancies, as well as at central and downstream MEK sites, potentially interesting MEK inhibitors are also being used in the treatment of intracranial tumors.

[0004] The blood-brain interface includes the cerebral microvascular endothelium that forms the blood-brain barrier (BBB) ​​and the choroid plexus epithelium that forms the blood-CSF barrier (BCSFB). The blood-brain barrier (BBB) ​​is a highly selective, physical transport and metabolic barrier that separates the 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 effectiveness of many molecularly targeted drugs in central nervous system tumors is limited by their penetration across the blood-brain barrier (BBB), which consists of a monolayer of endothelial cells connected by tight junctions that act as a physical barrier protecting the brain. In addition, these endothelial cells express multidrug efflux transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which are known to eliminate many anticancer drugs 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 prevent most blood-derived substances from passing into the brain, while selectively allowing certain substances to pass into the brain and facilitating the removal of brain metabolites and metabolites into the bloodstream. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] Therefore, there is still a need for treatments for MEK-mediated tumors, including therapies that can penetrate the BBB and / or BCSFB and target tumors in the CNS. [Means for solving the problem]

[0006] This specification provides, in part, compounds of formulas I and II, as well as pharmaceutically acceptable salts thereof. Such compounds can inhibit the activity of MEK, thereby deriving biological functions, and may be useful for treating subjects having MEK-related tumors. This specification also provides the solid form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyrizine-1,6(2H,7H)-dione. This specification also provides pharmaceutical compositions and pharmaceuticals comprising compounds according to any of the formulas described herein, and pharmaceutically acceptable salts thereof, which may be useful alone or in combination with further anti-cancer therapies for treating subjects having MEK-related tumors. This specification also provides compounds according to any of the formulas described herein and pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts, and pharmaceutical compositions, as well as methods for using the foregoing. This summary is provided to introduce the selected concepts into the simplified forms further described in the detailed description below. This summary is not intended to identify any very important or essential features of the claimed subject matter, nor is it intended to be used separately as an aid in determining the scope of the claimed subject matter.

[0007] In accordance with embodiments of the present invention, the compound of formula I is used herein.

[0008] [ka] Or a pharmaceutically acceptable salt thereof is provided [wherein, R , , a , , 2 , ,

[0009] , , , , b , 3 , 1 , , , , , ,

[0010] is H, Br, C1-C6 alkyl or phenyl, R 2 is H, halogen or CH3-, R 3 is H, hydroxy C1-C6 alkyl-, hydroxy C1-C6 alkoxy-, C1-C6 alkoxy, fluoro C1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)C1-C6 alkoxy-, R 4 is phenyl substituted with one, two or three substituents independently selected from halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoro C1-C6 alkylthio, fluoro C1-C6 alkyl, C1-C6 alkoxy, fluoro C1-C6 alkoxy, C3-C6 cycloalkyl, and C1-C6 alkyl-C(=O)-].

[0009] Also in the present specification, the compound of formula II

[0010]

Chemical formula

[0011] In one embodiment, the solid form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione is provided herein.

[0012] In one embodiment, this specification provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof conforming 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.

[0013] In one embodiment, the Specified herein provides a method and use of treatment comprising administering a compound or a pharmaceutically acceptable salt thereof according to any of the formulas described herein to a subject.

[0014] In one embodiment, the Specified provides a method for treating abnormal cell growth in a subject requiring such treatment, such as tumors, such as MEK-associated tumors, comprising administering to the subject a therapeutically effective amount of a compound according to any of the formulas described herein or a pharmaceutically acceptable salt thereof. The compounds according to any of the formulas described herein may be administered as monotherapy or in combination with one or more anticancer therapies.

[0015] In one embodiment, the Specified provides a method for treating abnormal cell growth in a subject requiring such treatment, such as tumors, such as MEK-associated tumors, comprising administering to the subject a certain amount of a compound or a pharmaceutically acceptable salt thereof according to any of the formulas described herein, in combination with a certain amount of an additional anticancer agent, such that the amounts thereof are effective together to treat the abnormal cell growth.

[0016] In one embodiment, the Specified herein provides compounds or pharmaceutically acceptable salts thereof that conform to any of the formulas described herein, for use as pharmaceuticals.

[0017] In one embodiment, the Specified herein provides compounds or pharmaceutically acceptable salts thereof that conform to any of the formulas described herein for use in the treatment of abnormal cell growth, such as tumors, such as MEK-associated tumors.

[0018] In one embodiment, the Specified Use of a compound or a pharmaceutically acceptable salt thereof conforming to any of the formulas described herein is provided for the manufacture of a pharmaceutical for the treatment of abnormal cell growth in a subject, such as tumors, such as MEK-associated tumors.

[0019] In one embodiment, this specification 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.

[0020] Each embodiment of a compound conforming to any of the formulas described herein can be combined with one or more other embodiments of a compound conforming to any of the formulas described herein, provided that such embodiments are not inconsistent with the embodiment(s) in which it is combined.

[0021] It should be understood that the above summary and the following detailed description are merely illustrative and explanatory, and do not limit the claimed invention. [Brief explanation of the drawing]

[0022] [Figure 1] Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, powder X-ray diffraction pattern of form 1. [Figure 2] Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, showing the powder X-ray diffraction pattern of form 2. [Figure 3] The crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione shows the powder X-ray diffraction pattern of form 3. [Figure 4] 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-naphthyridine-1,6(2H,7H)-dione, form 4, is shown. [Figure 5] The crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione shows the sorption isotherm of form 3. [Modes for carrying out the invention]

[0023] In one embodiment, the present invention relates to a compound of formula I.

[0024] [ka] or provide a pharmaceutically acceptable salt thereof [in the formula, R 1is H, Br, C1-C6 alkyl or phenyl, R 2 is H, halogen or CH3-, R 3 These are H, hydroxy C1-C6 alkyl-, hydroxy C1-C6 alkoxy-, C1-C6 alkoxy, fluoro C1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl) C1-C6 alkoxy-, R 4 [These are phenyl compounds substituted with one, two, or three substituents 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)-.]

[0025] As used herein, the singular forms "a," "an," and "the" refer to substituents, and unless otherwise specified, include multiple references. For example, "a substituent" includes one or more substituents.

[0026] In the context of complex chemical names used herein, substituents are typically named before the group to which they are bonded. For example, methoxyethyl contains an ethyl skeleton with a methoxy substituent.

[0027] The term "halogen" means -F (sometimes referred to herein as "fluoro" or "fluoros"), -Cl, -Br, and -I.

[0028] As used herein, the term "C1-C6 alkyl" refers to a saturated, linear or branched monovalent hydrocarbon radical comprising 1 to 6 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.

[0029] The term "hydroxy C1-C6 alkyl-" as used herein refers to a C1-C6 alkyl radical as defined herein, in which one hydrogen atom is replaced by a hydroxyl group.

[0030] The term "hydroxy" refers to the -OH group.

[0031] The term "C3-C6 cycloalkyl" refers to a fully saturated carbocyclic ring having 3 to 6 ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0032] The term "fluoroC1-C6 alkyl," as used herein, refers to a C1-C6 alkyl radical as defined herein, in which one, two, or three hydrogen atoms are replaced by one, two, or three fluoro atoms, respectively. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0033] The term "C1-C6 alkoxy," as used herein, refers to a C1-C6 alkyl radical, as defined herein, that is single-bonded to an oxygen atom, and that radical is located on the oxygen atom (i.e., C1-C6-O-). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy.

[0034] The term "fluoroC1-C6 alkoxy," as used herein, refers to a C1-C6 alkoxy as defined herein, in which one, two, or three hydrogen atoms are replaced by one, two, or three fluoro atoms, respectively. Examples include, but are not limited to, trifluoromethoxy.

[0035] The term "(C3-C6 cycloalkyl)C1-C6 alkoxy-" refers to a C1-C6 alkoxy- as defined herein, in which one hydrogen atom is replaced by a C3-C6 cycloalkyl group as defined herein.

[0036] The term "C1-C6 alkylthio," as used herein, refers to a (C1-C6 alkyl)S-radical in which the C1-C6 alkyl portion is as defined herein.

[0037] The term "fluoroC1-C6 alkylthio," as used herein, refers to a C1-C6 alkylthio group as defined herein, in which one, two, or three hydrogen atoms are replaced by one, two, or three fluoro atoms, respectively.

[0038] In one embodiment of formula I, R 1 H is H.

[0039] In one embodiment of formula I, R 1 It is Br.

[0040] In one embodiment of formula I, R 1 is a C1-C6 alkyl group. In one embodiment of formula I, R 1 It is methyl.

[0041] In one embodiment of formula I, R 1 It is phenyl.

[0042] In one embodiment of formula I, R 2 H is H.

[0043] In one embodiment, R 2 It is a halogen.

[0044] In one embodiment of formula I, R 2 It is F.

[0045] In one embodiment of formula I, R 2 It is Cl.

[0046] In one embodiment of formula I, R 2 It is Br.

[0047] In one embodiment of formula I, R 2 It is I.

[0048] In one embodiment of formula I, R 2 It is CH3-.

[0049] In one embodiment of formula I, R 1 H is R 2 H is H.

[0050] In one embodiment of formula I, R 3 H is H.

[0051] In one embodiment of formula I, R 3 These are hydroxy C1-C6 alkyl- groups. A non-limiting example is 2-hydroxyethyl.

[0052] In one embodiment of formula I, R 3 These are hydroxy C1-C6 alkoxy- molecules. As a non-limiting example, the structure of each is

[0053] [ka] Examples include 2-hydroxyethoxy and 2-hydroxypropoxy having the compound.

[0054] In one embodiment of formula I, R 3These are C1-C6 alkoxys. Non-limiting examples include methoxy, ethoxy, 1-methylethoxy, and 2,2-dimethylethoxy.

[0055] In one embodiment of formula I, R 3 These are fluoroC1-C6 alkoxys. A non-limiting example is 2,2-difluoroethoxy.

[0056] In one embodiment of formula I, R 3 These are C3-C6 cycloalkyl groups. A non-limiting example is cyclopropyl.

[0057] In one embodiment of formula I, R 3 These are (C3-C6 cycloalkyl)C1-C6 alkoxy- compounds. A non-limiting example is cyclopropylmethoxy.

[0058] In one embodiment of formula I, R 4 This refers to phenyl substituted with one, two, or three substituents independently selected from fluoro, chloro, bromo, iodo, ethyl, propyl, isopropyl, methylthio, difluoromethylthio, trifluoromethyl, methoxy, difluoromethoxy, cyclopropyl, and C1-C6 alkyl-C(=O)-.

[0059] In one embodiment of formula I, R 4 This is a phenyl compound substituted with one or two substituents 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)-.

[0060] In one embodiment of formula I, R 4This refers to phenyl substituted with one or two substituents independently selected from fluoro, chloro, bromo, iodo, ethyl, propyl, isopropyl, methylthio, difluoromethylthio, trifluoromethyl, methoxy, difluoromethoxy, cyclopropyl, and C1-C6 alkyl-C(=O)-.

[0061] In one embodiment of formula I, R 4 This is a phenyl compound substituted with one substituent 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)-.

[0062] In one embodiment of formula I, R 4 This refers to phenyl substituted with one substituent selected from fluoro, chloro, bromo, iodo, ethyl, propyl, isopropyl, methylthio, difluoromethylthio, trifluoromethyl, methoxy, difluoromethoxy, cyclopropyl, and C1-C6 alkyl-C(=O)-.

[0063] In one embodiment of formula I, R 4 is structure

[0064] [ka] Selected from.

[0065] In one embodiment of formula I, R 4 teeth,

[0066] [ka] That is the case.

[0067] In one embodiment of formula I, R 4 teeth,

[0068] [ka] That is the case.

[0069] In one embodiment of formula I, R 4 is structure

[0070] [ka] Selected from.

[0071] In one embodiment of formula I, R 4 is structure

[0072] [ka] Selected from.

[0073] In one embodiment, R 4 is structure

[0074] [ka] It has, in the formula, R a and R b R is independently selected from 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)-. In one embodiment, R a is a halogen. In one embodiment, R b is a halogen, a C1-C6 alkyl, a C1-C6 alkylthio, or a fluoroC1-C6 alkoxy. In one embodiment, R a It is a halogen, and R b These are halogens, C1-C6 alkyl groups, C1-C6 alkylthio groups, or fluoroC1-C6 alkoxy groups.

[0075] In one embodiment, the compound of formula II is used herein.

[0076] [ka] Or a pharmaceutically acceptable salt thereof is provided [in the formula, R 1 is H, Br, C1-C6 alkyl or phenyl, R 2 is H, halogen or CH3-, R 3 These are H, hydroxy C1-C6 alkyl-, hydroxy C1-C6 alkoxy-, C1-C6 alkoxy, fluoro C1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl) C1-C6 alkoxy-, R a and R b [These are independently selected from halogens, C1-C6 alkyls, C1-C6 alkylthios, fluoroC1-C6 alkylthios, fluoroC1-C6 alkyls, C1-C6 alkoxys, fluoroC1-C6 alkoxys, C3-C6 cycloalkyls, and C1-C6 alkyl-C(=O)-.

[0077] In one embodiment of formula II, R 1 H is H.

[0078] In one embodiment of formula II, R 1 It is Br.

[0079] In one embodiment of formula II, R 1 is a C1-C6 alkyl group. In one embodiment of formula II, R 1 It is methyl.

[0080] In one embodiment of formula II, R 1 It is phenyl.

[0081] In one embodiment of formula II, R 2 H is H.

[0082] In one embodiment of formula II, R2 It is a halogen.

[0083] In one embodiment of formula II, R 2 It is F.

[0084] In one embodiment of formula II, R 2 It is Cl.

[0085] In one embodiment of formula II, R 2 It is Br.

[0086] In one embodiment of formula II, R 2 It is I.

[0087] In one embodiment of formula II, R 2 It is CH3-.

[0088] In one embodiment of formula II, R 2 It is either H or CH3-.

[0089] In one embodiment of formula II, R 1 H is R 2 It is either H or CH3-.

[0090] In one embodiment of formula II, R 1 H is R 2 H is H.

[0091] In one embodiment of formula II, R 3 H is H.

[0092] In one embodiment of formula II, R 3 These are hydroxy C1-C6 alkyl- groups. A non-limiting example is 2-hydroxyethyl.

[0093] In one embodiment of formula II, R 3 These are hydroxy C1-C6 alkoxy- molecules. As a non-limiting example, the structure of each is

[0094] [Chemical formula] Examples include 2-hydroxyethoxy and 2-hydroxypropoxy which have

[0095] In one embodiment of Formula II, R 3 is C1-C6 alkoxy. Non-limiting examples include methoxy, ethoxy, 1-methylethoxy, and 2,2-dimethylethoxy.

[0096] In one embodiment of Formula II, R 3 is fluoro C1-C6 alkoxy. A non-limiting example is 2,2-difluoroethoxy.

[0097] In one embodiment of Formula II, R 3 is C3-C6 cycloalkyl. A non-limiting example is cyclopropyl.

[0098] In one embodiment of Formula II, R 3 is (C3-C6 cycloalkyl)C1-C6 alkoxy-. A non-limiting example is cyclopropylmethoxy

[0099] In one embodiment of Formula II, R 3 is H or hydroxy C1-C6 alkoxy-.

[0100] In one embodiment of Formula II, R a [[ID=4,2]]is halogen. In one embodiment of Formula II, R a is fluoro or chloro. In one embodiment of Formula II, R a is fluoro.

[0101] In one embodiment of Formula II, R b is fluoro, chloro, bromo, iodo, ethyl, propyl, isopropyl, methylthio, difluoromethylthio, trifluoromethyl, methoxy, difluoromethoxy, cyclopropyl, or CH3C(=O)-.

[0102] In one embodiment of Formula II, R b is halogen, C1-C6 alkyl, C1-C6 alkylthio, or fluoro C1-C6 alkoxy.

[0103] In one embodiment of Formula II, R b is bromo, iodo, ethyl, methylthio, or difluoromethoxy. In one embodiment of Formula II, R b is methylthio.

[0104] In one embodiment of Formula II, R a is fluoro and R b is methylthio.

[0105] In one embodiment of Formula II, R a is halogen and R b is halogen, C1-C6 alkyl, C1-C6 alkylthio, fluoro C1-C6 alkylthio, fluoro C1-C6 alkyl, C1-C6 alkoxy, fluoro C1-C6 alkoxy, C3-C6 cycloalkyl, or C1-C6 alkyl-C(=O)-.

[0106] In one embodiment of Formula II, R a is halogen and R b is halogen, C1-C6 alkyl, C1-C6 alkylthio, or fluoro C1-C6 alkoxy.

[0107] In one embodiment of Formula II, R a is halogen and R b is halogen. In one embodiment of Formula II, R a is halogen and R b is halogen and R 1 is H and R 2 is H.

[0108] In one embodiment of Formula II, R a is halogen and Rb is a C1-C6 alkyl group. In one embodiment of formula II, R a It is a halogen, and R b It is a C1-C6 alkyl group, and R 1 H is R 2 H is H.

[0109] In one embodiment of formula II, R a It is a halogen, and R b is a C1-C6 alkylthio. In one embodiment of formula II, R a It is a halogen, and R b R is a C1-C6 alkylthio, 1 H is R 2 H is H.

[0110] In one embodiment of formula II, R a It is a halogen, and R b is a fluoroC1-C6 alkylthio. In one embodiment of formula II, R a It is a halogen, and R b R is a fluoro C1-C6 alkylthio, 1 H is R 2 H is H.

[0111] In one embodiment of formula II, R a is fluoro, and R b It is methylthio, and R 1 H is R 2 H is H.

[0112] In one embodiment of formula II, R a It is a halogen, and R b is a fluoroC1-C6 alkyl group. In one embodiment of formula II, R a It is a halogen, and R b It is a fluoroC1-C6 alkyl, and R 1 H is R 2 H is H.

[0113] In one embodiment of formula II, R a It is a halogen, and R b R is a C1-C6 alkoxy. In one embodiment of formula II, R a It is a halogen, and R b These are C1-C6 alkoxys, and R 1 H is R 2 H is H.

[0114] In one embodiment of formula II, R a It is a halogen, and R b is a fluoroC1-C6 alkoxy. In one embodiment of formula II, R a It is a halogen, and R b These are fluoroC1-C6 alkoxys, and R 1 H is R 2 H is H.

[0115] In one embodiment of formula II, R a It is a halogen, and R b is a C3-C6 cycloalkyl group. In one embodiment of formula II, R a It is a halogen, and R b It is a C3-C6 cycloalkyl group, and R 1 H is R 2 H is H.

[0116] In one embodiment of formula II, R a It is a halogen, and R b is C1-C6 alkyl-C(=O)-. In one embodiment of formula II, R a It is a halogen, and R b It is C1~C6 alkyl-C(=O)-, and R 1 H is R 2 H is H.

[0117] In one embodiment of formula II, R 1 H is R 2 is H or CH3-, and R 3 is H or hydroxy C1-C6 alkoxy-, and Ra is a halogen, and R b is a 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)-.

[0118] In one embodiment of Formula II, R 1 is H, and R 2 is H or CH3-, and R 3 is H or hydroxy C1-C6 alkoxy-, and R a is a halogen, and R b is a halogen, C1-C6 alkyl, C1-C6 alkylthio, or fluorinated C1-C6 alkoxy.

[0119] In any one embodiment of the above embodiments of Formula II, the group

[0120]

Chemical formula

[0121]

Chemical formula

[0122] The term "compound" as used herein means to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures shown. A compound identified herein by name or structure as a particular tautomeric form is intended to include other tautomeric forms unless otherwise specified.

[0123] The compounds of the formulas provided herein can have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention are herein represented by solid lines (

[0124] <http: / / www.wipo.int / standards / XMLSchema / ST96 / ST96-20000901 / ST96-20000901.xsd#_

Chemical formula

[0125] [ka] ), or dotted wedge shape (

[0126] [ka] ) may be used to illustrate. The use of a solid line to illustrate a bond to a chiral carbon atom means that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. The use of either a solid wedge or a dotted wedge to illustrate a bond to a chiral carbon atom means that only the indicated stereoisomer is included. Compounds of the present invention may contain two or more chiral carbon atoms. In those compounds, the use of a solid line to illustrate a bond to a chiral carbon atom means that all possible stereoisomers are included and means that the bonded stereocenter is shown. For example, unless otherwise stated, compounds of the present invention are intended to exist as enantiomers and diastereomers, or as racemates and mixtures thereof. The use of a solid line to illustrate a bond to one or more chiral carbon atoms in a compound of the present invention, and the use of a solid wedge or dotted wedge to illustrate a bond to another chiral carbon atom in the same compound, means that a diastereomer mixture is present.

[0127] Compounds of the present invention having a chiral center can exist as stereoisomers, such as racemates, enantiomers, or diastereomers.

[0128] Stereoisomers of the compounds of the formulas herein may include cis and trans isomers, optical isomers, e.g., (R) and (S) enantiomers, diastereomers, geometric isomers, rotational isomers, atrop isomers, structural isomers, and tautomers of the compounds of the present invention, which include compounds exhibiting two or more types of isomerism, as well as mixtures thereof (e.g., racemates and pairs of diastereomers).

[0129] This also includes acid or base addition salts with optically active counterions, such as d-lactate or l-lysine, or racemic acid or base addition salts, such as dl-tartrate or dl-arginine.

[0130] When any racemic mixture crystallizes, two different types of crystals are possible. The first type is the aforementioned racemic compound (true racemic mixture), which results in one homogeneous crystalline form containing equimolar amounts of both enantiomers. The second type is a racemic mixture or aggregate, which results in two crystalline forms, each containing a single enantiomer, in equimolar amounts.

[0131] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from optically pure suitable precursors, or the resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC) or superfluid critical chromatography (SFC).

[0132] Alternatively, the racemic mixture (or racemic precursor) can be reacted with a suitable optically active compound, such as 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 diastereomer mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art.

[0133] The chiral compounds (and their chiral precursors) of the present invention can be obtained in enantiomerically concentrated form by chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of heptane or hexane containing hydrocarbons, typically 0-50% isopropanol, typically 2-20% isopropanol, and 0-5% alkylamine, typically 0.1% diethylamine. Concentrating the eluent yields a concentrated mixture.

[0134] Stereoisomers can be separated by prior art known to those skilled in the art. See, for example, “Stereochemistry of Organic Compounds” by E.L. Eliel (Wiley, New York, 1994), the entire disclosure of which is incorporated herein by reference.

[0135] The enantiomeric purity of the compounds described herein may be expressed in units of enantiomeric excess (ee), which indicates the degree to which a sample contains one enantiomeric isomer in greater quantities than the other. A racemic mixture has 0% ee, while a single, perfectly pure enantiomeric isomer has 100% ee. Similarly, diastereomer purity may be expressed in units of diastereomer excess (de).

[0136] The compounds of the present invention can exhibit tautomerism and structural isomerism. For example, the compounds can exist in several tautomer forms, including enol and imine forms, as well as keto and enamine forms, as well as geometric isomers and mixtures thereof. All such tautomer forms are included within the scope of the compounds of the present invention. Tautomers exist in solution as a mixture of tautomer sets. In solid form, one tautomer is usually dominant. Although one tautomer may be described, the present invention includes all tautomers of compounds of the provided formula. Tautomers of compounds of formula I include, for example, R 3 If it is hydrogen,

[0137] [ka] This can occur.

[0138] In addition, some of the compounds of the present invention can form atropisomers (e.g., substituted biaryls). Atropisomers are conformational stereoisomers with asymmetric substituents at both ends of a single bond, resulting from steric interactions with other parts of the molecule when rotation around a single bond in the molecule is hindered or significantly slowed. Interconversion of atropisomers is slow enough to allow separation and isolation under given conditions. The energy barrier to thermal racemization can be determined by steric hindrance to the free rotation of one or more bonds forming a chiral axis.

[0139] The present invention also includes pharmaceutically acceptable isotope-labeled compounds identical to those enumerated in one of the provided formulas, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature.

[0140] The isotope-labeled compounds of the present invention can generally be prepared by means of the prior art known to those skilled in the art or by methods similar to those described herein, using a suitable isotope-labeled reagent instead of the unlabeled reagent used in other cases.

[0141] Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F and 36 Examples include Cl. Certain isotope-labeled compounds of the present invention, for example 2 H, 3H or 14 Products incorporating radioactive isotopes such as 13C are useful in either or both drug- or substrate tissue distribution assays. Tritium labeling, i.e. 3 H, and carbon 14, i.e. 14 13C isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, deuterium, i.e. 2 Substitution with heavier isotopes, such as 1H, can lead to certain therapeutic benefits resulting from higher metabolic stability, such as increased in vivo half-life or reduced required dose, and may therefore be preferable in some environments. 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 16N may be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. The isotope-labeled compounds of the present invention can generally be prepared by using an isotope-labeled reagent instead of a non-isotope-labeled reagent, by following the procedures disclosed in the following scheme and / or examples and preparations.

[0142] The pharmaceutically acceptable solvates according to the present invention may have the crystallization solvent substituted with an isotope, for example, D2O, d 6 -acetone, d 6 -Contains DMSO

[0143] Unless otherwise specified, all references to the compounds of the present invention herein include references to their salts, solvates, hydrates and complexes, as well as references to solvates, hydrates and complexes of their salts, including their polymorphs, stereoisomers and isotopically labeled forms.

[0144] The compounds of the present invention may exist, for example, in the form of pharmaceutically acceptable salts, such as acid-addition salts and base-addition salts of one of the compounds of the formulas provided herein. As used herein, the term “pharmaceutically acceptable salt” refers to a salt that retains the biological effects and properties of the parent compound. As used herein, the phrase “pharmaceutically acceptable salts” (plural) includes, unless otherwise specified, salts of acidic or basic groups that may be present in the compounds of the formulas disclosed herein.

[0145] For example, the basic compounds of the present invention can form a wide variety of salts with various inorganic and organic acids. While such salts must be pharmaceutically acceptable for administration to animals, it is often practically desirable to first isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter back to a free base compound by treatment with an alkaline reagent, and subsequently convert the free base back into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the present invention can be prepared by treating the base compound with substantially equivalent amounts of a selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Evaporation of the solvent yields the desired solid salt. The desired salt can also be precipitated from a solution of the free base in an organic solvent by adding a suitable inorganic or organic acid to the solution.

[0146] Acids can be used to prepare pharmaceutically acceptable acid addition salts of basic compounds, such as those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, superphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0147] Examples of salts include acetates, acrylates, benzenesulfons, benzoates (e.g., chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, and methoxybenzoates), bicarbonates, bisulfates, bisulfites, bisulfites, borates, bromides, butynate-1,4-diates, calcium edetate, cansylates, carbonates, chlorides, caproates, caprylates, clavulanates, and citrates. Decanoate, dihydrochloride, dihydrogen phosphate, edetate, edislyate, estrate, esylate, ethylsuccinate, formate, fumarate, gluceptinate, gluconate, glutamate, glycolate, glycolyl arsanylate, heptanoate, hexyn-1,6-diate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyric acid Examples of salts include, but are not limited to, salts, isothionates, lactates, lactobionates, laurates, malates, maleates, malons, mandelates, mesylates, metaphosphates, methanesulfons, methylsulfates, monohydrogen phosphates, mucinates, napsylates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, nitrates, oleates, oxalates, pamoates (embonates), palmitates, pantothenates, phenylacetates, phenylbutyrates, phenylpropionates, phthalates, phosphates / diphosphates, polygalacturonates, propanesulfons, propions, propiolates, pyrophosphates, pyrosulfates, salicylates, stearates, basic acetates, suberates, succinates, sulfates, sulfonates, sulfites, tannates, tartrates, theoclates, tosylates, and valersates.

[0148] Examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary 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.

[0149] The compounds of the present invention, which contain basic moieties such as amino groups, can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above.

[0150] Alternatively, useful compounds that are acidic can form base salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly sodium and potassium salts. All of these salts are prepared by prior art. The chemical bases used as reagents for preparing the pharmacologically acceptable base salts of the present invention are those that form non-toxic base salts with the acidic compounds herein. These salts can be prepared by any suitable method, for example, by treatment of a free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), alkali metal hydroxide, or alkaline earth metal hydroxide. 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, the salts can also be prepared by mixing a lower 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 the integrity of the reaction and the maximum yield of the desired final product.

[0151] Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds of the present invention, which are acidic in nature, are those that form non-toxic base salts with such compounds. Examples of such non-toxic base 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, such as N-methylglucamine (meglumine), and lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0152] Hemi salts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed.

[0153] For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention, as well as methods for interconverting salt and free base forms, are known to those skilled in the art.

[0154] The salts of the present invention can be prepared according to methods known to those skilled in the art. A pharmaceutically acceptable salt of the compound of the present invention can be readily prepared by appropriately mixing a solution of the compound with a desired acid or base. The salt can precipitate from the solution and be collected by filtration, or recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to nearly non-ionized.

[0155] Those skilled in the art will understand that the compounds of the present invention in the form of a free base having a basic functional group can be converted to an acid addition salt by treatment with a suitable acid in a stoichiometric excess. The acid addition salts of the compounds of the present invention can be converted back to the corresponding free base by treatment with a suitable base in a stoichiometric excess, such as potassium carbonate or sodium hydroxide, typically in the presence of an aqueous solvent at a temperature between about 0°C and 100°C. The free base form can be isolated by conventional means such as extraction with an organic solvent. In addition, the acid addition salts of the compounds of the present invention can be exchanged by taking advantage of the differential solubility of the salt, the volatility or acidity of the acid, or by treatment with a appropriately packed ion exchange resin. For example, the exchange may be influenced by the reaction of a salt of the compound of the present invention with an acid in a small stoichiometric excess, with a pK lower than the acid component of the starting salt. This conversion typically occurs at temperatures between about 0°C and the boiling point of the solvent used as the medium for the procedure. Similar exchanges are possible using a base addition salt, typically mediated by the free base form.

[0156] The compounds of the present invention can exist in both non-solvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometric amount independent of humidity. However, when the solvent or water is weakly bound, such as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and dry conditions. In such cases, the non-stoichiometric amount is the standard. The term "solvate" is used herein to describe molecular complexes comprising the compounds of the present invention with one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water. Pharmaceutically acceptable solvates according to the present invention include hydrates and solvates in which the solvent of crystallization may be isotope-substituted, such as D2O, d6-acetone, and d6-DMSO.

[0157] The present invention also relates to prodrugs of compounds of the formulas provided herein. Thus, certain derivatives of the compounds of the present invention, which themselves possess little or no pharmacological activity, can be converted to the compounds of the present invention, for example, by hydrolytic cleavage, when administered to a patient. Such derivatives are called “prodrugs.” Further information regarding 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 (Ed. E. 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 thereof are incorporated herein by reference in their entirety.

[0158] Prodrugs according to the present invention can be produced, for example, by replacing suitable functional groups present in the compounds of the present invention with certain parts known to those skilled in the art as “pro parts” as described, for example, in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985), the disclosure thereof, which is incorporated herein by reference in its entirety.

[0159] Some non-limiting examples of prodrugs according to the present invention include: (i) If the compound contains a carboxylic acid functional group (-COOH), hydrogen substitution with its ester, for example, (C1-C6) alkyl, (ii) If the compound contains an alcohol functional group (-OH), hydrogen substitution with its ether, for example, (C1-C6) alkanoyloxymethyl or phosphate ether group, and (iii) If the compound contains a primary or secondary amino functional group (NH2 or NHR, where R is not H), substitution of one or both hydrogens by an amide, for example, a metabolically unstable group such as an amide, carbamate, urea, phosphonate, or sulfonate. These are some examples.

[0160] Further examples of substitution groups following the examples described above and other prodrug types can be found in the references mentioned above.

[0161] Finally, certain compounds of the present invention can themselves act as prodrugs of other compounds of the present invention.

[0162] The scope of the present invention also includes metabolites of compounds of the formulas described herein, i.e., compounds that are formed in vivo, often by oxidation or dealkylation, upon administration of a drug. Some examples of metabolites according to the present invention are: (i) If the compound of the present invention contains an alkyl group, its hydroxyalkyl derivative (-CH → -COH), (ii) If the compound of the present invention contains an alkoxy group, its hydroxy derivative (-OR→-OH), (iii) If the compound of the present invention contains a tertiary amino group, its secondary amino derivative (-NRR' → -NHR or -NHR'), (iv) If the compound of the present invention contains a secondary amino group, its primary derivative (-NHR→-NH2), (v) If the compound of the present invention contains a phenyl moiety, its phenol derivative (-Ph→-PhOH) (vi) If the compound of the present invention contains an amide group, its carboxylic acid derivative (-CONH2→COOH), and (vii) If the compound contains a hydroxyl or carboxylic acid group, the compound can be metabolized, for example, by conjugation with glucuronic acid to form a glucuronide. These are some examples, but are not limited to them. Other metabolic pathways involving conjugates exist. These pathways are often known as phase II metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, can also be conjugated.

[0163] In one embodiment, the solid form of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione is provided herein. In one embodiment, the solid form is crystalline. In one embodiment, the solid form is amorphous.

[0164] As used herein, the term "crystalline" means having a regularly repeating arrangement of molecules or external planes. A single compound can give rise to various crystalline forms, each of which has different physical properties of distinct solid states, such as different solubility profiles, dissolution rates, melting points, fluidity, and / or different X-ray diffraction peaks. Differences in physical properties can affect pharmaceutical parameters, such as storage stability, compressibility, and density (which can be important in the manufacture of formulations and products), as well as dissolution rate (which can be an important factor in bioavailability).

[0165] The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Typically, such materials do not give a distinctive X-ray diffraction pattern and are more formally described as liquids, even if they exhibit solid properties. Upon heating, a change occurs from solid to liquid properties, and this change is typically characterized by a secondary state transition ("glass transition").

[0166] There are several analytical methods that those skilled in solid-state chemistry can use to analyze solid forms. Powder X-ray diffraction (PXRD) can also be suitable for quantifying the amount of one (or more) crystalline solid forms in a mixture. In powder X-ray diffraction, X-rays are directed at 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 by the sample. The intensities of these diffracted X-rays can be plotted as peaks on a graph, with the x-axis being the angle between the X-ray source and the diffracted X-rays (known as the "2-theta" angle) and the y-axis being the intensity of the diffracted X-rays. This graph is called a powder X-ray diffraction pattern or powder pattern. The location of the peaks on the x-axis is a characteristic of the solid structure of the crystal, so different crystalline solid forms will show different powder patterns.

[0167] Those skilled in the art will recognize that the typical precision of the 2-theta x-axis value of a powder pattern peak is approximately plus or minus 0.2 degrees 2-theta (±0.2 degrees 2-theta). Therefore, for example, a diffraction peak appearing at “approximately 18.0 degrees 2-theta” means that the peak appears at 18.0 ± 0.2 degrees 2-theta, i.e., it can be between 17.8 degrees 2-theta and 18.2 degrees 2-theta when measured with most X-ray diffractometers under most conditions. Furthermore, those skilled in the art will recognize that relative peak intensity reflects variations between instruments, as well as variations due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be interpreted merely as a qualitative measure. Therefore, as used herein, the term “essentially the same” when referring to powder X-ray diffraction peak position means that the typical variation in peak position and intensity is approximately ±0.2 degrees 2-theta.

[0168] Powder X-ray diffraction is just one of several analytical techniques that can be used to characterize and / or identify crystalline solid forms. Spectroscopic techniques, such as Raman (including micro-Raman), infrared, and solid-state NMR spectroscopy, can also be used to characterize and / or identify crystalline solid forms. These techniques can also be used to quantify the amount of one or more crystalline solid forms in a mixture, and peak values ​​may be reported with the modifier "approximately" preceding the peak value.

[0169] As used herein, the term "anhydrous" refers to a crystalline form that does not contain any solvent or water molecules in its crystal lattice.

[0170] The term "hydrate" refers to a solvate of a compound containing a stoichiometric or non-stoichiometric amount of water. The term "monohydrate" refers to a hydrate containing one water molecule per compound molecule (i.e., a 1:1 stoichiometric ratio of water and compound).

[0171] 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-naphthyridine-1,6(2H,7H)-dione, Form 1.

[0172] In one embodiment, crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 1, is characterized by powder X-ray diffraction (PXRD) (2 theta).

[0173] Table X provides a PXRD peak list for crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 1, in 2-theta degrees (±0.2 degrees).

[0174] [Table 1]

[0175] In one embodiment, the present invention provides a crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, Form 1, having a PXRD pattern including characteristic peaks at 5.0, 8.7, 9.3, 10.8, 14.5, 15.3, 18.8 and 20.5 degrees 2-theta (±0.2 degrees 2-theta).

[0176] In one embodiment, the present invention provides a crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 1, which has a PXRD pattern including a peak at essentially the same 2-theta value as shown in Figure 1.

[0177] 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-naphthyridine-1,6(2H,7H)-dione, form 2.

[0178] In one embodiment, crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 2 is characterized by powder X-ray diffraction (PXRD) (2-theta). In one embodiment, PXRD analysis of crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 2 is carried out at 25°C and a relative humidity below 10%, as described, for example, in Example 77.

[0179] Table Y provides a PXRD peak list for crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 2, in 2-theta degrees (±0.2 degrees 2-theta).

[0180] [Table 2]

[0181] In one embodiment, the present invention provides a crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 2, having a PXRD pattern including 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 degrees 2 theta (±0.2 degrees 2 theta).

[0182] In one embodiment, the present invention provides a crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 2, which has a PXRD pattern including a peak at essentially the same 2-theta value as shown in Figure 2.

[0183] 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-naphthyridine-1,6(2H,7H)-dione, form 3.

[0184] In one embodiment, the crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 3, is characterized by powder X-ray diffraction (PXRD) (2-theta). 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-naphthyridine-1,6(2H,7H)-dione, form 3 is performed at 25°C and a relative humidity above 30%.

[0185] Table Z provides a PXRD peak list for crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 3, in 2-theta degrees (±0.2 degrees).

[0186] [Table 3]

[0187] 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-naphthyridine-1,6(2H,7H)-dione, form 3, having a PXRD pattern including characteristic peaks at 13.7, 18.0 and 18.3 degrees 2-theta (±0.2 degrees 2-theta).

[0188] 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-naphthyridine-1,6(2H,7H)-dione, form 3, having a PXRD pattern including characteristic peaks at 6.9, 9.1, 13.7, 18.0, and 18.3 degrees 2-theta (±0.2 degrees 2-theta).

[0189] 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-naphthyridine-1,6(2H,7H)-dione, form 3, having a PXRD pattern including 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 degrees 2 theta (±0.2 degrees 2 theta).

[0190] 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-naphthyridine-1,6(2H,7H)-dione, form 3, which has a PXRD pattern including a peak at essentially the same 2-theta value as shown in Figure 3.

[0191] In one embodiment, the present invention provides amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 4.

[0192] In one embodiment, amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 4, is characterized by powder X-ray diffraction (PXRD) (2-theta).

[0193] In one embodiment, the present invention provides amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 4, which has a PXRD pattern including a peak at essentially the same 2-theta value as that shown in Figure 4.

[0194] The present invention further provides therapeutic methods and uses comprising administering the compound of the present invention or a pharmaceutically acceptable salt thereof, alone or in combination with other therapeutic or palliative agents.

[0195] Compounds of formulas I and II, as well as pharmaceutically acceptable salts thereof, are useful for treating diseases and disorders that can be treated with MEK kinase inhibitors, such as MEK-related diseases and disorders, and for example, for treating abnormal cell growth, such as tumors, such as MEK-related tumors. The ability of compounds of formulas I and II, as well as pharmaceutically acceptable salts thereof, to act as MEK inhibitors can be demonstrated by the assay described in Example A. 50 The values ​​are shown in Table A.

[0196] Accordingly, in one embodiment, the Specified provides a method for treating a tumor, comprising administering to a subject 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-related tumor.

[0197] As used herein, the terms “MEK kinase inhibitor” and “MEK inhibitor” are interchangeable and refer to compounds that inhibit the mitogen-activated protein kinase kinase enzymes MEK1 and / or MEK2.

[0198] The terms "MEK-related" and "MEK-mediated" are interchangeable and refer to diseases or disorders having constitutive activation of MEK kinase that can be treated with MEK inhibitors. Examples include MEK-related abnormal cell growth, e.g., MEK-related tumors, e.g., MEK-related cancers. In one embodiment, the term "MEK-related" refers to diseases or disorders having dysregulation of MEK kinase expression or activity, or dysregulation of the BRAF gene or BRAF kinase.

[0199] The phrase "dysregulation of MEK kinase expression or activity" refers to gene amplification resulting in overexpression of the MEK protein, or autocrine activity resulting from overexpression of the MEK gene in cells, which leads to increased pathogenicity of the kinase domain of the MEK protein (e.g., the constitutively active kinase domain of the MEK protein) in cells.

[0200] The phrase "dysregulation of the BRAF gene or BRAF kinase" refers to a genetic mutation (e.g., a BRAF gene translocation resulting in the expression of a fusion protein, a deletion in the BRAF gene resulting in the expression of a BRAF protein containing at least one amino acid deletion compared to the wild-type BRAF protein, or a mutation in the BRAF gene resulting in the expression of a BRAF protein having one or more point mutations compared to the wild-type BRAF protein). As another example, dysregulation of the expression, activity, or level of the BRAF gene, BRAF protein, or either thereof may be a mutation in the BRAF gene encoding a BRAF protein that is constitutively active or has increased activity compared to a protein encoded by a BRAF gene without the mutation. For example, dysregulation of the expression, activity, or level of the BRAF gene, BRAF protein, or either thereof may be the result of a gene or chromosomal translocation resulting in the expression of a fusion protein containing a first portion of BRAF containing a functional kinase domain and a second portion of a partner protein (i.e., not BRAF).

[0201] In one embodiment, the MEK-related disease or disorder has an activated BRAF mutation. In one embodiment, the MEK-related disease or disorder is a MEK-related cancer having 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.

[0202] In one embodiment, MEK-related diseases or disorders include 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, and GTF2I-BRAF. MEK-related tumors having one or more BRAF fusions resulting in constitutive kinase activation and conversion, including but not limited to AF, 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.

[0203] In one embodiment, MEK-related disease or disorder is a MEK-related tumor having a BRAF fusion protein, and the tumor is a breast cancer (e.g., invasive ductal carcinoma), colorectal cancer (e.g., colonic adenocarcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), glioma (e.g., fibrillating infantile ganglion glioma of the brain, pilocytic astrocytoma of the brain, pleomorphic xanthoblastoma of the brain, low-grade glioma (NOS) of the spinal cord, anaplastic oligodendroglioma, anaplastic ganglion glioma), or carcinoma of the head and neck (e.g., neuroendocrine carcinoma of the head and neck). These include lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer (NOS)), melanoma (e.g., Spitziform cutaneous melanoma, non-Spitziform mucosal melanoma, Spitziform cutaneous melanoma, melanoma of unknown primary origin, non-Spitziform 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), cancer of unknown primary origin (e.g., adenocarcinoma of unknown primary origin), pleural mesothelioma, rectal adenocarcinoma, endometrial cancer (e.g., endometrial adenocarcinoma (NOS)), or ovarian serous carcinoma.

[0204] In one embodiment, MEK-related cancers are selected from cancers having the BRAF fusion protein listed in Table 1 (JSRoss et al., Int, J. Cancer:138, 881-890 (2016)).

[0205] [Table 4-1]

[0206] [Table 4-2]

[0207] In one embodiment, the MEK-associated tumor is a BRAF wild-type tumor.

[0208] The term "wild-type" describes a nucleic acid (e.g., the BRAF gene or BRAF mRNA) that is typically found in subjects without a disease or disorder related to a reference nucleic acid or protein.

[0209] The term "wild-type BRAF" refers to BRAF nucleic acids (e.g., BRAF genes or BRAF mRNA) or BRAF proteins found in subjects that do not have activating BRAF mutations.

[0210] As used herein, "abnormal cell growth," unless otherwise specified, refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition), such as tumors. Abnormal cell growth may be benign (non-cancerous) or malignant (cancerous).

[0211] The term "cancer" or "malignant" refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth. Cancers include primary cancers, which begin in a specific part of the body; metastatic cancers, which spread from where the cancer started to other parts of the body; recurrences of the original primary cancer after remission; and secondary primary cancers, which are new primary cancers in patients who have a history of a different type of cancer. Cancers include solid tumors, blood, bone marrow, or lymphatic cancers, named after the cell type that forms them. Solid tumors are abnormal growths or masses of tissue that do not usually contain cysts or fluid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemia (a type of blood cancer) generally does not form solid tumors (National Cancer Institute, Cancer Terminology Dictionary).

[0212] As used herein, the terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical outcomes include, but are not limited to, a whole or partial reduction of symptoms associated with a disease or disorder or condition, whether detectable or undetectable; a decrease in the severity of the disease; a stabilization (i.e., non-exacerbating) state of the disease; a delay or slowing of disease progression; remission or relief (whether partial or whole) of a condition (e.g., one or more symptoms of the disease).

[0213] The terms “to treat” or “to treat” cancer, as used herein, mean administering the compounds of the present invention to a subject having or diagnosed with cancer to achieve at least one positive therapeutic effect, such as a reduction in the number of cancer cells, a reduction in tumor size, a reduction in the rate of cancer cell invasion into surrounding organs, or a reduction in the rate of tumor metastasis or tumor growth, or to improve, alleviate, or inhibit the process of one or more symptoms of the disorder or condition to which such terms apply. The term “treatment,” as used herein, means the act of treating as defined immediately prior to “to treat,” unless otherwise specified. The term “to treat” also includes adjuvant and neoadjuvant treatment of a subject.

[0214] For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reduction (or destruction) of neoplasm or cancerous cell proliferation; inhibition of metastatic or neoplasmic cells; reduction or decrease in tumor size; extension of the period of remission in a subject (e.g., compared to one or more metrics in a subject with a similar cancer that has not been treated or has been treated differently, or compared to one or more metrics in the same subject before treatment); reduction of symptoms resulting from cancer; improvement of the quality of life of a patient with cancer; reduction of the dose of other medicines required to treat cancer; delay of cancer progression; cure of cancer; overcoming one or more resistance mechanisms of cancer; and / or extension of survival in a patient with cancer. Positive therapeutic effects in cancer can be measured in several ways (WA 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) standards, a T / C of 42% or less is considered a minimum level of antitumor activity. A T / C of <10% is considered a high level of antitumor activity, and T / C (%) = median treated tumor volume / median control tumor volume × 100.

[0215] In one embodiment, the treatment achieved by administration of the compounds of the present invention is defined by referring 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 during which the cancer does not grow, and includes the length of time during which the patient experiences CR or PR, and the length of time during which the patient experiences stable disease (SD). DFS refers to the length of time during and after treatment during which the patient remains disease-free. OS refers to the extension of life expectancy compared to an untreated or untreated subject or patient. In one embodiment, the response to treatment with the compounds of the present invention is any of PR, CR, OR, PFS, DFS, or OS, which is assessed using the response evaluation criteria in the Solid Tumor (RECIST) 1.1 Response Criteria.

[0216] Treatment regimens for the compounds of the present invention that are effective in treating cancer patients may vary according to factors such as the patient's condition, age and weight, and the ability of the treatment to elicit an anti-cancer response in the subject. No embodiment of any aspect of the present invention may be effective in achieving a positive therapeutic effect in all subjects, but it should be achieved in a statistically significant number of subjects as determined by any statistical test known in the art, such as the Student's t-test, chi-squared test, Mann-Whitney U test, Kruskal-Wallis test (H test), Jonkhiel-Tapstra test, and Wilcoxon test.

[0217] The terms “treatment regimen,” “administration protocol,” and “administration regimen” are interchangeable to refer to the dose and timing of administration of the compound of the present invention, either alone or in combination with another therapeutic agent.

[0218] "Remission" means that, compared to not administering the combination described herein, treatment with the combination reduces or improves one or more symptoms. "Remission" also includes shortening or reducing the duration of symptoms.

[0219] As used herein, the term “Subject” means any animal, including mammals, e.g., humans. In one embodiment, the subject had experienced and / or exhibited at least one symptom of a disease or disorder to be treated and / or prevented. In one embodiment, the subject had been identified or diagnosed with having a MEK-associated tumor (e.g., determined using a regulatory authority-approved, e.g., FDA-approved assay or kit). In one embodiment, the subject has a MEK-associated tumor that is positive for a BRAF mutation (e.g., determined using a regulatory authority-approved assay or kit). The subject may be a subject whose tumor has a MEK mutation (e.g., the tumor is identified by itself using a regulatory authority-approved, e.g., FDA-approved kit or assay). In one embodiment, the subject is suspected to have a MEK-associated tumor. In one embodiment, the subject has a clinical record indicating that the subject has a MEK-associated tumor with a BRAF mutation (the clinical record may indicate that the subject should be treated with any of the compositions provided herein). In one embodiment, the subject is human. In one embodiment, the human subject is a pediatric subject.

[0220] Where used herein, the term “pediatric subjects” refers to subjects under 21 years of age at the time of diagnosis or treatment. The term “pediatric subjects” can be further divided into various subgroups, including: neonates (from birth to 1 month of age), infants (1 month to 2 years of age), children (2 years to 12 years of age), and adolescents (12 years to 21 years of age (up to their 22nd birthday, but not including that day)). Berhman RE, Kliegman R, Arvin AM, Nelson WE, Nelson Textbook of Pediatrics, 15th edition, Philadelphia: WBSaunders Company, 1996; Rudolph AM et al., Rudolph's Pediatrics, 21st edition, New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd edition, Baltimore: Williams & Wilkins; 1994. In one embodiment, the target age group for children is from birth to 28 days old, from 29 days old to under 2 years old, from 2 years old to under 12 years old, or from 12 years old to 21 years old (up to their 22nd birthday, but not including that day). In another embodiment, the target age group for children is from birth to 28 days old, from 29 days old to under 1 year old, from 1 month to under 4 months old, from 3 months to under 7 months old, from 6 months to under 1 year old, from 1 year old to under 2 years old, from 2 years old to under 3 years old, from 2 years old to under 7 years old, from 3 years old to under 5 years old, from 5 years old to under 10 years old, from 6 years old to under 13 years old, from 10 years old to under 15 years old, or from 15 years old to under 22 years old.

[0221] In one embodiment, the Specified Public Service provides a method for treating a tumor, comprising administering to a subject 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, for example, a BRAF fusion disclosed herein. In one embodiment, the MEK-associated tumor is a BRAF wild-type tumor.

[0222] 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-associated tumor. In one embodiment, the tumor is intracranial. In one embodiment, the tumor is extracranial. In any embodiment of the methods described herein, the tumor (e.g., MEK-associated tumor) is a malignant tumor (i.e., cancer), e.g., MEK-associated cancer. In any embodiment of the methods of use described herein, MEK-associated cancer is 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 cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), breast cancer, ovarian cancer, cancer of the CNS, bone cancer, cancer of the anus, anal canal or anorectum, eye cancer, bile duct cancer, ductal carcinoma in situ, liver cancer, gallbladder or pleural cancer, oral cancer These include oral cancer, lip cancer, oropharyngeal cancer, cancer of the nose, nasal cavity or middle ear, genital cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, hypopharyngeal cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, melanoma, nasopharyngeal cancer, peripheral nervous system cancer (e.g., neuroblastoma), ovarian cancer, pancreatic cancer, cancer of the peritoneum, retinoplasm and mesentery, pharyngeal cancer, prostate cancer, kidney cancer (e.g., renal cell carcinoma (RCC)), small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, uterine cancer, ureteral cancer, or bladder cancer.

[0223] In any embodiment of the methods of use described herein, the MEK-associated 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-associated cancer is melanoma. In one embodiment, the MEK-associated cancer is colorectal cancer. In one embodiment, the MEK-associated cancer is thyroid cancer. In one embodiment, the MEK-associated cancer is non-small cell lung cancer. In one embodiment, the MEK-associated cancer is ovarian cancer. In one embodiment, the MEK-associated cancer is neuroblastoma.

[0224] In any embodiment of the methods of use described herein, MEK-related cancer is CNS cancer.

[0225] In any embodiment of the methods of use described herein, MEK-related cancer is intracranial cancer (brain tumor).

[0226] In any embodiment of the methods of use described herein, the cancer is metastatic cancer.

[0227] The term "metastasis" is a well-known term in the art, referring to the spread of cancer cells from the site where they first formed (primary site) to one or more other sites in the body (one or more secondary sites). In metastasis, cancer cells escape from the original (primary) tumor and travel through the blood or lymphatic system to form a new tumor (metastatic tumor) in another organ or tissue of the body. The new metastatic tumor contains cancer cells that are the same as or similar to those of the primary tumor. In the secondary site, tumor cells proliferate, and the secondary tumor may begin to grow or establish itself in this distal site.

[0228] The term “metastatic cancer” (also known as “secondary cancer”), as used herein, refers to a type of cancer that begins in one tissue type but then spreads to one or more tissues outside the (primary) cancer origin. Metastatic brain tumor refers to cancer within the brain, i.e., cancer that begins in tissues other than the brain and metastasizes to the brain.

[0229] 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 penetration into the brain and / or CNS. Such compounds can cross the BBB and inhibit MEK kinase in the brain and / or other CNS structures. Therefore, in one embodiment, the compounds provided herein are useful for treating CNS tumors, e.g., CNS cancers.

[0230] In one embodiment, the MEK-associated tumor is a malignant CNS tumor (i.e., MEK-associated CNS cancer). In one embodiment, the MEK-associated CNS cancer has a BRAF mutation. In one embodiment, the MEK-associated CNS 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 MEK-associated CNS cancer has a BRAF V600E mutation. In one embodiment, the MEK-associated CNS cancer has a BRAF V600K mutation. In one embodiment, the MEK-associated tumor has a BRAF fusion. In one embodiment, the MEK-associated tumor is a BRAF wild-type tumor.

[0231] The terms “CNS cancer” or “cancer of the CNS” as used interchangeably herein refer to cancers of the CNS (i.e., malignant tumors), including cancers of the brain (also known as intracranial tumors), cancers of the spinal cord, and cancers of the meninges surrounding the brain and spinal cord. Cancers of the brain include metastatic brain tumors (i.e., metastatic intracranial cancers) and malignant primary brain tumors.

[0232] In one embodiment, MEK-associated CNS cancer is MEK-associated metastatic brain tumor. MEK-associated metastatic brain tumor may be the result of any of the cancers described herein in which the subject has developed at least one brain metastasis. In one embodiment, the metastatic brain tumor is melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, or neuroblastoma. In one embodiment, MEK-associated metastatic brain tumor is metastatic melanoma, metastatic colorectal cancer, or metastatic non-small cell lung cancer. In one embodiment, MEK-associated metastatic brain tumor is metastatic melanoma. In one embodiment, MEK-associated metastatic brain tumor is metastatic colorectal cancer. In one embodiment, MEK-associated metastatic brain tumor is metastatic non-small cell lung cancer. In one embodiment, MEK-associated metastatic brain tumor is metastatic ovarian cancer. In one embodiment, the metastatic brain tumor is metastatic thyroid cancer. In one embodiment, MEK-associated metastatic brain tumor is kidney cancer. In one embodiment, the cancer is a MEK-associated metastatic cancer with at least one brain metastasis (i.e., a metastatic brain tumor). In one embodiment, the cancer is a MEK-associated metastatic melanoma with at least one brain metastasis. In one embodiment, the cancer is a MEK-associated metastatic colorectal cancer with at least one brain metastasis. In one embodiment, the cancer is a MEK-associated metastatic non-small cell lung cancer with at least one brain metastasis. In one embodiment, the cancer is a MEK-associated metastatic ovarian cancer with at least one brain metastasis. In one embodiment, the cancer is a MEK-associated metastatic thyroid cancer with at least one brain metastasis. In one embodiment, the cancer is a MEK-associated neuroblastoma with at least one brain metastasis. In any one embodiment of the MEK-associated metastatic brain tumors, 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-associated tumor has a BRAF fusion.In one embodiment, the MEK-associated tumor is a BRAF wild-type tumor.

[0233] In one embodiment, MEK-associated cancer is leptomeningeal metastasis (leptomeningeal disease (LMD)). LMD represents a subset of CNS metastases, or leptomeningeal carcinomatosis, that grow in the inner layers of the brain or spinal cord and / or in the cerebrospinal fluid (CSF). In mammals, the meninges are the dura mater, arachnoid mater, and pia mater. The CSF is located in the subarachnoid space between the arachnoid mater and the pia mater. The arachnoid mater and pia mater are sometimes collectively called the leptomeninges. When LMD occurs in the leptomeninges and / or CSF surrounding the spinal cord, LMD is sometimes called “extracranial LMD.” When LMD occurs in the leptomeninges and / or CSF of the brain, LMD is sometimes called “intracranial LMD.” Because LMD cancer cells can be suspended in the CSF, they can rapidly spread within the CNS. As a result, LMD has a poor prognosis, with survival typically measured as a few months. In one embodiment, metastatic cancer is LMD. In one embodiment, the metastatic cancer is MEK-associated LMD. In one embodiment, the metastatic cancer is MEK-associated intracranial LMD. In one embodiment, the metastatic cancer is 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 any one embodiment of the MEK-associated LMD, 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 the BRAF V600E mutation. In one embodiment, the MEK-associated LMD has the BRAF V600K mutation. In one embodiment, the MEK-associated LMD has a BRAF fusion. In one embodiment, the MEK-associated LMD is a BRAF wild-type tumor.

[0234] In one embodiment, MEK-associated tumors are cancers with a high risk of metastasis. In one embodiment, tumors with a high risk of metastasis are cancers having BRAF V600E, V600D, V600K, V600R and / or V600S mutations. In one embodiment, cancers with a high risk of metastasis have BRAF fusions, e.g., 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 having BRAF V600E mutations or BRAF V600K mutations. In one embodiment, the cancer with a high risk of metastasis is 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 having a BRAF V600E mutation or a BRAF V600K mutation.In one embodiment, cancers with a high risk of metastasis have a KIAA11549-BRAF fusion.

[0235] In one embodiment, a CNS tumor is a primary brain tumor. Primary brain tumors are tumors that originate in the brain or spinal cord and are collectively known as gliomas. The term "glioma" is used to describe tumors that originate in glial cells present in the CNS. According to the WHO classification of brain tumors, gliomas are graded by cellular activity and invasiveness on a scale that includes Grade I (benign CNS tumors) and Grades II-IV (malignant CNS tumors).

[0236] Grade I gliomas (pilocytic astrocytomas): These typically occur in the cerebellum or brainstem of children, occasionally in the cerebral hemispheres, and grow slowly. Grade I gliomas can also occur in adults. Although Grade I gliomas are benign (WHO Grade I), the difficulty in curing this disease can lead to malignant growth behavior and a higher incidence (Rostami, Acta Neurochir (Wien). 2017;159(11):2217~2221).

[0237] Grade II gliomas (low-grade gliomas) include astrocytoma, oligodendroglioma, and mixed oligoastrocytoma. Grade II gliomas typically occur in young adults (e.g., 20-50 years of age) and are almost always found in the cerebral hemispheres. Due to the invasive nature of these tumors, recurrence is possible. Some grade II gliomas recur and develop into more high-grade tumors (grade III or IV).

[0238] Grade III gliomas (malignant gliomas) include anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic mixed oligodendroglioma. Grade III tumors are invasive, high-grade cancers that invade nearby brain tissue with tentacle-like projections, making complete surgical removal more difficult.

[0239] Grade IV gliomas include glioblastoma multiforme (GBM) and gliosarcoma. Glioblastoma multiforme (GBM) is a malignant glioma. GBM is the most invasive and most common primary brain tumor. Glioblastoma multiforme usually grows rapidly and invades other parts of the brain with tentacle-like projections, making complete surgical removal more difficult. Gliosarcoma is a malignant cancer and is defined as a glioblastoma consisting of glioma and sarcoma components.

[0240] 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 low-grade glioma in children.

[0241] In one embodiment, the primary brain tumor is a benign primary brain tumor. Benign primary brain tumors may cause severe pain, permanent brain injury, and death, and in some cases, they may become malignant. Non-limiting examples of benign primary brain tumors include grade I gliomas, papillary craniopharyngiomas, meningiomas (including rhabdoid meningiomas), atypical teratomatous / rhabdoid tumors, and germinal dysplastic neuroepithelial tumors (DNTs), pilocytic astrocytomas, oligodendrogliomas, mixed oligodendrogliomas, anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic mixed oligodendrogliomas, diffuse astrocytomas, ependymomas, pleomorphic astrocytomas (PXA), gangliogliomas, gliosarcomas, or anaplastic gangliogliomas.

[0242] In one embodiment, the cancer is a peripheral nervous system cancer. In one embodiment, the peripheral nervous system cancer is a neuroblastoma.

[0243] In one embodiment, this specification provides a method for treating a MEK-associated CNS tumor, 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 a subject in need. In one embodiment, the MEK-associated CNS tumor has a BRAF V600 mutation. In one embodiment, the MEK-associated CNS tumor has a BRAF V600E and / or V600K and / or V600D and / or V600R and / or V600S mutation. 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, e.g., any of the BRAF fusions disclosed herein, e.g., the KIAA11549-BRAF fusion. In one embodiment, the MEK-associated CNS tumor is a BRAF wild-type tumor. In one embodiment, the subject was treated with one or more anticancer treatments independently selected from anticancer drugs, surgery, and radiotherapy before administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, as described herein, for example. In one embodiment, the subject is treated with a combination of a therapeutically effective 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 one or more anticancer treatments independently selected from anticancer drugs, surgery, and / or radiotherapy, as described herein, for example. In one embodiment, the subject is treated with one or more anticancer treatments independently selected from anticancer drugs, surgery, and radiotherapy after administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, as described herein, for example. 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 cancer). In one embodiment, the malignant CNS tumor is metastatic CNS cancer.In one embodiment, 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, metastatic CNS cancer is metastatic melanoma. In one embodiment, metastatic CNS cancer is colorectal cancer. In one embodiment, metastatic CNS cancer is metastatic non-small cell lung cancer. In one embodiment, metastatic CNS cancer is metastatic thyroid cancer. In one embodiment, metastatic CNS cancer is metastatic ovarian cancer. In one embodiment, MEK-associated CNS cancer is LMD. In one embodiment, LMD is intracranial. In one embodiment, LMD is extracranial. In one embodiment, 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-associated CNS cancer 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-associated CNS tumor is a benign tumor. In one embodiment, the benign CNS tumor is a papillary craniopharyngioma, meningioma (including rhabdoid meningioma), atypical teratomatous / rhabdoid tumor, or germinal dysplastic 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.

[0244] The ability to determine whether a compound may be suitable for treating CNS cancer can be determined, as described herein, for example, by identifying whether the compound is a substrate for an efflux transporter, and / or by measuring its cell permeability, and / or by measuring the ratio of free blood to free plasma.

[0245] 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. A method for determining the permeability of the compounds of the present invention can be determined according to the assay described in Example B, and the permeability coefficients are provided in Table B1.

[0246] The compounds of the present invention exhibit low efflux. An in vitro method for evaluating whether the compounds of the present invention are substrates for the efflux transporter P-glycoprotein (P-gp or multidrug resistance 1 (MDR1) protein) and breast cancer resistance protein (BCRP) is described in Example B, and the efflux ratios of the compounds of the present invention are provided in Table B3.

[0247] In one embodiment, the compounds of the present invention exhibit a moderate to high brain (unbound) / plasma (unbound) ratio (i.e., a moderate to high free brain / plasma ratio). The ability of the compounds of the present invention to penetrate the blood-brain barrier (BBB) ​​of a target (e.g., human) can be determined in a suitable animal model (e.g., rodents, e.g., mouse). For example, the ability of a particular compound to penetrate the BBB of a mouse can be determined by evaluating the ratio of unbound brain concentration to unbound plasma (free B / P) in mice, as described, for example, in Example C, and the ratio of free brain to free plasma is provided in Table C2. By calculating the ratio of free brain to free plasma of a compound, it becomes possible to predict the effective concentration required to achieve efficacy in the periphery and brain based on dose-dependent exposure in an animal model. These distribution data, along with relevant pharmacokinetic data, can be used for the model to predict the dose required to achieve efficacy in human patients.

[0248] Accordingly, in one embodiment, the present invention provides a method for treating MEK-associated CNS cancer in a subject requiring it, comprising administering a compound of formula II or a pharmaceutically acceptable salt thereof, wherein at least a portion of the compound of formula II penetrates the blood-brain barrier (BBB) ​​as demonstrated in preferred animal models. In one embodiment, the brain / plasma ratio of the total drug is at least about 0.3 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.35 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.4 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.45 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.5 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.55 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.6 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.65 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.7 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.75 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.8 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.85 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 0.9 after administration to the subject (e.g., orally or intravenously). In another embodiment, the brain / plasma ratio of the total drug is at least about 0.95 after administration to the subject (e.g., orally or intravenously).In one embodiment, the brain / plasma ratio of the total drug is at least about 1.0 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.0 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.1 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.2 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.3 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.4 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.5 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.6 after administration to the subject (e.g., orally or intravenously). In one embodiment, the brain / plasma ratio of the total drug is at least about 1.7 after administration to the subject (e.g., orally or intravenously). The percentage of the compound that penetrates the blood-brain barrier is the area under the concentration-time curve (AUC) in the brain relative to the plasma over a given period. 0-t It should be noted that it is calculated based on the (AUC) of the compound. Therefore, the percentage represents the concentration ratio. 0-24h If the concentration in the brain is 20 ng / mL and in the plasma is 80 ng / mL, then the percentage of the compound that penetrates the blood-brain barrier (BBB) ​​is 20% (20 ng / mL in the brain divided by the total concentration (20 ng / mL + 80 ng / mL)) (i.e., the ratio of brain to plasma is 0.20). In one embodiment, the percentage is the area under the concentration-time curve (AUC) for the time from t=0 (timing of administration) to the final concentration point that can be quantified. 0-last It is calculated based on the following:

[0249] Cancers with a high frequency of brain metastasis are known to have MAPK pathway activating mutations, such as BRAF mutations including the BRAF mutations disclosed herein, or BRAF fusions including the BRAF fusions disclosed herein. Activating mutations can occur at various levels in the classical pathway, but all require mitogen / extracellular signal-regulated kinase (MEK) signaling to increase growth and survival (Schubbert S, Shannon K, Bollag G., Nat Rev Cancer. 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, as well as their metastatic tumors, and primary brain tumors (Davies H. et al., Nature 417(6892):949~954, 2002). For example, BRAF mutations, such as the BRAF V600 mutation, have been observed in brain metastases from melanoma (Flaherty KT et al., Nat Rev Cancer (2012) 12(5):349~61), brain metastases from colorectal cancer, and brain metastases from 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).

[0250] BRAF mutations, such as those disclosed herein, and BRAF fusions, such as those disclosed herein, have also been observed in primary malignant brain tumors, including grade IV gliomas, such as glioblastoma and gliosarcoma, anaplastic astrocytoma (high-grade tumor), and WHO grade III anaplastic ganglioglioma, in pediatric and adult populations (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).

[0251] BRAF mutations, such as those disclosed herein, and BRAF fusions, such as those disclosed herein, have also been observed in benign primary brain tumors in pediatric and adult populations, such as WHO-grade II astrocytoma, WHO-grade II pleomorphic xanthoblastoma (PXA), pleomorphic xanthoblastoma with anaplasia, pilocytic astrocytoma (PA), papillary craniopharyngioma, ganglioglioma, astroblastoma, pilocytic astrocytoma, atypical teratomatous / rhabdoid tumor, and rhabdoid meningioma (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); (Behling et al., Diagn Pathol 11(1):55, 2016; Brastianos et al., Nat Genet 46(2):161~165, 2014; Dougherty et al., Neuro Oncol 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).

[0252] 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 patients with neuroblastoma initially have tumors that respond to chemotherapy, but the majority experience treatment-resistant relapses.

[0253] Accordingly, the Specified also provides a method for treating a subject diagnosed or identified as having a MEK-related tumor, e.g., any of the exemplary MEK-related tumors disclosed herein, comprising administering to the subject 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 subject has been identified or diagnosed as having a tumor with a BRAF mutation of BRAF fusion, e.g., by using a regulatory-approved test or assay, e.g., an FDA-approved test or assay, for identifying BRAF mutations or fusions in the subject or a biopsy sample from the subject, or by performing any non-limiting example of an assay described herein. In one embodiment, the test or assay is provided as 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-approved assay, e.g., an FDA-approved kit.

[0254] In one embodiment, the biopsy is a tumor biopsy (e.g., a tumor sample obtained during conventional surgery, or a stereotactic needle biopsy, e.g., a stereotactic needle biopsy guided by a CT or MRI scan). The tissue biopsy method can be used to detect total tumor tissue volume and / or BRAF mutations and / or BRAF fusions.

[0255] In one embodiment, BRAF mutations or fusions can be identified using liquid biopsy (variably referred to as fluid biopsy or fluid-phase biopsy). See, for example, Karachialiou et al., "Real-time liquid biopsies become a reality in cancer treatment," Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy can be used to detect total tumor tissue volume and / or BRAF mutations. Liquid biopsy can be performed with biological samples that are relatively easily obtained from the subject (e.g., by a simple blood draw) and is generally less invasive than conventional methods used to detect tumor tissue volume and / or BRAF mutations. In one embodiment, liquid biopsy can be used to detect the presence of BRAF mutations at an earlier stage than conventional methods. In one embodiment, biological samples to be used in liquid biopsy may include CSF, blood, plasma, urine, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cystic fluid, feces, ascites, and combinations thereof. In one embodiment, liquid biopsy can be used to detect circulating tumor cells (CTCs). In one embodiment, liquid biopsy can be used to detect cell-free DNA. In one embodiment, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using high-sensitivity detection techniques, such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify BRAF mutations or BRAF fusions.

[0256] In one embodiment, BRAF mutations or BRAF fusions identified using liquid biopsy are also present in cancer cells present in the subject (e.g., a tumor). In one embodiment, any type of BRAF mutation or fusion can be detected using liquid biopsy. In one embodiment, genetic mutations identified by liquid biopsy can be used to identify the subject as a candidate for a specific treatment.

[0257] "Tumor tissue volume," also known as "tumor mass," refers to the total amount of tumor material distributed throughout the body. Tumor tissue volume refers to the total number of cancer cells or the total size of tumors (or multiple tumors) throughout the body, including lymph nodes and bone marrow. Tumor tissue volume can be determined by various methods known in the art, for example, by measuring the dimensions of the tumor(s) after removal from the subject, for example, using calipers, or, if it is in the body, by imaging techniques such as magnetic resonance imaging (MRI) scans, computed tomography (CT), multi-detector CT (MDCT), positron emission tomography (PET), X-rays, ultrasound, or bone scans.

[0258] The term "tumor size" refers to the total size of a tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by various methods known in the art, for example, by measuring the dimensions of the tumor(s) after removal from the subject, for example, using calipers, or, if it is in the body, by imaging techniques, such as MRI scans, bone scans, ultrasound, or CT scans.

[0259] Liquid biopsies may be performed at multiple points in time during the diagnostic process, monitoring process, and / or treatment process to determine one or more clinically relevant parameters, including, but not limited to, disease progression or the effectiveness of the treatment after administration to the subject. For example, during the diagnostic process, monitoring process, and / or treatment process, a first liquid biopsy may be performed at a first point in time, and a second liquid biopsy may be performed at a second point in time. In one embodiment, the first point in time may be before the subject is diagnosed with the disease (e.g., when the subject is healthy), and the second point in time may be after the subject has developed the disease (e.g., the second point in time can be used to diagnose that the subject has the disease). In one embodiment, the first point in time may be before the subject is diagnosed with the disease (e.g., when the subject is healthy), and the subject is subsequently monitored, and the second point in time may be after the subject has been monitored. In one embodiment, the first time point may be after the subject has been diagnosed with the disease, and thereafter the treatment has been administered to the subject, and the second time point may be after the treatment has been administered. In such a case, the second time point can be used to assess the effectiveness of the treatment (for example, if the genetic mutation(s) detected at the first time point are significantly reduced or undetectable).

[0260] The compound of formula I or a pharmaceutically acceptable salt thereof, or the 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 subjects having abnormal cell growth, such as MEK-related tumors, such as MEK-related cancers.

[0261] 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 further anticancer treatments, such as surgery, radiotherapy, and one or more treatments independently selected from anticancer agents acting by the same or different mechanisms of action. In one embodiment, treatment of a subject having MEK-associated cancer, using 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 surgery, radiotherapy, and one or more further treatments independently selected from one or more anticancer agents (e.g., any of the anticancer agents described below herein, where the anticancer agent is 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), may have increased therapeutic efficacy compared to treatment of the same or similar subjects using a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula II or a pharmaceutically acceptable salt thereof, as monotherapy. When combination therapy is used, and one or more anticancer therapies, for example one, two, or three, are independently selected from one or more anticancer agents, for example, those disclosed herein, the anticancer agents(s) may be administered simultaneously or separately, in any order with the compounds of the present invention, using various administration schedules with variable intervening time limits. In one embodiment, the anticancer agents(s) are administered to the subject before the administration of the compounds of the present invention. In another embodiment, the anticancer agents(s) are administered to the subject after the administration of the compounds of the present invention. In yet another embodiment, the anticancer agents(s) are administered to the subject simultaneously with the administration of the compounds of the present invention. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, is used in combination with surgery, radiotherapy, or one further anticancer therapy which is an anticancer agent acting by the same or different mechanism of action.

[0262] Accordingly, in one embodiment, the Specified provides a method for treating a subject having a MEK-related tumor (e.g., any of the MEK-related tumors described herein), comprising administering to the subject 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 further anticancer therapies. In one embodiment, the anticancer therapy is 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 embodiment, the anticancer therapy is one anticancer agent 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 embodiment, the further anticancer therapy is surgery. In one embodiment, the further anticancer therapy is radiotherapy.

[0263] Furthermore, this specification provides compounds of formula I or pharmaceutically acceptable salts thereof, or compounds of formula II or pharmaceutically acceptable salts thereof, for use in combination with one or more anticancer treatments, for example, one or more anticancer treatments. In one embodiment, further anticancer treatments are independently selected from surgery, radiotherapy, and / or one or more anticancer agents that act by the same or different mechanisms of action.

[0264] Furthermore, this specification provides one or more, for example, one or more anticancer therapies for use 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. In one embodiment, further anticancer therapies are independently selected from surgery, radiotherapy, and / or one or more anticancer agents that act by the same or different mechanisms of action.

[0265] Furthermore, this specification provides compounds of formula I or pharmaceutically acceptable salts thereof, or compounds of formula II or pharmaceutically acceptable salts thereof, for use in combination with one or more, for example, one or more further anticancer therapies, for treating MEK-related tumors.

[0266] Furthermore, this specification provides one or more, for example, one or more further anticancer therapies for use in treating MEK-related tumors 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.

[0267] In one embodiment for treating subjects with MEK-associated tumors, the subject is administered one or more anticancer therapies other than the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, prior to administration of the compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more anticancer therapies are selected from surgery, radiotherapy, and anticancer agents that act by the same or different mechanisms of action. For example, in one embodiment, a subject in need may undergo at least partial resection of the tumor prior to administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, treatment by at least partial resection of the tumor reduces tumor size (e.g., tumor tissue volume) prior to administration of one or more doses of the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, a subject requiring it may receive radiotherapy before administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, a subject requiring it may receive treatment with one or more anticancer agents other than the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, before administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has cancer that is refractory or intolerant to one or more previous treatments.

[0268] Accordingly, in one embodiment, the Specified provides a method for treating a subject having a MEK-associated tumor, comprising: (i) administering one or more, for example, one or more anticancer therapies to the subject; and (ii) after (i), (a) administering a compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof as monotherapy, or (b) administering 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, for example, one or more further anticancer therapies. In one embodiment, the further anticancer therapy is independently selected from surgery, radiotherapy, and / or one or more anticancer agents acting by the same or different mechanisms of action. In one embodiment, the further anticancer therapy is one or more anticancer agents acting by the same or different mechanisms of action. In one embodiment, the further anticancer therapy is one anticancer agent acting by the same or different mechanisms of action. In one embodiment, the further anticancer therapy is surgery. In one embodiment, further anti-cancer treatment is radiation therapy.

[0269] Non-limiting examples of further anticancer agents that can be used in combination with the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof, according to any of the combination therapies described herein include MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER2 and / or HER3 inhibitors, SHP2 inhibitors, Axl inhibitors, PI3K inhibitors, SOS1 inhibitors, signaling pathway inhibitors, checkpoint inhibitors, apoptotic pathway modulators, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapies, and immunotherapy agents, as well as further kinase inhibitors other than the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof.

[0270] In one embodiment, an anticancer agent that can be used 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, according to any of the combination therapies described herein, is a targeted therapeutic agent. “Targeted therapeutic agent,” as used herein, refers to a molecule that blocks the growth of cancer cells by interfering with specific targeted molecules necessary for carcinogenesis and tumor growth, rather than simply by interfering with all rapidly dividing cells (e.g., by conventional cytotoxic chemotherapy), and includes, but is not limited to, receptor tyrosine kinase targeted therapeutic agents, signaling pathway inhibitors (e.g., Ras-Raf-MEK-ERK pathway inhibitors, PI3K-Akt-mTOR-S6K pathway inhibitors ("PI3K inhibitors")), and apoptotic pathway modulators.

[0271] In one embodiment, an anticancer agent that can be used 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, according to any of the combination therapies described herein, is a BRAF inhibitor. Non-limiting examples of other BRAF inhibitors include encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), and pharmaceutically acceptable salts thereof, for example, 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-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-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)-phenyl)-3-fluoropropane-1-sulfonamide; N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)oxy]-4-fluorophenyl}propane-1-sulfonamide; N-(3-chloro-4-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluoropyridine-2-yl)propan-1-sulfonamide; and N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)oxy]-4-fluorophenyl}-3-fluoropropane-1-sulfonamide; Compounds disclosed in international application PCT / IB2020 / 055992, published on December 30, 2020 as PCT Publication WO2020 / 261156A1, comprising a compound selected from or a pharmaceutically acceptable salt thereof, Compounds disclosed in PCT Publication WO2021 / 250521, published on 6 December 2021, including, for example, 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-fluoroazetidine-1-sulfonamide, or pharmaceutically acceptable salts thereof. These are some examples.

[0272] In one embodiment, the BRAF inhibitor is selected from encorafenib or a pharmaceutically acceptable salt thereof, 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, and N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide or a pharmaceutically acceptable salt thereof.

[0273] In one embodiment, the BRAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof. In one embodiment, 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. In one embodiment, the BRAF inhibitor is N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide or a pharmaceutically acceptable salt thereof.

[0274] Further examples of BRAF inhibitors are known in the art.

[0275] In one embodiment, an anticancer agent that can be used 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, according to any of the combination therapies described herein, is an EGFR inhibitor. Non-exclusive examples of EGFR inhibitors include cetuximab (Erbitux®), panitumumab (Vectibix®), osimertinib (merelectinib, Tagrisso®), erlotinib (Tarceva®), gefitinib (Iressa®), necitumumab (Portrazza®), neratinib (Nerlynx®), lapatinib (Tykerb®), vandetanib (Caprelsa®), brigatinib (Alunbrig®), and EGFR inhibitors disclosed in PCT publications WO2019 / 071351 and WO2017 / 117680. Further examples of EGFR inhibitors are known in the art.

[0276] In one embodiment, an anticancer agent that can be used 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, according to any of the combination therapies disclosed herein, is an SHP2 inhibitor. Non-limiting examples of SHP2 inhibitors include 6-(4-amino-4-methylpiperidine-1-yl)-3-(2,3-dichlorophenyl)pyrazine-2-amine (SHP099), [3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-yl]methanol (RMC-4550), RMC-4630, TNO155, and compounds disclosed in WO2020 / 081848, WO2020 / 201991, WO2015 / 107493, WO2015 / 107494, WO2015 / 107495 and WO2019 / 075265. In one embodiment, the SHP2 inhibitor is a compound disclosed in WO2020 / 201991. In one embodiment, the SHP2 inhibitor is (S)-1'-(6-((2-amino-3-chloropyridine-4-yl)thio)-1,2,4-triazine-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine or a pharmaceutically acceptable salt thereof.

[0277] In one embodiment, an anticancer agent that can be used 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, according to any of the combination therapies disclosed herein, is a PI3K inhibitor.Non-limiting examples include buparlisib (BKM120), alpelisib (BYL719), samotricib (LY3023414), 8-[(1R)-1-[(3,5-difluorophenyl)amino]ethyl]-N,N-dimethyl-2-(morpholine-4-yl)-4-oxo-4H-chromen-6-carboxamide (AZD8186), tenalisib (RP6530), voxtalisib hydrochloride (SAR-245409), gedatricib (PF-05212384), and panulisib. (P-7170), Taselisib (GDC-0032), Trans-2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridine-3-yl)-4-methylpyrido[2,3-d]pyrimidine-7(8H)-one (PF-04691502), Dubellisib (ABBV-954), N2-[4-oxo-4-[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholine-4-ium-4-ylmethoxy]butyryl]-L-arginyl-glycyl-L-aspartic acid L-serine acetate (SF-1126), pictilicib (GDC-0941), 2-methyl-1-[2-methyl-3-(trifluoromethyl)benzyl]-6-(morpholine-4-yl)-1H-benzimidazole-4-carboxylic acid (GSK2636771), idelalicib (GS-1101), umbralicib tosylate (TGR-1202), pictilicib (GDC-0941), copanlicib hydrochloride (BAY84-1236), dactricib (BEZ-235), 1-(4-[5-[5-amino-6-(5- Examples include tert-butyl-1,3,4-oxadiazole-2-yl)pyrazine-2-yl]-1-ethyl-1H-1,2,4-triazole-3-yl]piperidine-1-yl)-3-hydroxypropan-1-one (AZD-8835), 5-[6,6-dimethyl-4-(morpholine-4-yl)-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purine-2-yl]pyrimidine-2-amine (GDC-0084), everolimus, rapamycin, perifosin, sirolimus, and temsirolimus.

[0278] In one embodiment, an anticancer agent that can be used 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, according to any of the combination therapies disclosed herein, is an immunotherapy. The term “immunotherapy” refers to an agent that modulates the immune system. In one embodiment, immunotherapy can increase the expression and / or activity of immune system modulators. In one embodiment, immunotherapy can decrease the expression and / or activity of immune system modulators. In one embodiment, immunotherapy can mobilize and / or enhance the activity of immune cells.

[0279] In one embodiment, an immunotherapy that can be used 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, according to any of the combination therapies disclosed herein, is an antibody therapy (e.g., a monoclonal antibody, a conjugate antibody). In one embodiment, antibody therapy includes bevacizumab (Mvasti®, Avastin®), trastuzumab (Herceptin®), rituximab (MabThera®, Rituxan®), edrecolomab (Panorex), daratumumab (Darzalex®), olaratumumab (Lartruvo®), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), olegovomab, pembrolizumab (Keytruda®), dinutuximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675, 206), and ramucirumab (C Yramza (registered trademark), Ubrituximab (TG-1101), Panitumumab (Vectibix (registered trademark)), Elotuzumab (Empliciti (trademark)), Necitumumab (Portrazza (trademark)), Cirmutuzumab (CIRMtuzumab) (UC-961), Ibritumomab (Zevalin (registered trademark)), Isatuximab (SAR650984), Nemo These include tuzumab, fresolimmab (GC1008), lirirumab (INN), mogamulizumab (Poteligeo®), ficratuzumab (AV-299), denosumab (Xgeva®), ganitumab, urerumab, pidilizumab, amatsuximab, blinatumomab (AMG103; Blincyto®), or midostaurin (Rydapt).

[0280] In one embodiment, an immunotherapy that can be used 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, according to any of the combination therapies disclosed herein, is an immune checkpoint inhibitor. In one embodiment, the immunotherapy comprises one or more, for example, 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 (Yervoy®) or tremelimumab (CP-675,206). In one embodiment, the PD-1 inhibitor is pembrolizumab (Keytruda®), nivolumab (Opdivo®), and sasanlimab (RN888). In one embodiment, the PD-L1 inhibitor is atezolizumab (Tecentriq®) or durvalumab (Imfinzi®).

[0281] In one embodiment, an anticancer therapy that can be used 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, according to any of the combination therapies disclosed herein, is radiotherapy. Non-limiting examples of radiotherapy include external beam therapy (e.g., external beam therapy using kilovoltage or megavoltage X-rays) or internal radiotherapy. Internal radiotherapy (also called close-range radiotherapy) may include, for example, the use of low-dose internal radiotherapy or high-dose internal radiotherapy. Low-dose internal radiotherapy includes, for example, inserting a small radioactive pellet into or near the target cancer tissue. High-dose internal radiotherapy includes, for example, inserting an elongated tube (e.g., a catheter) or implant into or near the target cancer tissue and using a radiologic device to deliver a high dose of radiation to the elongated tube or implant. Methods for administering radiotherapy to subjects having cancer are known in the art. In embodiments where the tumor is a CNS tumor, radiotherapy may include whole-brain radiotherapy (WBRT) or stereotactic radiotherapy (SRS), such as Cyberknife®, XKnife®, Gamma knife®, or ExacTrac®.

[0282] In one embodiment, an anticancer treatment that can be used 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, according to any of the combination therapies disclosed herein is surgery. Non-limiting examples of surgery include, for example, open surgery or minimally invasive surgery. Surgery may include, for example, at least partial resection of a tumor, removal of an entire tumor, reduction of a tumor, or removal of a tumor that is causing pain or compression in the subject. Methods for performing open surgery and minimally invasive surgery on subjects having cancer are known in the art.

[0283] In one embodiment, the Specified Public Service provides a method for treating a MEK-related tumor (e.g., any of the MEK-related tumors described herein) comprising administering to a subject 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, and a BRAF inhibitor (e.g., any of the BRAF inhibitors disclosed herein) in any order, together or separately. In one embodiment, the compound of formula I is a compound selected from Examples 1 to 69 or a pharmaceutically acceptable salt thereof.

[0284] In one embodiment, the Specified Public Service provides a method for treating a MEK-related tumor (e.g., any of the MEK-related tumors described herein) comprising administering to a subject 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, and an EGFR inhibitor (e.g., any of the EGFR inhibitors disclosed herein) in any order, together or separately. In one embodiment, the compound of formula I is a compound or a pharmaceutically acceptable salt thereof selected from any one of Examples 1 to 69.

[0285] In one embodiment, the Specified Public Service provides a method for treating a MEK-related tumor (e.g., any of the MEK-related tumors described herein) comprising administering to a subject 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, and an SHP2 inhibitor (e.g., any of the SHP2 inhibitors disclosed herein) in any order, together or separately. In one embodiment, the compound of formula I is a compound or a pharmaceutically acceptable salt thereof selected from any one of Examples 1 to 69.

[0286] In one embodiment, the Specified Public Service provides a method for treating a MEK-related tumor (e.g., any of the MEK-related tumors described herein) comprising administering to a subject 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, and a checkpoint inhibitor (e.g., any of the checkpoint inhibitors disclosed herein) in any order, together or separately. In one embodiment, the compound of formula I is a compound or a pharmaceutically acceptable salt thereof selected from any one of Examples 1 to 69.

[0287] Furthermore, this specification provides for a pharmaceutically acceptable combination for treating MEK-associated tumors in a subject requiring such treatment, 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 further anticancer agent (e.g., any exemplary further anticancer agent described herein or known in the art), wherein the 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, for example, one or more further anticancer agents, treat the tumor. Provided are a pharmaceutical combination, (ii) the use of such a combination for the preparation of a medicament for the treatment of a tumor, and (iii) a combination such as a combined preparation for simultaneous, separate, or sequential use, 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 an amount thereof, which is separately formulated for simultaneous or separate use for treatment, and an amount of further anticancer agents(s) effective together for treatment of a tumor; (ii) the use of such a combination for the preparation of a medicament for treatment of a tumor; and a commercial package or product including such combinations, such as a combined preparation, for simultaneous, separate, or sequential use, and a method for treating a tumor in a subject requiring it.

[0288] The term “pharmaceutical combination,” as used herein, refers to a non-fixed combination of active ingredients. “Non-fixed combination” means that 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, for example, one or more additional anticancer agents, can be administered simultaneously or separately to a subject requiring them, in any order, with variable intervening time limits, and such administration is formulated in separate compositions or dosages so as to yield effective levels of two or more compounds in the subject’s body. These also apply to cocktail therapies, for example, the administration of three or more active ingredients. Similarly, the term “combination” refers to a non-fixed combination when referring to 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 a combination of one or more anticancer agents.

[0289] Accordingly, the Specified also provides a method for treating MEK-related tumors, comprising administering to a subject in need of such treatment a pharmaceutically appropriate combination for treating the tumor, 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) one or more, for example, one or more further anticancer agents, for simultaneous, separate or sequential use for treating the tumor, wherein the amounts of the compound of formula I or a pharmaceutically acceptable salt thereof or a compound of formula II or a pharmaceutically acceptable salt thereof and the further anticancer agents are effective together for treating the tumor.

[0290] In one embodiment, the Specified provides a method for treating 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, to a subject in need thereof, wherein the subject has not undergone treatment with surgery, radiotherapy, or one or more anticancer therapies selected independently from anticancer agents acting by the same or different mechanisms of action, for example, one or more anticancer therapies selected from one or more anticancer therapies. In one embodiment, the patient has not been treated with anticancer agents prior to the 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. In one embodiment, the patient has not undergone surgery prior to the 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. In one embodiment, the patient has not been treated with radiotherapy prior to administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof.

[0291] In one embodiment, the Specified provides a method for treating a subject having a MEK-associated tumor (e.g., benign, malignant, or metastatic tumor), 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 subject has been treated with previous or standard treatments (e.g., treatment with one or more anticancer agents other than the compound of formula I or a pharmaceutically acceptable salt thereof, and / or radiotherapy and / or surgery), and the MEK-associated tumor has become refractory or intolerant to the said previous treatment. In one embodiment, the subject developed brain metastases during the said previous treatment.

[0292] In one embodiment of the method disclosed herein for treating subjects having MEK-related tumors, subjects having metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) had been 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 subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394). In one embodiment, the subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, and vemurafenib. In one embodiment, the subject became refractory to the aforementioned prior treatment. In one embodiment, the subject developed brain metastases during the aforementioned prior treatment.

[0293] In one embodiment of the method disclosed herein for treating subjects having MEK-related tumors, subjects having metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) had been treated with a BRAF inhibitor and a MEK 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 subjects are BRAF inhibitors selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), as well as binimetinib, trametinib, cobimetinib, selumetinib, and pimace. The subjects were previously treated with MEK inhibitors selected from lutib, refametinib, N-[2(R),3-dihydroxypropaoxy]-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). In one embodiment, the subjects were previously treated with BRAF inhibitors selected from encorafenib, dabrafenib, and vemurafenib, as well as MEK inhibitors selected from binimetinib, trametinib, and cobimetinib. In one embodiment, the subject was previously treated with encorafenib and binimetinib. In one embodiment, the subject was previously treated with dabrafenib and trametinib. In one embodiment, the subject was previously treated with vemurafenib and cobimetinib. In one embodiment, the subject became refractory to the aforementioned prior treatments.In one embodiment, the subject developed brain metastases during the aforementioned previous treatment.

[0294] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, a subject having metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) had been treated with one or more, e.g., one or two, checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., 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 subject was previously treated with one or more, e.g., one or two, checkpoint inhibitors independently selected from ipilimumab, nivolumab, and pembrolizumab. In one embodiment, the subject became refractory to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0295] In one embodiment of a method disclosed herein for treating subjects having MEK-related tumors, subjects having metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) had been treated with one or more, for example, 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 embodiment, the subjects are buparulisib (BKM120), alpelisib (BYL719), samotricib (LY3023414), 8-[(1R)-1-[(3,5-difluorophenyl)amino]ethyl]-N,N-dimethyl-2-(morpholine-4-yl)-4-oxo-4H-chromen-6-carboxamide (AZD8186), tenalisib (RP6530), voxtalisib hydrochloride (SAR-245409), gedatricib (PF-05212384), panulisib (P-7170), and taselicib (GDC-0032). Trans-2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridine-3-yl)-4-methylpyrido[2,3-d]pyrimidine-7(8H)-one (PF-04691502), dubellisib (ABBV-954), N2-[4-oxo-4-[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholine-4-ium-4-ylmethoxy]butyryl]-L-arginyl-glycyl-L-aspartyl-L-serine acetate (SF-1126), pictilisib (GDC-0941), 2-methyl-1-[2-methyl-3-(trifluoromethyl)benzyl]-6-(morpholine-4-yl)-1H-benzimidazole-4-carboxylic acid (GSK2636771), idelalisib (GS-1101), umbralicib tosylate (TGR-1202), pictilisib (GDC-0941), copanlisib hydrochloride (BAY84-1236), dactrisib (BEZ-235), 1-(4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazole-2-yl)pyrazine The patients were previously treated with one or more PI3K inhibitors selected from everolimus, rapamycin, perifosin, sirolimus, and temsirolimus, for example, one or two PI3K inhibitors: -2-yl]-1-ethyl-1H-1,2,4-triazole-3-yl]piperidine-1-yl)-3-hydroxypropan-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, perifosin, sirolimus, and temsirolimus.In one embodiment, the subject was previously treated with buparlisib or alperisib alone or in combination. In one embodiment, the subject became refractory to the previous treatment. In one embodiment, the subject developed brain metastases during the previous treatment. In one embodiment, the subject developed brain metastases during the previous treatment.

[0296] In one embodiment of the method disclosed herein for treating subjects having MEK-related tumors, subjects having metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) had been treated with a BRAF inhibitor and one or more, for example, one or two, checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., 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 embodiment, the subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), as well as one or more, for example, one or two, checkpoint inhibitors independently selected from ipilimumab, nivolumab, and pembrolizumab. In one embodiment, the subject became refractory to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0297] In one embodiment of the method disclosed herein for treating subjects having MEK-related tumors, subjects having metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) had been treated with a BRAF inhibitor, a MEK inhibitor, and one or more, for example, one or two, checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., 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 embodiment, the subject is a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), binimetinib, trametinib, cobimetinib, selumetinib, pimacertib, refametinib, N-[2(R),3-dihydroxypropaoxy]-3,4-difluoro The subjects were previously treated with a MEK inhibitor selected from -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), as well as one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors).In one embodiment, the subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, and vemurafenib, a MEK inhibitor selected from binimetinib, trametinib, and cobimetinib, and one or more, for example, one or two checkpoint inhibitors independently selected from ipilimumab, nivolumab, and pembrolizumab. In one embodiment, the subject became refractory to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0298] In one embodiment of a method disclosed herein for treating subjects having MEK-associated tumors, subjects having metastatic melanoma (e.g., metastatic melanoma with a BRAF V600 mutation or BRAF fusion) had been treated with one or more, for example, 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 subject was previously treated with an alkylating agent selected from temozolomide, fotemustine, lomustine, and carmustine. In one embodiment, the subject was previously treated with temozolomide. In one embodiment, the subject became refractory to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0299] In one embodiment of the method disclosed herein for treating subjects having MEK-related tumors, subjects having metastatic colorectal cancer (e.g., metastatic colorectal cancer having a BRAF V600 mutation or BRAF fusion) were treated with a MEK inhibitor and one or more, for example, one or two, checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., 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 formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the subjects are vinimetinib, trametinib, cobimetinib, selumetinib, pimacertib, refametinib, N-[2(R),3-dihydroxypropaoxy]-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) The subjects were previously treated with a MEK inhibitor selected from [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, e.g., CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors). In one embodiment, the subjects were previously treated with a MEK inhibitor selected from binimetinib, trametinib, and cobimetinib, and one or more, e.g., one or two checkpoint inhibitors independently selected from ipilimumab, nivolumab, and pembrolizumab. In one embodiment, the subjects were previously treated with a MEK inhibitor which is binimetinib, and a checkpoint inhibitor which is nivolumab, ipilimumab, or pembrolizumab. In one embodiment, the subject became refractory to the previous treatment. In another embodiment, the subject developed brain metastases during the previous treatment.

[0300] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, a subject having metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF V600 mutation or BRAF fusion) had been treated with one or more, for example, one or two, checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., 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 subject was previously treated with one or more, for example, one or two, checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab, and sasamrimab. In one embodiment, the subject became refractory to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0301] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, a subject having metastatic colorectal cancer (e.g., mutant metastatic colorectal cancer with a BRAF V600 mutation or BRAF fusion) had 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 subject had been treated with oxaliplatin, irinotecan, FOLFOXIRI (oxaliplatin, irinotecan, and fluorouracil), FOLFIRI (folic acid, 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 subject became refractory to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0302] In one embodiment of the method disclosed herein for treating subjects having MEK-associated tumors, subjects having metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF V600 mutation or BRAF fusion) had been treated 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 embodiment, a subject having metastatic colorectal cancer is given an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, nesitumumab, neratinib, lapatinib, vandetanib, and brigatinib, encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorofenib The subject had previously received treatment with a BRAF inhibitor selected from [nyl]propan-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), as well as one or more cytotoxic chemotherapeutic agents. In one embodiment, the subject had previously received treatment with an EGFR inhibitor selected from cetuximab and panitumumab, a BRAF inhibitor which is vemurafenib, and a cytotoxic chemotherapeutic agent which is irinotecan. In one embodiment, the subject became refractory to the aforementioned prior treatment. In one embodiment, the subject developed brain metastases during the aforementioned prior treatment.

[0303] In one embodiment of a method disclosed herein for treating subjects having MEK-related tumors, subjects having metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF V600 mutation or BRAF fusion) had previously been treated 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 subjects had previously been treated with an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, nesitumumab, neratinib, lapatinib, vandetanib, and brigatinib, as well as one or more chemotherapeutic agents. In one embodiment, the subject had previously received treatment with an EGFR inhibitor selected from cetuximab and panitumumab, as well as a cytotoxic chemotherapeutic agent such as irinotecan or FOLFIRI (folic acid, fluorouracil, and irinotecan). In one embodiment, the subject became refractory to the aforementioned prior treatment. In one embodiment, the subject developed brain metastases during the aforementioned prior treatment.

[0304] In one embodiment of a method disclosed herein for treating subjects having MEK-associated tumors, subjects having metastatic non-small cell lung cancer (e.g., metastatic non-small cell lung cancer with a BRAF V600 mutation or BRAF fusion) had been treated with one or more, e.g., 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 subjects were previously treated with one or more, e.g., one or two EGFR inhibitors independently selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, nesitumumab, neratinib, lapatinib, vandetanib, and brigatinib. In one embodiment, the subjects were previously treated with erlotinib. In one embodiment, the subjects were previously treated with gefitinib. In one embodiment, the subjects were previously treated with erlotinib and gefitinib. In one embodiment, the subject became refractory to the previous treatment. In another embodiment, the subject developed brain metastases during the previous treatment.

[0305] In one embodiment of the method disclosed herein for treating subjects having MEK-associated tumors, subjects having metastatic non-small cell lung cancer (e.g., metastatic non-small cell lung cancer with a BRAF mutation) are treated with encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2, A BRAF inhibitor selected from (3-b)pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), vinimetinib, Lametinib, cobimetinib, selumetinib, pimacertib, refametinib, N-[2(R),3-dihydroxypropaoxy]-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-dihydroxyprop The subject had previously received treatment with a MEK inhibitor selected from [Pyr]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733), and an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, nesitumumab, neratinib, lapatinib, vandetanib, and brigatinib. In one embodiment, the subject was previously treated with a BRAF inhibitor selected from vemurafenib, dabrafenib, and encorafenib, 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 subject became refractory to the aforementioned prior treatment. In one embodiment, the subject developed brain metastases during the aforementioned prior treatment.

[0306] In one embodiment of the method disclosed herein for treating subjects having MEK-related tumors, subjects having metastatic thyroid cancer (e.g., metastatic thyroid cancer with a BRAF V600 mutation or BRAF fusion) are treated with encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sodium before treatment with the compound of formula I or a pharmaceutically acceptable salt thereof, or the compound of formula II or a pharmaceutically acceptable salt thereof. BRAF inhibitors selected from sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), including vinimetinib, trametinib, cobimetinib, selumetinib, pimacertib, and le Fametinib, N-[2(R),3-dihydroxypropaoxy]-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-( The subjects had previously received treatment with a MEK inhibitor selected from 2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733), and an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, nesitumumab, neratinib, lapatinib, vandetanib, and brigatinib. In one embodiment, the subjects were previously treated with a BRAF inhibitor selected from vemurafenib, dabrafenib, and encorafenib prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the subjects became refractory to the aforementioned prior treatment. In one embodiment, the subjects developed brain metastases during the aforementioned prior treatment.

[0307] In one embodiment of the method disclosed herein for treating a subject having a MEK-associated tumor, the subject has LMD and has been previously treated with a BRAF inhibitor and one or more, for example, one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., CTLA-4 inhibitor, PD-1 inhibitor, and / or PD-L1 inhibitor) prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), as well as one or more, for example, one or two, checkpoint inhibitors independently selected from ipilimumab, nivolumab, and pembrolizumab. In one embodiment, the subject became refractory to the aforementioned prior treatment.

[0308] In one embodiment of the method disclosed herein for treating a subject having a MEK-associated tumor, the subject has LMD and has been previously treated with a BRAF inhibitor, a MEK inhibitor, and one or more, for example, one or two, checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., 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, a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), binimetinib, trametinib, cobimetinib, selumetinib, pimacertib, refametinib, N-[2(R),3-dihydroxypropaoxy]-3,4-di The samples were previously treated with a MEK inhibitor selected from fluoro-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), as well as a checkpoint inhibitor (e.g., any of the checkpoint inhibitors disclosed herein, e.g., CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors).In one embodiment, the subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, and vemurafenib, a MEK inhibitor selected from binimetinib, trametinib, and cobimetinib, and one or more, for example, one or two, checkpoint inhibitors independently selected from ipilimumab, nivolumab, and pembrolizumab. In one embodiment, the subject became refractory to the aforementioned prior treatment.

[0309] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has LMD and has been previously treated with one or more, for example, one or two checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., 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, a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with one or more, for example, one or two checkpoint inhibitors independently selected from ipilimumab, nivolumab, and pembrolizumab. In one embodiment, the subject has become refractory to the aforementioned prior treatment.

[0310] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a glioma and has been previously treated surgically 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 subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0311] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a glioma and has been previously treated with radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiotherapy) prior to treatment with a compound of formula I or a pharmaceutically acceptable salt thereof, a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0312] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a 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 subject has been previously treated with one or more cytotoxic chemotherapeutic agents independently selected from cisplatin, pemetrexed, vinorelbine, and paclitaxel. In one embodiment, the subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0313] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a MEK-associated 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 subject has been previously treated with an ornithine decarboxylase inhibitor, which is eflornithine (racemic or as a D or L enantiomer). In one embodiment, the subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0314] In one embodiment of the method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a MEK-associated 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 subject has been previously treated with an alkylating agent selected from temozolomide, lomustine, and carmustine. In one embodiment, the subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0315] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a MEK-associated 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 subject has been previously treated with an alkylating agent selected from temozolomide, lomustine, and carmustine, and an ornithine decarboxylase inhibitor, which is eflornithine (racemic or as a D or L enantiomer). In one embodiment, the subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0316] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a MEK-associated glioma and has been previously treated with radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiotherapy) 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 subject has previously received radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiotherapy) and an alkylating agent selected from temozolomide, lomustine, and carmustine. In one embodiment, the subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0317] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a MEK-associated glioma and has been previously 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 subject has previously received treatment with antibody therapy, which is bevacizumab. In one embodiment, the subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0318] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a MEK-associated glioma and has been previously treated with surgery and radiotherapy 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 subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0319] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a MEK-associated glioma and has been previously treated with surgery, radiotherapy 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 subject has been previously treated with surgery, radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiotherapy), and an alkylating agent selected from temozolomide, lomustine and carmustine. In one embodiment, the subject has become refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3 or grade 4 glioma.

[0320] In one embodiment of a method disclosed herein for treating a subject having a MEK-associated tumor, the subject has a MEK-associated glioma and has been previously treated with a BRAF inhibitor prior to treatment with a compound of formula II or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor selected from N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide (PLX4720), vemurafenib, dabrafenib, encorafenib, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394). In one embodiment, the subject has become refractory to the aforementioned previous treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0321] In one embodiment of the method disclosed herein for treating a subject having a MEK-related tumor, the subject has a 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 compound of formula II, or a pharmaceutically acceptable salt, solvate, or polymorph thereof. In one embodiment, the subjects are BRAF inhibitors selected from N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide (PLX4720), vemurafenib, dabrafenib, encorafenib, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), as well as binimetinib, trametinib, cobimetinib, selumetinib, and pi. The patient had previously received treatment with a MEK inhibitor selected from macertib, refametinib, N-[2(R),3-dihydroxypropaoxy]-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). In one embodiment, the subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, and vemurafenib, and a MEK inhibitor selected from binimetinib, trametinib, and cobimetinib. In one embodiment, the subject became refractory to the aforementioned prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0322] In one embodiment of the method disclosed herein for treating a subject having a MEK-related tumor, the subject has a MEK-related brainstem ganglioglioma 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 subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-ylcarbonyl)-2,4-difluorophenyl]propan-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394). In one embodiment, the subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, and vemurafenib. In one embodiment, the subject became refractory to the aforementioned prior treatment.

[0323] While the genetic basis of tumorigenesis may vary among different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar across all solid tumor types. During the metastatic cascade, cancer cells lose their growth-inhibiting response, undergo changes in adhesion, and produce enzymes that can degrade extracellular matrix components. This allows tumor cells to detach from the original tumor and infiltrate the circulation through newly formed vascular structures, enabling them to migrate and extravasate to preferred distant sites, where they can form colonies. Several genes have been identified as promoters or inhibitors of metastasis.

[0324] Accordingly, the Specified also provides a method for treating, inhibiting, preventing, aiding in the prevention or reduction of metastasis of MEK-associated tumors in a subject requiring such treatment, comprising administering to the subject 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 surgical procedures (e.g., at least partial resection of the tumor), radiotherapy, and anticancer agents.

[0325] As used herein, the term “treating metastases” means reducing the size, progression, and / or further expansion of one or more metastases.

[0326] As used herein, the term “inhibiting metastasis” 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.

[0327] In one embodiment, a subject treated according to any of the methods disclosed herein may be evaluated according to one or more standard response evaluation criteria known in the art, including RECIST (Response Evaluation Criteria in Solid Tumors, e.g., RECIST version 1.0, RECIST version 1.1, and modified RECIST 1.1 (mRECIST 1.1)), RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases), Macdonald, RANO-LMD, and NANO (Neurologic Assessment in Neuro-Oncology). In one embodiment of any of the criteria, the tumor is evaluated by imaging studies (e.g., MRI, CT, MDCT, or PET). In one embodiment, the treatment response is assessed according to RECIST version 1.1, where complete response (CR) is defined as complete disappearance of all tumor lesions, partial response (PR) as a reduction of at least 30% of the total tumor measurement, progressive disease (PD) as an increase of at least 20% of the total tumor measurement (development of new lesions or substantial progression of non-target lesions is also defined as PD), an increase of at least 5 mm from baseline is assessed as PD, and stable disease (SD) is defined as not having reduced enough to qualify as PR and not having increased enough to qualify as PD, based on the smallest total diameter during treatment. In one embodiment, the assessment includes intracranial response (assessed according to modified RECIST using gadolinium-enhanced MRI), extracranial response, comprehensive response rate, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

[0328] As used herein, “effective dose” or “effective amount” of a drug, compound or pharmaceutical composition is an amount sufficient to produce any one or more beneficial or desired effects, including the biochemical, histological and / or behavioral symptoms of a disease, its complications, and intermediate pathological phenotypes that appear during the development of the disease. For therapeutic use, “therapeutic effective dose” means the amount of compound administered that reduces, to some extent, one or more symptoms of the disorder being treated. Referring to the treatment of cancer, a therapeutic effective dose means an amount that has the effect of (1) reducing tumor size, (2) inhibiting (i.e., slowing, preferably stopping) tumor metastasis, (3) inhibiting (i.e., slowing, preferably stopping) tumor growth or tumor invasiveness to some extent, (4) reducing (or preferably eliminating) one or more signs or symptoms associated with cancer to some extent, (5) reducing the dose of other medicines required to treat the disease, and / or (6) enhancing the effect of another medicine, and / or (7) delaying the progression of the disease in the patient.

[0329] The effective dose can be administered in one or more doses. 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 a prophylactic or therapeutic action. As understood in a clinical context, the effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.

[0330] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention as active ingredients, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug 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.

[0331] In one embodiment, the present invention provides a pharmaceutical composition comprising the 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.

[0332] Accordingly, in one embodiment, the present invention provides a pharmaceutical composition for use in treating abnormal cell growth in a subject requiring such treatment, comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0333] As used herein, “pharmaceutically acceptable carrier” means a carrier or diluent that does not cause significant irritation to the organism and does not inhibit the biological activity and properties of the administered compound.

[0334] Pharmacoherent carriers may include any conventional pharmaceutically acceptable carrier or excipient. The choice of carrier and / or excipient will depend largely on factors such as the specific administration method, the effect of the carrier or excipient on solubility and stability, and the properties of the dosage form.

[0335] Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents (e.g., hydrates and solvates). The pharmaceutical composition may optionally contain further components such as flavoring agents, binders, and excipients.

[0336] The term “excipient” is used herein to describe any component other than the compound(s) of the present invention. The choice of excipient will depend largely on factors such as the method of administration, the effect of the excipient on solubility and stability, and the properties of the dosage form.

[0337] As used herein, “excipients” include any physiologically compatible solvent, dispersion medium, coating, antimicrobial and antifungal agent, isotonic and absorption retardant, carrier, diluent, etc. Examples of excipients include water, physiological saline, phosphate buffer solution, glucose, glycerol, ethanol, etc., and one or more combinations thereof, and the composition may include isotonic agents, such as sugars, sodium chloride, or polyhydric alcohols, such as mannitol or sorbitol. Examples of excipients also include various organic solvents (e.g., hydrates and solvates). The pharmaceutical composition may optionally contain further excipients, such as flavoring agents, binders / binding agents, lubricants, disintegrants, sweeteners or flavoring agents, colorants, or dyes. For example, for oral administration, tablets containing various excipients such as citric acid can be used with various disintegrants, such as starch, alginic acid, and certain complex silicates, as well as binders, such as sucrose, gelatin, and acacia. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Therefore, for oral administration, tablets containing various excipients such as citric acid can be used with various disintegrants, such as starch, alginic acid, and certain complex silicates, as well as binders, such as sucrose, gelatin, and acacia. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. In addition, lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc, are often useful for tablet formation. Similar types of solid compositions are sometimes used in soft and hard-filled gelatin capsules. Therefore, non-limiting examples of such materials include lactose and high molecular weight polyethylene glycol.If an aqueous suspension or elixir is preferred for oral administration, the active compound therein may be combined with a diluent, such as water, ethanol, propylene glycol, glycerin, or a combination thereof, along with various sweeteners or flavorings, colorants or dyes, and optionally emulsifiers or suspending agents.

[0338] Examples of excipients include pharmaceutically acceptable substances that enhance the shelf life or efficacy of a compound, such as humectants, or small amounts of auxiliary substances, such as humectants or emulsifiers, preservatives, or buffers.

[0339] The pharmaceutical composition may be in forms suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, and solution suspensions; sterile solutions; liquid solutions suitable for parenteral injection, such as suspensions or emulsions (e.g., injectable insoluble solutions); ointments or creams suitable for topical administration; powders; liposomes; and suppositories (e.g., suppositories suitable for rectal administration). Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, such as aqueous propylene glycol solutions or dextrose solutions. Such dosage forms can be suitably buffered as desired. The form is determined according to the intended method of administration and therapeutic application.

[0340] The pharmaceutical composition may be in a unit dosage form suitable for a single dose of a precise amount.

[0341] The compounds of the present invention can be administered orally. Oral administration may involve swallowing to allow the compound to enter the gastrointestinal tract, or it may involve oral buccal or sublingual administration to allow the compound to enter the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations, such as tablets, microparticles, capsules containing liquid or powder, licks (including those filled with liquid), chewable formulations, multiply and nanoparticle formulations, gels, solid solutions, liposomes, films (including those that adhere to mucous membranes), vaginal suppositories, sprays, and liquid formulations. Such capsules or tablets may include controlled-release formulations. In the case of capsules, tablets, and pills, the dosage form may include a buffer or may be prepared with an enteric coating.

[0342] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillers in soft or hard capsules and typically include carriers or adjuvants, such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners) or fragrances, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oils, as well as one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared, for example, by restoring a solid from a sachet.

[0343] The compounds of the present invention may also be used in rapidly soluble, rapidly disintegrating dosage forms, such as those described by Liang and Chen in Expert Opinion in Therapeutic Patents, 11(6), 981-986(2001), the disclosure of which is incorporated herein by reference in its entirety.

[0344] For tablet dosage forms, the drug can constitute 1 wt% to 80 wt%, more typically 5 wt% to 60 wt%, of the dosage form, depending on the dose. Tablets generally contain a disintegrant in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant constitutes 1 wt% to 25 wt%, preferably 5 wt% to 20 wt%, of the dosage form. Binders are generally used to impart tackiness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. The tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate. The tablets may also contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and flow enhancers, such as silicon dioxide and talc. If present, surfactants are typically present in amounts of 0.2 wt% to 5 wt% of the tablet, and flow enhancers are typically present in amounts of 0.2 wt% to 1 wt% of the tablet. The tablets also generally contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants are generally present in amounts of 0.25 wt% to 10 wt%, preferably 0.5 wt% to 3 wt%, of the tablet. Other conventional ingredients include antioxidants, colorants, flavorings, preservatives, and taste modifiers. The tablet blend can be formed into tablets either directly or by compression using rollers.Alternatively, a tablet blend or portion of a blend may be wet, dry, or melt-granulated, melt-solidified, or extruded and then tableted. The final formulation may contain one or more layers, may be coated or uncoated, or may be encapsulated. Solid formulations for oral administration may be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained pulse, controlled, targeted, and programmed release.

[0345] For oral administration, the composition may be provided in the form of tablets or capsules 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 milligrams of the active ingredient in order to adjust the dosage to the patient according to their symptoms. The pharmacopoeia typically contains about 0.01 mg to about 100 mg of the active ingredient. In another embodiment, the pharmacopoeia contains about 0.01 to 0.25 mg of the active ingredient. In yet another embodiment, the pharmacopoeia contains about 0.25, 0.5, 1.0, 5.0, 15, or 25 mg of the active ingredient.

[0346] The compounds of the present invention can also be administered directly into the bloodstream, muscles, or internal organs. Suitable means of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and injection techniques. Injectable preparations (i.e., injectable sterile aqueous or oily suspensions) can be formulated according to known techniques using one or more suitable dispersants, wetting agents, or suspending agents. Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably to a pH of 3-9), but in some applications they can be more preferably formulated as sterile non-aqueous solutions or as a dry form used in combination with a suitable vehicle, e.g., sterile pyrogen-free water. Preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be easily achieved 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 using appropriate formulation techniques, for example, by incorporating solubility enhancers.

[0347] Formulations for parenteral administration can be formulated to be immediate and / or modified-release. Modified-release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Accordingly, the compounds of the present invention can be formulated as solids, semi-solids, or thixotropic liquids for administration as an implanted depot that provides a modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

[0348] The compounds of the present invention may also be administered topically to the skin or mucous membranes, i.e., transdermally or transdermally, for example by transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. When the compounds of the present invention are administered by a transdermal device, administration is achieved using either a reservoir and porous membrane type patch or a solid matrix type patch. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders for application, bandages, foams, films, skin patches, wafers, implants, sponges, fibers, adhesive bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated. Other means of local administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., Powderject®, Bioject®, etc.).

[0349] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compound of the present invention is dissolved or suspended in a suitable excipient. Typical formulations suitable for administration to the eye or ear may be in the form of microparticle suspensions or droplets of solution in isotonic, pH-adjusted sterile saline. Other formulations suitable for administration to the eye or ear include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and microparticles, or vesicle systems, such as niosomes or liposomes. Cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers, such as hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymers, such as gellan gum, can be incorporated together with preservatives such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0350] Formulations for topical administration can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0351] The compounds of the present invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, as a mixture, for example, in a dry blend with lactose, or as mixed component particles mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer using electromagnetic hydrodynamics to produce a fine mist) or nebulizer, with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive, such as chitosan or cyclodextrin. A pressurized vessel, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the present invention, for example, ethanol, an aqueous solution of ethanol, or an alternative agent suitable for the dispersion, solubilization, or extension of the release of an activator, a propellant(s) as a solvent, and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid. Before use in a dry powder or suspension formulation, the drug product can be atomized to a size suitable for inhalation delivery (typically less than 5 microns). This can be achieved by any suitable crushing method, such as spiral jet milling, fluidized bed jet milling, critical fluid treatment to form nanoparticles, high-pressure homogenization, or spray drying.

[0352] Capsules (e.g., made from gelatin or HPMC), blisters, and cartridges for use in inhalers or blowers can be formulated to contain the compound of the present invention, a suitable powder base, such as lactose or starch, and a performance modifier, such as a powder mix of I-leucine, mannitol, or magnesium stearate. The lactose may be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0353] A suitable flavor, such as menthol and levomenthol, or a sweetener, such as saccharin or sodium saccharin, may be added to the formulation of the present invention intended for inhalation / intranasal administration.

[0354] The compounds of the present invention can be administered rectally or vaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is a conventional suppository base, but various substitutes can be appropriately used.

[0355] Formulations for rectal / vaginal administration can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0356] The compounds of the present invention can also be administered directly to the eyes or ears in the form of microparticle suspensions or solution droplets in typically isotonic, pH-adjusted sterile saline. Other formulations suitable for administration to the eyes and ears include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and microparticles, or vesicle systems, such as niosomes or liposomes. Cross-linked polyacrylic acids, polyvinyl alcohols, hyaluronic acid, cellulose polymers, such as hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, such as gellan gum, can be incorporated together with preservatives such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0357] Formulations for ocular / ear administration can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0358] Other excipients and administration methods known in the field of pharmaceuticals may also be used. The pharmaceutical compositions of the present invention can be prepared by either well-known pharmaceutical techniques, such as effective formulation and administration procedures. The above considerations regarding effective formulation and administration procedures are well-known in the art and are described in standard textbooks. The formulation of drugs is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.

[0359] Acceptable excipients are nontoxic to the subject at the doses and concentrations used and may include one or more of the following: 1) Buffers, e.g., phosphates, citrates, or other organic acids; 2) Salts, e.g., sodium chloride; 3) Antioxidants, e.g., ascorbic acid or methionine; 4) Preservatives, e.g., octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl, or benzyl alcohol; 5) Alkylparabens, e.g., methyl or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) Low molecular weight (less than approximately 10 residues) polypeptides; 7) Proteins, e.g., serum albumin, gelatin, or immunoglobulin; 8 ) Hydrophilic polymers, e.g., polyvinylpyrrolidone; 9) Amino acids, e.g., glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) Monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrin; 11) Chelating agents, e.g., EDTA; 12) Sugars, e.g., sucrose, mannitol, trehalose, or sorbitol; 13) Salt-forming counterions, e.g., sodium, metal complexes (e.g., Zn-protein complexes); or 14) Nonionic surfactants, e.g., polysorbate (e.g., polysorbate 20 or polysorbate 80), poloxamer, or polyethylene glycol (PEG).

[0360] 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 prepared by reverse-phase evaporation using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivativeized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter of a defined pore size to obtain liposomes having a desired diameter.

[0361] The compounds of the present invention can also be captured in microcapsules prepared in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions by, for example, coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000).

[0362] Sustained-release preparations can be used. A preferred example of a sustained-release preparation is a semipermeable matrix of a solid hydrophobic polymer containing the compound of the present invention, the matrix being in the form of a molded article, e.g., a film 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-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, e.g., those used in leuprolide acetate for depot suspensions (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyrate.

[0363] Preparations used for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane. The compounds of the present invention are generally placed in containers having a sterile access port, such as intravenous solution bags or vials having a stopper that can be penetrated by a subcutaneous injection needle.

[0364] Suitable emulsions can be prepared using commercially available lipid emulsions, such as lipid emulsions containing soybean oil, lipid emulsions for intravenous administration (e.g., containing safflower oil, soybean oil, egg phosphatide, and glycerin in water), emulsions containing soybean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient can be dissolved in a pre-mixed emulsion composition, or alternatively in oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil), and the emulsion is formed when mixed with phospholipids (e.g., egg phospholipids, soybean phospholipids, or soybean lecithin) and water. It will be noted that other components, such as glycerol or glucose, can be added to adjust the osmotic pressure of the emulsion. Suitable emulsions typically contain up to 20% oil, for example, between 5 and 20% oil. The lipid emulsion may contain lipid droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and may have a pH in the range of 5.5 to 8.0.

[0365] For example, the emulsion composition may be prepared by mixing the compound of the present invention with a lipid emulsion containing soybean oil or its components (soybean oil, egg phospholipid, glycerol, and water).

[0366] Drug product intermediates (DPIs) are partially processed materials that must undergo further processing steps before becoming bulk drug products. The compounds of the present invention can be formulated into drug product intermediate DPIs containing the active ingredient 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 material transport across the mucous layer adjacent to epithelial cells, and, in some cases, to overcome biological barriers, e.g., limitations due to metabolism and transporters. Other reasons may include improved solid-state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains the compound of the present invention isolated and stabilized in an amorphous state (e.g., an amorphous solid dispersion (ASD)). There are many techniques known in the art for producing ASDs that produce materials suitable for integration into bulk drug products, e.g., spray-dried dispersions (SDDs), molten extrudes (often called HMEs), co-precipitates, amorphous drug nanoparticles, and nanoadsorbents. In one embodiment, the amorphous solid dispersion comprises the compound of the present invention and a polymer excipient. The concentrations of other excipients, as well as the excipients and compounds of the present invention, are well known in the art and are described in standard textbooks. For example, see "Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al.

[0367] In another embodiment, the present invention provides compounds or pharmaceutically acceptable salts thereof for use as pharmaceuticals, particularly for the treatment of abnormal cell growth.

[0368] In yet another aspect, the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the treatment of abnormal cell growth in a subject, for example, tumors in a subject, for example, MEK-related tumors.

[0369] In yet another aspect, the present invention provides compounds or pharmaceutically acceptable salts thereof according to any of the formulas described herein for use in the treatment of abnormal cell growth, such as tumors, such as MEK-associated tumors.

[0370] The compounds of the present invention may be administered by any method that can deliver the compounds to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), topical, and rectal administration.

[0371] Dosage regimens can be adjusted to produce the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgency of the treatment situation. For ease of administration and uniformity of dosage, it is particularly advantageous to formulate parenteral compositions into unit dosage forms. As used herein, a unit dosage form refers to a physically distinct unit suitable as a unit dose for the mammalian subject being treated, each unit containing a predetermined amount of the active compound calculated to produce the desired therapeutic effect, along with the necessary pharmaceutically acceptable carrier. The specifications for unit dosage forms of the present invention depend directly on (a) the unique characteristics of the compound being administered and the specific therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the field in which such active compounds are formulated for the treatment of the susceptibility of an individual.

[0372] Accordingly, those skilled in the art will recognize that, based on the disclosures provided herein, doses and administration regimens are adjusted according to methods well known in the therapeutic field. That is, the maximum tolerable dose can be easily established, and the effective dose that provides a detectable therapeutic benefit to the patient can be determined, as can the time requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Thus, although certain doses and administration regimens are illustrated herein, these examples do not in any way limit the doses and administration regimens that may be provided to a patient in practice of the invention.

[0373] It should be noted that dosage values ​​vary depending on the type and severity of the condition being alleviated and may include single or multiple doses. Furthermore, specific dosage regimens for any particular subject should be adjusted over time according to individual needs and the professional judgment of the personnel administering and supervising the administration of the composition, and it should be understood that the dosage ranges described herein are merely illustrative and not intended to limit the scope or implementation of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects, e.g., toxic effects and / or clinical laboratory values. Thus, the present invention encompasses intra-patient dose escalation as determined by those skilled in the art. Determining appropriate dosages and regimens for the administration of chemotherapeutic agents is well known in the relevant art and should be understood to be encompassed by those skilled in the art once the teachings disclosed herein are provided. In one embodiment, the effective dose is typically in the range of about 0.001 to about 100 mg per kg of body weight per day, often in single or divided doses of about 0.01 to about 35 mg / kg / day. For a 70kg person, the dosage should be approximately 0.07mg / day to 7000mg / day, more generally 10mg / day to 1000mg / day. Occasionally, the dosage may be 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 1000mg / day.Sometimes the dosage is approximately 10 mg / day to 1000 mg / day, approximately 10 mg / day to 750 mg / day, approximately 10 mg / day to 600 mg / day, approximately 10 mg / day to 300 mg / day, approximately 10 mg / day to 150 mg / day, approximately 20 mg / day to 750 mg / day, approximately 20 mg / day to 600 mg / day, approximately 20 mg / day to 300 mg / day, approximately 20 mg / The dosage ranges from approximately 150 mg / day to approximately 750 mg / day, approximately 50 mg / day to approximately 600 mg / day, approximately 50 mg / day to approximately 300 mg / day, approximately 50 mg / day to approximately 150 mg / day, approximately 75 mg / day to approximately 750 mg / day, approximately 75 mg / day to approximately 600 mg / day, approximately 75 mg / day to approximately 300 mg / day, or approximately 75 mg / day to approximately 150 mg / day. In some cases, a dosage level below the lower end of the above range may be sufficient, while in other cases, a larger dose may be used that does not cause any adverse side effects, and such larger doses are typically divided into several smaller doses to be administered throughout the day. In one embodiment, the subject is administered approximately 50 mg / day.

[0374] For example, since it may be desirable to administer a combination of active compounds for the purpose of treating a specific disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, each containing at least one compound according to the present invention, can be conveniently combined in the form of a kit suitable for the combined administration of the compositions. Accordingly, a kit of the present invention comprises two or more separate pharmaceutical compositions, each containing at least one compound according to the present invention, and means for holding the compositions separately, such as containers, divided bottles, or divided foil packets. An example of such a kit is the well-known blister pack, which is used for packaging tablets, capsules, and the like.

[0375] The kits of the present invention are particularly suitable for administering different dosage forms, such as oral and parenteral dosage forms, for administering separate compositions at different dosing intervals, or for titrating separate compositions against each other. To aid in medication adherence, the kits typically include a dosing instruction sheet and may be equipped with memory aids. In some embodiments, the kits include a compound or its pharmaceutical composition and a diagnostic agent. In other embodiments, the kits include a compound or its pharmaceutical composition and one or more therapeutic agents, such as BRAF inhibitors, e.g., N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)propan-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoro Propan-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)propan-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)propan-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-ox So-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)-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-fluoropyridine-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;The BRAF inhibitor comprises 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-fluoroazetidine-1-sulfonamide; or a pharmaceutically acceptable salt thereof selected from these.

[0376] The following scheme and description provide general details regarding the preparation of the compounds of the present invention.

[0377] The compounds of the present invention can be prepared by any method known in the art for the preparation of compounds of similar structures. In particular, the compounds of the present invention can be prepared by the procedure described by reference to the following scheme, or by the specific method described in the examples, or by a method similar to any of these.

[0378] Those skilled in the art will recognize that the experimental conditions described in the following scheme are examples of suitable conditions for producing the transformations shown, and that it may be necessary or desirable to modify the exact conditions used for the preparation of the compound of formula I, and compounds contained in formula I, such as the compound of formula II.

[0379] In addition, those skilled in the art will recognize that at any stage of the synthesis of the compounds of the present invention, it may be necessary or desirable to protect one or more sensitive groups to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino or alcohol groups. Protecting groups (PGs) used in the preparation of the compounds of the present invention can be used in conventional ways. For example, see "Greene's Protective Groups in Organic Synthesis," 3rd edition (John Wiley and Sons, 1999) by Theodora W Greene and Peter GM Wuts, incorporated herein by reference, particularly Chapter 7 ("Protection of Amino Groups") and Chapter 2 ("Protection of Hydroxyl Groups Including 1,2- and 1,3-Diols"), which also describes methods for the removal of such groups.

[0380] [ka]

[0381] Scheme 1 describes a general method for preparing compound 8, and compound 8 is R 1 H is R 2 H is R 3 is a C3-C6 cycloalkyl group, and R 4 The compound is of formula I, as defined for formula I. Commercially available 2,6-dichloro-4-methylnicotinic acid (compound 1) can be converted to ester analog 2 by treatment with (trimethylsilyl)diazomethane. Compound 2 can be converted to dimethylaminovinyl intermediate compound 3 by treatment with N,N-dimethylformamide dimethylacetal. Compound 3 can be converted to aldehyde intermediate compound 4 by treatment with a suitable acid, such as hydrochloric acid, in a suitable solvent, such as ether. The cyclization of compound 4 can be performed in a suitable solvent, such as methanol, in the presence of a reducing agent (e.g., sodium cyanoborohydride), using formula R 3 NH2 (in the formula, R 3Compound 5 can be obtained by treating compound 4 with a reagent having (where is C3-C6 cycloalkyl). Compound 5 can be converted to compound 6 by treating compound 5 with trimethylsilyl iodide in a suitable solvent, e.g., acetonitrile. Compound 6 can be methylated to compound 7 by treating it with methyl iodide in a suitable solvent, e.g., in the presence of THF and a suitable base, e.g., an alkali carbonate, e.g., potassium carbonate, in the presence of methyl iodide. Compound 7 can be methylated with formula R in a suitable solvent, e.g., THF and a strong base, e.g., lithium hexamethyldisilazide. 4 NH2 (in the formula, R 4 When treated with a reagent having (as defined for formula I), it undergoes aromatic nucleophilic substitution, providing compound 8.

[0382] [ka]

[0383] Scheme 2 describes a general method for preparing compound 17, and compound 17 is R 1 H is R 2 H is R 3 R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy-, 4Compound I is a compound of formula I, as defined for formula I. Commercially available 4-bromo-2,6-dichloropyridine can be lithified with a reagent, such as lithium diisopropylamide, and captured with carbon dioxide to obtain carboxylic acid 10. Compound 10 can be converted to compound 11 by refluxing in an aqueous base solution, such as 4M sodium hydroxide. Compound 11 can be methylated by treatment with methyl iodide in the presence of a suitable solvent, such as DMF, and a suitable base, such as an alkali carbonate, such as potassium carbonate, to provide compound 12. Compound 12 can be converted to vinyl ether intermediate 13 by a Suzuki reaction with (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound (i)) using a catalyst, such as methanesulfonate (2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) and an alkaline base (e.g., an alkaline carbonate, e.g., an aqueous potassium carbonate solution) in a suitable solvent, e.g., 1,4-dioxane. Compound 13 can be converted to vinyl ether intermediate 13 by a Suzuki reaction with (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound (i)) using a catalyst, such as methanesulfonate (2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) and an alkaline base (e.g., an alkaline carbonate, e.g., an aqueous potassium carbonate solution) in a suitable solvent, e.g., 1,4-dioxane. 3a -NH2HCl (wherein, R 3a is P 1 O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy-, P 1 When treated with a reagent containing an alcohol protecting group (e.g., tert-butyl, benzyl, or tert-butyldimethylsilyl), it undergoes oxyimine formation to provide compound 14. Compound 14 can be reduced to alkoxyamine intermediate 15 using a suitable reducing agent, such as sodium borohydride, in a suitable solvent, such as isopropanol. Compound 15 can be reduced to compound R in a suitable solvent, such as THF, in the presence of a strong base, such as lithium hexamethyldisilazide. 4 NH2 (in the formula, R 4When treated with a reagent having (as defined for formula I), it undergoes aromatic nucleophilic substitution and simultaneous cyclization, followed by compound 16 becoming P 1 If a protecting group is present, R can be removed by optional deprotection (using standard alcohol deprotection conditions known to those skilled in the art, such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride). 3 We can provide compound 17 in which is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy-.

[0384] [ka]

[0385] Scheme 3 describes a general method for preparing compound 20, and compound 20 is R 1 H is R 2 is CH3-, and R 3 R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy-, 4 The compound is of formula I, as defined for formula I. Compound 15 (wherein R is present in formula I) was prepared as described in Scheme 2. 3a is P 1 O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy-, P 1 R is an alcohol protecting group, for example, tert-butyl, benzyl, or tert-butyldimethylsilyl. 4 (As defined for formula I) in a suitable solvent, e.g., THF, in the presence of a strong base, e.g., lithium hexamethyldisilazide, formula R 4 NH2 (in the formula, R 4Compound 16 can be obtained by cyclization when treated with a reagent having (as defined for formula I). ​​Compound 16 can be obtained by iodinating it with n-iodosuccinimide and p-toluenesulfonic acid in a suitable solvent, e.g., 1:1 MeOH:THF. Compound 18 undergoes Negishi coupling with methylzinc(II) chloride in a suitable solvent, e.g., THF, using a catalyst, e.g., a palladium catalyst, e.g., bis(tri-t-butylphosphine)palladium(O), and then, if compound 19 contains a protecting group, undergoes optional deprotection (using standard alcohol deprotection conditions known to those skilled in the art, e.g., phosphoric acid, trifluoroacetic acid or tetrabutylammonium fluoride), R 3 We can provide a compound 20 in which is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy.

[0386] [ka]

[0387] Scheme 4 describes a general method for preparing compound 24, and compound 24 is R 1 H is R 2 H is R 3 H is R 4 The compound is of formula I, as defined for formula I. Compound 13, prepared as described in Scheme 2, is subjected to a reaction of formula R in a suitable solvent, for example, THF, in the presence of a strong base, for example, lithium hexamethyldisilazide. 4 NH2 (in the formula, R 4When treated with a reagent having (as defined for formula I), it can undergo aromatic nucleophilic substitution to provide compound 21. Compound 21 can be hydrolyzed to aldehyde intermediate 22 under acidic conditions using an acid, such as trifluoroacetic acid, in a suitable solvent, such as dichloromethane. Compound 22 can be hydrolyzed to formula P using a reducing agent, such as sodium triacetoxyborohydride, in a suitable solvent, such as dichloroethane. 2- NH2 (in the formula, P 2 Compound 23 can be obtained by cyclization when treated with a reagent having an amine protecting group (e.g., benzyl, p-methoxybenzyl, or 2,4-dimethoxybenzyl). Compound 24 can be obtained by deprotecting compound 23 using standard deprotection conditions known to those skilled in the art, such as heating with trifluoroacetic acid or hydrochloric acid.

[0388] [ka]

[0389] Scheme 5 describes a general method for preparing compound 27, and compound 27 is R 1 H is R 2 H is R 3 R is a hydroxy C1-C6 alkyl group, 4 Compound 13 is a compound of formula I, as defined for formula I. Compound 13, prepared as described in Scheme 2, can be hydrolyzed to aldehyde intermediate 25 using a suitable acid, for example, trifluoroacetic acid. Compound 25 can be hydrolyzed to formula P using a suitable solvent, for example, dichloroethane, and a suitable reducing agent, for example, sodium triacetoxyborohydride and acetic acid. 1 O-(C1~C6 alkyl)-ONH2HCl (wherein, P 1 The compound 26 can be cyclized and deprotected by reacting it with a reagent containing an alcohol protecting group (e.g., tert-butyldimethylsilyl) at 60°C. Compound 26 can then be subjected to a reaction with a strong base (e.g., lithium hexamethyldisilazide) in a suitable solvent (e.g., THF) with the formula R4 NH2 (in the formula, R 4 When treated with a reagent having (as defined for formula I), it undergoes aromatic nucleophilic substitution, providing compound 27.

[0390] [ka]

[0391] Scheme 6 describes an alternative general method for preparing compound 17, and compound 17 is R 1 H is R 2 H is R 3 R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, 4 Compound I is a compound of formula I, as defined for formula I. Compound 28, prepared according to a method similar to the method described for compound 13, is subjected to a reaction in a suitable solvent, e.g., THF, in the presence of a strong base, e.g., lithium hexamethyldisilazide, with formula R 4 NH2 (in the formula, R 4 When treated with a reagent having formula R (as defined for formula I), it undergoes aromatic nucleophilic substitution to provide compound 29. Compound 29 can be subjected to a suitable solvent, for example, triethylamine and HCl in 1,4-dioxane and heated to obtain compound R 3a NH2HCl (where R 3a is P 1 O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, P 1 When treated with a reagent containing an alcohol protecting group (e.g., tert-butyl, benzyl, or tert-butyldimethylsilyl), it undergoes oxyimine formation to provide compound 30. Compound 30 is cyclized in a suitable solvent, e.g., isopropanol, using a suitable reducing agent, e.g., sodium borohydride and acetic acid, and subsequently compound 30 is P 1If a protecting group is present, R can be removed by optional deprotection (using standard alcohol deprotection conditions known to those skilled in the art, such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride). 3 We can provide compound 17 in which is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy.

[0392] [ka]

[0393] Scheme 7 describes an alternative general method for preparing compound 17, and compound 17 is R 1 H is R 2 H is R 3 R is a hydroxy C1-C6 alkoxy, 4 Compound 28 is a compound of formula I, as defined for formula I. When compound 28 is treated with the reagent of formula TBSO-(C1~C6 alkyl)-ONH2HCl using a suitable solvent, e.g., 1,4-dioxane, triethylamine, HCl, and heating, it undergoes oxyimine formation to provide compound 32. Compound 32 can be treated with a suitable alcohol protecting group P using a suitable solvent, e.g., DMF, tert-butyldimethylsilyl chloride, and a suitable base, e.g., imidazole. 1 For example, compound 14 can be provided by protecting it with tert-butyldimethylsilyl. Compound 14 can be reduced to alkoxyamine intermediate 15 using a suitable reducing agent, such as sodium borohydride, in a suitable solvent, such as isopropanol. Compound 15 can be reduced to a compound of formula R in a suitable solvent, such as THF, in the presence of a strong base, such as lithium hexamethyldisilazide. 4 NH2 (in the formula, R 4When treated with a reagent having (as defined for formula I), it undergoes aromatic nucleophilic substitution to provide compound 16. Compound 16 can 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.

[0394] [ka]

[0395] Scheme 8 describes an alternative general method for preparing compound 20, and compound 20 is R 1 H is R 2 is CH3-, and R 3 R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, 4 Compound 28 is a compound of formula I, as defined for formula I. Compound 28 is mixed with a strong base, such as lithium hexamethyldisilazide, in a suitable solvent, such as THF, and formula R 4 NH2 (in the formula, R 4 When treated with a reagent having (as defined for formula I), it undergoes aromatic nucleophilic substitution to provide compound 29. Compound 29 can be hydrolyzed to aldehyde intermediate 22 using a suitable acid, for example, trifluoroacetic acid. Compound 22 can be hydrolyzed to formula R in a solvent, for example, dichloroethane, using a suitable reducing agent, for example, sodium triacetoxyborohydride and acetic acid. 3a NH2HCl (where R 3a is P 1 O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, P 1Compound 16 can be obtained by reacting compound 16 with an alcohol protecting group (e.g., tert-butyl, benzyl, or tert-butyldimethylsilyl) at 60°C. Compound 16 can be iodinated using n-iodosuccinimide and p-toluenesulfonic acid in a suitable solvent, e.g., 1:1 MeOH:THF, to provide compound 18. Compound 18 undergoes coupling with methylzinc(II) chloride in a suitable solvent, e.g., THF, using a catalyst, e.g., bis(tri-t-butylphosphine)palladium(O), and subsequently compound 18 becomes P 1 If a protecting group is present, it undergoes optional deprotection (using standard alcohol deprotection conditions known to those skilled in the art, such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride), R 3 We can provide a compound 20 in which is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy.

[0396] [ka]

[0397] Scheme 9 describes a general method for synthesizing compound 35, and compound 35 is R 1 H is R 2 is halogen, R 3 R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, 4 Compound 12 is a compound of formula I, as defined for formula I. Compound 12 is mixed with a strong base, such as lithium hexamethyldisilazide, in a suitable solvent, such as THF, and compound R 4 NH2 (in the formula, R 4When treated with a reagent having (as defined for formula I), it can undergo aromatic nucleophilic substitution to provide compound 33. Compound 33 can be converted to vinyl ether intermediate 21 by a Suzuki reaction with (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using a suitable solvent, e.g., 1,4-dioxane, a catalyst, e.g., a palladium catalyst, e.g., methanesulfonate (2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) and an alkaline base, e.g., an alkaline carbonate base, e.g., an aqueous potassium carbonate solution. Compound 21 can be converted to vinyl ether intermediate 21 by a Suzuki reaction with (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using a suitable solvent, e.g., 1,4-dioxane, triethylamine and HCl and heating to obtain compound R 3a NH2HCl (where R 3a is P 1 O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, P 1 When compound 31 is treated with a reagent containing an alcohol protecting group (e.g., tert-butyl, benzyl, or tert-butyldimethylsilyl), it undergoes oxyimine formation to provide compound 30. Compound 30 can be treated with a suitable reducing agent (e.g., sodium borohydride and acetic acid) in a suitable solvent (e.g., isopropanol) to produce a cyclized compound 31. Compound 31 can be halogenated using conditions such as treatment with N-iodosuccinimide and p-toluenesulfonic acid in 1:1 THF / MeOH, or a suitable solvent (e.g., N-bromosuccinimide in DMF), or a suitable solvent (e.g., N-chlorosuccinimide in DMF), or a suitable solvent (e.g., Selectfluor in acetonitrile), and subsequently compound 31 is P 1 If a protecting group is present, R can be removed by optional deprotection (e.g., phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride). 2 These are iodine, bromo, chloro, or fluoro, respectively, and R 3We can provide compound 35 in which is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy.

[0398] [ka]

[0399] Scheme 10 describes an alternative general method for preparing compound 17, and compound 17 is R 1 H is R 2 H is R 3 R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, 4 Compound 12 is a compound of formula I, as defined for formula I. Compound 12 is prepared in a suitable solvent, e.g., THF, in the presence of a suitable base, e.g., potassium tert-butoxide, and compound R 4 NH2 (in the formula, R 4 When treated with a reagent having (as defined for formula I), it undergoes aromatic nucleophilic substitution 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-dioxaborolane using a solvent, e.g., 2-methyltetrahydrofuran, a catalyst, e.g., a palladium catalyst, e.g., methanesulfonate (2-dicyclohexylphosphin-2',6'-di-i-propoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) and a suitable base, e.g., an alkaline base, e.g., an alkaline carbonate base, e.g., an aqueous potassium carbonate solution. Compound 29 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-dioxaborolane using a suitable solvent, e.g., 1,4-dioxane, triethylamine and hydrochloric acid, using formula R 3a NH2HCl (where R 3a is P 1O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, P 1 The compound 29 is reacted with an alcohol protecting group (e.g., tert-butyl, benzyl, or tert-butyldimethylsilyl), then treated with a suitable reducing agent (e.g., pyridineborane and hydrochloric acid), heated at 60°C, and subsequently compound 29 is P 1 If a protecting group is present, R can be removed by optional deprotection (e.g., phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride). 3 Compound 17 can be obtained in which is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy.

[0400] [ka]

[0401] Scheme 11 describes a method for preparing compound 43, and compound 43 is R 1 is phenyl, and R 2 is hydrogen, R 3 is hydrogen, R 4Compound I is a compound of formula I, as described for formula I. Commercially available 2,6-dichloro-4-iodopyridine can be lithified with a reagent, e.g., lithium diisopropylamide, and captured with carbon dioxide to obtain compound 37. Compound 37 can be converted to compound 38 by refluxing in an aqueous base solution, e.g., 4M sodium hydroxide. Compound 38 can be methylated with methyl iodide in the presence of a suitable base, e.g., an alkali carbonate, e.g., potassium carbonate, in the presence of a suitable solvent, e.g., 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-dioxaborolane in a suitable solvent, e.g., 1,4-dioxane, using a suitable catalyst, e.g., a palladium catalyst (e.g., Pd(dppf)Cl2) and a base, e.g., an alkali carbonate (e.g., aqueous potassium carbonate solution). Compound 40 is subjected to a reaction in a suitable solvent, for example, THF, in the presence of a strong base, for example, lithium hexamethyldisilazide, with formula R 4 NH2 (in the formula, R 4 When treated with a reagent having (as defined for formula I), it undergoes aromatic nucleophilic substitution to provide compound 41. Compound 41 can be cyclized with (2,4-dimethoxyphenyl)methaneamine by heating in a suitable solvent, e.g., toluene, in the presence of a Lewis acid, e.g., trimethylaluminum, to obtain compound 42. Compound 42 can be deprotected by heating with a suitable acid, e.g., TFA, to obtain compound 43.

[0402] [ka]

[0403] Scheme 12 describes a method for preparing compound 51, and compound 51 is R 1 is methyl, R 2 is hydrogen, R 3R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, 4 Compound 44 is a compound of formula I, as defined for formula I. Compound 44 can be treated with NH3, Fe(NO3)3,9H2O and NaNH2 at low temperature, followed by treatment with methyl iodide to obtain compound 45. Compound 45 can be heated with benzo[d][1,3,2]dioxabolol in a suitable solvent, e.g., toluene, with a catalyst, e.g., NiCl2(dppe), to obtain compound 46. Compound 46 can be converted to compound 47 by reacting compound 39 with compound 39 using Suzuki reaction conditions in the presence of a catalyst, e.g., palladium catalyst, e.g., Pd(dppf)Cl2, and a base, e.g., K3PO4, K2CO3, KOtBu, Cs2CO3, NaOH, or triethylamine in a suitable solvent, e.g., a mixture of one solvent, e.g., toluene / THF. Compound 47 can be converted to compound R using a suitable solvent, e.g., 1,4-dioxane, triethylamine and HCl and heating. 3a NH2HCl (where R 3a is P 1 O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy, P 1 When treated with a reagent containing an alcohol protecting group (e.g., tert-butyl, benzyl, or tert-butyldimethylsilyl), it undergoes oxyimine formation to provide compound 48. Compound 48 can be treated with a suitable solvent, e.g., isopropanol, and a suitable reducing agent, e.g., sodium cyanoborohydride and acetic acid, to produce a cyclized product 49. Compound 49 can be treated with a suitable solvent, e.g., THF, in the presence of a strong base, e.g., lithium hexamethyldisilazide, to produce compound R 4 NH2 (in the formula, R 4 When treated with a reagent having (as defined for formula I), it undergoes aromatic nucleophilic substitution, and subsequently compound 49 becomes P 1If a protecting group is present, R can be removed by optional deprotection (using standard alcohol deprotection conditions known to those skilled in the art, such as phosphoric acid, trifluoroacetic acid, or tetrabutylammonium fluoride). 3 Compound 51 can be provided, wherein is a hydroxy-C1-C6 alkoxy-, C1-C6 alkoxy, fluoroC1-C6 alkoxy, or (C3-C6 cycloalkyl)C1-C6 alkoxy.

[0404] The term “amine protecting group,” as used herein, refers to derivatives of groups commonly used to block or protect an amino group while a reaction is taking place on other functional groups on a compound. Examples of protecting groups suitable for use in any of the methods described herein include carbamates, amides, alkyl and aryl groups, imines, and many N-heteroatom derivatives, which can be removed to regenerate the desired amine group. Non-limiting examples of amine protecting groups include t-butyloxycarbonyl ("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.

[0405] As used herein, the term "alcohol protecting group" refers to derivatives of groups commonly used to block hydroxyl groups while reactions are taking place on other functional groups on a compound. Examples of protecting groups suitable for use in any of the methods described herein include benzyl, trityl, and silyl ethers.

[0406] Intermediate compounds 7, 15, 18, 22, 26, 29, 30, and 31 are novel intermediates useful for the preparation of the compound of formula I, as shown in the scheme above, and provide further embodiments of the present invention.

[0407] In one embodiment, this specification provides a method for preparing a compound of formula I, the method being: (a)R 1 H is R 2 H is R 3 is a C3-C6 cycloalkyl group, and R 4 For compounds of formula I, as defined for formula I, the compounds of formula 7

[0408] [ka] The formula R 4 NH2 (in the formula, R 4 Reacting a reagent having (as defined for formula I) in the presence of a strong base, or (b)R 1 H is R 2 H is R 3 R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy or (C3~C6 cycloalkyl)C1~C6 alkoxy-, 4 For compounds of formula I, as defined for formula I, the compounds of formula 15

[0409] [ka] [In the formula, R 3a is P 1 O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy-, P 1 [is an alcohol protecting group], formula R 4 NH2 (in the formula, R 4 The cyclization may be carried out in the presence of a reagent having (as defined for formula I), in the presence of a strong base, and then the alcohol protecting group may be removed if present, or (c)R 1 H is R 2 is CH3-, and R 3R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy or (C3~C6 cycloalkyl)C1~C6 alkoxy-, 4 For compounds of formula I, as defined for formula I, the compounds of formula 18

[0410] [ka] [In the formula, R 3a is P 1 P 1 R is an alcohol protecting group, 4 As defined for formula I, the product is treated with methylzinc(II) chloride in the presence of a palladium catalyst, followed by the removal of any alcohol protecting groups present, or (d)R 1 H is R 2 H is R 3 H is R 4 For compounds of formula I, as defined for formula I, the compounds of formula 22

[0411] [ka] [In the formula, R 4 As defined for equation I, 2- NH2 (in the formula, P 2 Cyclization in the presence of a reagent having an amine protecting group, followed by removal of the amine protecting group, or (e)R 1 H is R 2 H is R 3 R is a hydroxy C1-C6 alkyl group, 4 For compounds of formula I, as defined for formula I, the compounds of formula 26

[0412] [ka] [In the formula, R 4 As defined for formula I, in the presence of a strong base, formula R 4 The reaction is carried out in the presence of a reagent containing NH2, or (f)R 1 H is R 2 H is R 3 R is a hydroxy C1-C6 alkyl group, 4 For compounds of formula I, as defined for formula I, the compounds of formula 30

[0413] [ka] [In the formula, P 1 is an alcohol protecting group, R 4 As defined for formula I, this involves cyclizing the alcohol protecting group in the presence of a reducing agent, followed by the removal of the alcohol protecting group, or (g)R 1 H is R 2 is halogen, R 3 R is a hydroxy C1-C6 alkoxy-, C1-C6 alkoxy, fluoro C1-C6 alkoxy or (C3-C6 cycloalkyl) C1-C6 alkoxy-, 4 For compounds of formula I, as defined for formula I, the compounds of formula 31

[0414] [ka] [In the formula, R 4 As defined for equation I, R 3a is P 1 O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy-, P 1 [is an alcohol protecting group] is halogenated, and then the alcohol protecting group is removed if present, or (h)R 1 H is R2 H is R 3 R is hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy or (C3~C6 cycloalkyl)C1~C6 alkoxy-, 4 For compounds of formula I, as defined for formula I, the compounds of formula 29

[0415] [ka] [In the formula, R 4 [This is defined for equation I] and equation P 1 O-(C1~C6 alkyl)-ONH2HCl (wherein, P 1 The reagent (which is an alcohol protecting group) is reacted with triethylamine and hydrochloric acid in the presence of these two substances, followed by the removal of the alcohol protecting group, or (i)R 1 is phenyl, and R 2 is hydrogen, R 3 is hydrogen, R 4 For compounds of formula I as described for formula I, the compounds having formula 41

[0416] [ka] [In the formula, R 4 [As defined for formula I] is cyclized with (2,4-dimethoxyphenyl)methaneamine at an elevated temperature in the presence of a Lewis acid to form a compound having formula 42.

[0417] [ka] This involves providing and subsequently treating compound 42 with acid, or (j)R 1 is methyl, R 2 is hydrogen, R 3R is a hydroxy-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy or (C3~C6 cycloalkyl)C1~C6 alkoxy, 4 For compounds of formula I as defined for formula I, the compounds having formula 49

[0418] [ka] [In the formula, R 3a is P 1 O-C1~C6 alkoxy-, C1~C6 alkoxy, fluoroC1~C6 alkoxy, or (C3~C6 cycloalkyl)C1~C6 alkoxy-, P 1 [is an alcohol protecting group], formula R 4 NH2 (in the formula, R 4 A reagent having (as defined for formula I) is reacted in the presence of a strong base, and then P if present. 1 Removing the protecting group, and The compound of formula I may be converted into a pharmaceutically acceptable salt. Includes.

[0419] 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 represent further embodiments of the present invention.

[0420] The present invention can be further understood by referring to the following detailed description of embodiments of the present invention and examples contained herein. It should be understood that the present invention is not limited to specific preparation and synthesis methods, and that such methods may, of course, vary. It should also be understood that the terms used herein are for the sole purpose of describing specific embodiments and are not intended to limit them.

[0421] E1. Compounds of formula I

[0422] [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 is H, Br, C1-C6 alkyl or phenyl, R 2 is H, halogen or CH3-, R 3 These are H, hydroxy C1-C6 alkyl-, hydroxy C1-C6 alkoxy-, C1-C6 alkoxy, fluoro C1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl) C1-C6 alkoxy-, R 4 [These are phenyl compounds substituted with one, two, or three substituents 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)-.]

[0423] E2.R 1 A compound or pharmaceutically acceptable salt thereof according to Embodiment E1, wherein H is present.

[0424] E3.R 2 A compound or pharmaceutically acceptable salt thereof according to Embodiment E1 or E2, wherein H is present.

[0425] E4.R 2 A compound or pharmaceutically acceptable salt thereof according to Embodiment E1 or E2, wherein the compound is CH3-.

[0426] E5.R 3 A compound or pharmaceutically acceptable salt thereof according to any one of Embodiments E1 to E4, wherein the compound is hydroxy C1-C6 alkyl-.

[0427] E6.R 4A compound according to any one of Embodiments E1 to E5 or a pharmaceutically acceptable salt thereof, wherein the phenyl is substituted with one or two substituents 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)-.

[0428] E7.R 4 A compound or pharmaceutically acceptable salt thereof according to any one of Embodiments E1 to E6, wherein the compound is a phenyl substituted with one or two substituents independently selected from halogens and C1-C6 alkylthios.

[0429] E8. Compounds of formula II

[0430] [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 is H, Br, C1-C6 alkyl or phenyl, R 2 is H, halogen or CH3-, R 3 These are H, hydroxy C1-C6 alkyl-, hydroxy C1-C6 alkoxy-, C1-C6 alkoxy, fluoro C1-C6 alkoxy, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl) C1-C6 alkoxy-, R a and R b [These are independently selected from halogens, C1-C6 alkyls, C1-C6 alkylthios, fluoroC1-C6 alkylthios, fluoroC1-C6 alkyls, C1-C6 alkoxys, fluoroC1-C6 alkoxys, C3-C6 cycloalkyls, and C1-C6 alkyl-C(=O)-.

[0431] E9.R 1A compound or pharmaceutically acceptable salt thereof according to Embodiment E8, wherein H is present.

[0432] E10.R 2 A compound or pharmaceutically acceptable salt thereof according to Embodiment E8 or E9, wherein H is present.

[0433] E11.R 2 A compound or pharmaceutically acceptable salt thereof according to Embodiment E8 or E9, wherein the compound is CH3-.

[0434] E12.R 3 A compound or pharmaceutically acceptable salt thereof according to any one of embodiments E8 to E11, wherein the compound is hydroxy C1-C6 alkyl-.

[0435] E13.R 3 A compound or pharmaceutically acceptable salt thereof according to any one of embodiments E8 to E11, wherein H is present.

[0436] E14.R a A compound or pharmaceutically acceptable salt thereof according to any one of embodiments E8 to E13, which is a halogen.

[0437] E15.R b A compound or pharmaceutically acceptable salt thereof according to any one of embodiments E8 to E14, wherein the compound is a halogen, a C1-C6 alkyl, a C1-C6 alkylthio, or a fluoroC1-C6 alkoxy.

[0438] E16.R b A compound or pharmaceutically acceptable salt thereof according to Embodiment E15, wherein the compound is a C1-C6 alkylthio.

[0439] E17. 8-((4-bromo-2-fluorophenyl)amino)-2-cyclopropyl-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(cyclopropylmethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-ethoxy-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 2-Cyclopropyl-8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 2-Cyclopropyl-8-((2-fluoro-4-iodophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-chloro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-chlorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2,3-difluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-3-chloro-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-ethyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-cyclopropyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-methoxyphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-((trifluoromethyl)thio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-isopropylphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-chloro-4-cyclopropylphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-acetyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-chloro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-chloro-4-ethylphenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(trifluoromethoxy)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-((difluoromethyl)thio)-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-isopropoxy-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-2-isopropoxy-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 2-Ethoxy-8-((2-fluoro-4-iodophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-2-methoxy-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 2-(tert-butoxy)-8-((2-fluoro-4-iodophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; (S)-8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; (R)-8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; (S)-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; (R)-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxypropoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; (R)-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxypropoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-5-chloro-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 5-Chloro-8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-5-fluoro-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5-iodo-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 5-Bromo-8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 4-Bromo-8-((2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-ethyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-cyclopropyl-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-iodophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-iodo-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-ethyl-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-cyclopropyl-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-propylphenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-ethyl-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-cyclopropyl-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-chlorophenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethyl)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-(difluoromethoxy)-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-5,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 2-(2,2-difluoroethoxy)-8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-7-methyl-4-phenyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-7-methyl-4-phenyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-4,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-4,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((4-bromo-2-fluorophenyl)amino)-2-(2-hydroxyethoxy)-4,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-4,7-dimethyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione; A compound or a pharmaceutically acceptable salt thereof according to Embodiment E1 selected from the above.

[0440] E18. Structure

[0441] [ka] A compound or pharmaceutically acceptable salt thereof that is 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione having the above.

[0442] E19. Structure

[0443] [ka] A compound having 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.

[0444] Crystals containing E20.8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.

[0445] E21. Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 1.

[0446] Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 1, according to embodiment E21, having a PXRD pattern including characteristic peaks at E22.5.0, 8.7, 9.3, 10.8, 14.5, 15.3, 18.8 and 20.5 degrees 2 theta (±0.2 degrees 2 theta).

[0447] E23. Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 1, according to embodiment E21, having a PXRD pattern including a peak at essentially the same 2-theta value as shown in Figure 1.

[0448] E24. Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 2.

[0449] Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 2, according to embodiment E24, having a PXRD pattern including characteristic peaks at E25.7.1, 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 degrees 2 theta (±0.2 degrees 2 theta).

[0450] E26. Crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 2, according to embodiment E24, having a PXRD pattern including a peak at essentially the same 2-theta value as shown in Figure 2.

[0451] E27. The PXRD pattern is obtained by PXRD analysis performed at 25°C and a relative humidity below 10%, according to Embodiment E25 or E26, of crystalline anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, Form 2.

[0452] E28. Crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 3.

[0453] Crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 3, according to embodiment E28, having PXRD peaks at E29.13.7, 18.0 and 18.3 degrees 2-theta (±0.2 degrees 2-theta).

[0454] Crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 3, according to embodiment E28, having PXRD peaks at E30.6.9, 9.1, 13.7, 18.0 and 18.3 degrees 2-theta (±0.2 degrees 2-theta).

[0455] E31.2 The units in theta are 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 having a PXRD peak at 36.5 degrees 2 theta (±0.2 degrees 2 theta), crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 3, according to embodiment E28.

[0456] E32. Crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 3, according to embodiment E28, having a PXRD pattern including a peak at essentially the same 2-theta value as shown in Figure 3.

[0457] E33. The PXRD pattern is obtained by PXRD analysis performed at 25°C and a relative humidity above 35% for crystalline monohydrate 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 3, according to any one of embodiments E29 to E32.

[0458] E34. Amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, form 4.

[0459] E35. Amorphous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione according to Embodiment E34, having a PXRD pattern including a peak at essentially the same 2-theta value as shown in Figure 4, Embodiment 4.

[0460] 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.

[0461] E37. A method for treating MEK-related tumors, comprising administering to a subject in need of such treatment a therapeutically effective dose of a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E1 to E35.

[0462] E38. A method according to Embodiment E37, wherein the tumor has a BRAF V600 mutation selected from V600E, V600K, V600D, V600R, and V600S.

[0463] E39. A method according to embodiment E37 or E38 in which a tumor has a BRAF V600E mutation.

[0464] E40. A method according to any one of embodiments E37-E39, wherein the tumor is an extracranial tumor.

[0465] E41. A method according to Embodiment E40, wherein the extracranial tumor is selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, and neuroblastoma.

[0466] E42. A method according to any one of embodiments E37-E39, wherein the tumor is a CNS tumor.

[0467] E43. A method according to embodiment E42, wherein the CNS tumor is an intracranial tumor.

[0468] E44. A method according to embodiment E43 in which an intracranial tumor is a brain tumor.

[0469] E45. A method according to embodiment E44 in which the brain tumor is a metastatic brain tumor.

[0470] E46. A method according to Embodiment E45, wherein the metastatic brain tumor is selected from metastatic melanoma, metastatic colorectal cancer, metastatic non-small cell lung cancer, metastatic thyroid cancer, and metastatic ovarian cancer.

[0471] E47. A method according to embodiment E42, wherein the CNS tumor is an intracranial LMD or an extracranial LMD.

[0472] E48. A method according to embodiment E47, wherein LMD is selected from metastatic melanoma, metastatic colorectal cancer, and metastatic non-small cell lung cancer.

[0473] E49. A method according to embodiment E43 in which the intracranial tumor is a primary tumor.

[0474] E50. The method of embodiment E49, wherein the primary brain tumor is a malignant tumor.

[0475] E51. A method according to embodiment E50, wherein the primary brain tumor is a grade 2 glioma, a grade 3 glioma, or a grade 4 glioma.

[0476] E52. A method according to embodiment E49 in which the primary brain tumor is a benign tumor.

[0477] E53. The tumor has BRAF fusion. Method according to Embodiment E37.

[0478] E54.The tumor is 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 A method according to Embodiment E53, having a BRAF fusion selected from -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.

[0479] E55. Tumors include breast cancer (e.g., invasive ductal carcinoma), colorectal cancer (e.g., adenocarcinoma of the colon), esophageal cancer (e.g., adenocarcinoma of the esophagus), glioma (e.g., fibrillating infantile ganglion glioma of the brain, pilocytic astrocytoma of the brain, pleomorphic xanthoblastoma of the brain, low-grade glioma (NOS) of the spinal cord, anaplastic oligodendroglioma, anaplastic ganglion glioma), carcinomas of the head and neck (e.g., neuroendocrine carcinomas of the head and neck), lung cancer (e.g., adenocarcinoma of the lung, non-small cell lung cancer (NOS)), melanoma ( For example, the method according to Embodiment E54 is a cancer (e.g., Spitziform cutaneous melanoma, non-Spitziform mucosal melanoma, Spitziform cutaneous melanoma, melanoma of unknown primary origin, non-Spitziform cutaneous melanoma), pancreatic cancer (e.g., adenocarcinoma, acinar cell carcinoma of the pancreas), prostate cancer (e.g., acinar adenocarcinoma of the prostate), sarcoma (malignant solid fibroma), thyroid cancer (papillary thyroid carcinoma), cancer of unknown primary origin (e.g., adenocarcinoma of unknown primary origin), pleural mesothelioma, rectal adenocarcinoma, endometrial cancer (e.g., endometrial adenocarcinoma (NOS)), or ovarian serous carcinoma.

[0480] E56. A method according to embodiment E37, wherein the tumor is a BRAF wild-type tumor.

[0481] A method according to any one of embodiments E37 to E56, further comprising administering one or more additional anti-cancer therapies.

[0482] E58. A method according to Embodiment E57, in which one or more additional anti-cancer treatments are independently selected from surgery, radiotherapy and anticancer drugs.

[0483] E59. A method according to Embodiment E58, wherein further anticancer treatment is selected from one or more anticancer agents.

[0484] E60. A method according to Embodiment E59, wherein the anticancer agent is selected from immunotargeting agents, including MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER2 and / or HER3 inhibitors, SHP2 inhibitors, Axl inhibitors, PI3K inhibitors, SOS1 inhibitors, signaling pathway inhibitors, checkpoint inhibitors, apoptotic pathway modulators, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapies, and immunotherapies.

[0485] E61. The method of embodiment E60, wherein the anticancer agent is a BRAF inhibitor.

[0486] E62. The method of Embodiment E61, wherein the BRAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof.

[0487] E63.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-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-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)-phenyl)-3-fluoropropane-1-sulfonamide; N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)oxy]-4-fluorophenyl}propane-1-sulfonamide; N-(3-chloro-4-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluoropyridine-2-yl)propan-1-sulfonamide; and N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)oxy]-4-fluorophenyl}-3-fluoropropane-1-sulfonamide; Alternatively, the method of Embodiment E61, selected from pharmaceutically acceptable salts thereof.

[0488] E64. The method of Embodiment 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.

[0489] E65.BRAF inhibitors 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-fluoroazetidine-1-sulfonamide, Alternatively, the method of Embodiment E61, selected from pharmaceutically acceptable salts thereof.

[0490] E66. The method of Embodiment 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-fluoroazetidine-1-sulfonamide or a pharmaceutically acceptable salt thereof.

[0491] E67. The method of embodiment E60, wherein the anticancer drug is an SHP2 inhibitor.

[0492] E68. The method of Embodiment E67, wherein the SHP2 inhibitor is (S)-1'-(6-((2-amino-3-chloropyridine-4-yl)thio)-1,2,4-triazine-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine or a pharmaceutically acceptable salt thereof.

[0493] 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-naphthirizine-1,6(2H,7H)-dione, and the subject is administered 50 mg of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthirizine-1,6(2H,7H)-dione once daily.

[0494] E70. Compounds or pharmaceutically acceptable salts thereof according to any one of embodiments E1 to E35, for use as pharmaceuticals.

[0495] E71. Compounds or pharmaceutically acceptable salts thereof according to any one of embodiments E1 to E35 for use in the treatment of MEK-related tumors.

[0496] E72. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments E1 to E35 for the manufacture of a pharmaceutical for the treatment of MEK-related tumors in a subject.

[0497] To better understand the present invention, the following examples are provided. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0498] The compounds and intermediates listed below were named using the nomenclature provided in ChemDraw, version 20.1.1.125 (Perkin Elmer Informatics). The nomenclature provided in ChemDraw, version 20.1.1.125 is well known to those skilled in the art and is generally considered to conform to the IUPAC (International Union of Pure and Applied Chemistry) recommendations regarding organic chemical nomenclature and CAS indexing. Unless otherwise stated, all reactants were obtained commercially without further purification or prepared using methods known in the literature. [Examples]

[0499] Biological examples (Example A) Cellular Phosphosph p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) Assay Inhibition of ERK1 / 2(Thr202 / Tyr204) phosphorylation was determined by the following cell assay, which included incubating cells with the compound for 1 hour, quantifying the pERK signal by in-cell Western blotting in fixed cells, and standardizing it to the GAPDH signal. A375 cells were obtained from ATCC and grown in DMEM supplemented with 10% fetal bovine serum, penicillin / streptomycin, Glutamax(C), non-essential amino acids, and sodium pyruvate. Cells were plated in 96-well plates at 30,000 cells / well and adhered overnight at 37°C / 5% CO2. Cells were treated with the compound, which was prepared as a 10-point 1:3 dilution series (range: 20 μM to 0.05 nM; maximum concentration varied from 20 μM to 1 μM) using a final DMSO concentration of 0.5%. Control wells contained either 0.5% DMSO alone (no inhibitory control) or 1 μM of a potent control compound (complete inhibitory control). After a 1-hour incubation, the cells were fixed in 3.7% formaldehyde in dPBS (Dulbeccio phosphate buffer) at room temperature for 20 minutes. Next, the cells were washed with dPBS and permeabilized in 100% MeOH at room temperature for 10 minutes. After permeabilization, the cells were washed with dPBS and incubated in LI-COR blocking buffer (LI-COR Biosciences, catalog no. 927-40000) for more than 1 hour. The plates were then incubated with antibodies (Cell Signaling Technologies, catalog no. 9101) specific to threonine 202 and tyrosine 204, MEK-dependent ERK1 / 2 phosphorylation sites downstream of MEK in the MAP kinase signaling pathway, as well as GAPDH (Millipore, catalog no. MAB374). The pErk1 / 2(Thr202 / Tyr204) antibody was diluted with LI-COR blocking buffer containing 0.05% Tween-20 at a ratio of 1:250, and GAPDH was diluted at a ratio of 1:2,500. The plates were incubated overnight at 4°C.After washing with PBS / 0.05% Tween-20, cells were incubated for 1 hour with fluorescently labeled secondary antibodies (anti-rabbit Alexa Flour680, Invitrogen catalog number A21109; anti-mouse IRDye800CW, LI-COR Biosciences catalog number 926-32210, both at 1:1000 dilution). Cells were then washed as described above and analyzed for fluorescence at both 680 nm and 800 nm wavelengths using the Odyssey CLx infrared imaging system (LI-COR Biosciences). Phosphorylated Erk1 / 2 (Thr202 / Tyr204) signals were normalized to GAPDH signals per well. IC. 50 The values ​​are calculated from standardized values ​​using a 4-parameter fit in BioAssay software and provided in Table A.

[0500] [Table 5-1]

[0501] [Table 5-2]

[0502] (Example B) MDR1 LLC-PK1 and BCRP MDCKII Permeability Assay LLC-PK1 cells transfected with both LLC-PK1 and MDR1 were cultured and plated according to the manufacturer's recommendations, except that the subculture medium contained only 2% fetal bovine serum to extend the subculturing time to 7 days.

[0503] MDCKII canine P-gp knockout cell lines transfected with BCRP were cultured and plated according to the manufacturer's recommendations.

[0504] P-gp or BCRP efflux function was assessed in the assay using both positive and negative controls. Stock solutions of the assay control and test substance were prepared at final test concentrations of 10 μM and 1 μM in DMSO, respectively. The final organic matter concentration in the assay was 1%. All dosing solutions contained 10 μM Lucifer Yellow to monitor the integrity of the LLC-PK1 or MDCKII cell monolayer.

[0505] For apex-to-bottom (AB) determination, 75 μL of the test substance in transport buffer was added to the apex side of each transwell, and 250 μL of bottom medium without the compound or Lucifer Yellow was added to each well. For bottom-to-apex (BA) determination, 250 μL of the test substance in transport buffer was added to each well, and 75 μL of transport buffer without the compound or Lucifer Yellow was added to each transwell. All tests were performed in triplicate, and each compound was tested for both apex-to-bottom and bottom-to-apex transport. The plates were incubated in a Lab-Line Instruments titration orbital shaker (VWR, West Chester, PA) at 50 rpm and 37°C with 5% CO2 for 2 hours. All culture plates were removed from the incubator, 50 μL of medium was removed from the apical and lateral bottom portions of each well, and added to 150 μL of 1 μM labetalol in 2:1 acetonitrile (acetonitrile):H2O, v / v.

[0506] The plates were read using a Gemini fluorometer from Molecular Devices (Sunnyvale, CA) to assess the Lucifer Yellow concentration at excitation / emission wavelengths of 425 / 535 nm. These values ​​were observed when apical-to-basolateral flow was less than 2% and basolateral-to-apical flow was less than 5% across a monolayer of MDR1-transfected LLC-PK1 or BCRP-transfected MDCKII cells. The plates were sealed, and the contents of each well were analyzed by LC-MS / MS. Compound concentrations were determined from the ratio of the peak area of ​​the compound to an internal standard (labetalol) compared to the administration solution.

[0507] LC-MS analysis 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 4000QTrap system (Applied Biosystems, Foster City, CA). Chromatographic separation of analytes and internal standards was achieved at room temperature using a C18 column (Reaction Rate®, 50 × 300 mm, particle size 2.6 μm, Phenomenex, Torrance, CA) with gradient conditions using mobile phases A (water containing 1% isopropyl alcohol and 0.1% formic acid) and B (0.1% formic acid in acetonitrile). The total runtime, including re-equilibriumization for single injections, was 1.2 minutes. Mass spectrometry detection of analytes was achieved using the positive mode of an ion spray. The response of the analytes was measured by multiple reaction monitoring (MRM) of transitions unique to each compound (protonation precursor ions and product ions selected for each test substance, as well as m / z 329 to m / z 162 for the internal standard lavetalol).

[0508] Transmission coefficient (P app ) is calculated using the following equation. P app =[((C d *V*(1×106 )) / (t*0.12cm 2 *C)] In the formula, C d V, t, and C0 are the detection concentration (μM), volume at the administration site (mL), incubation time (seconds), and initial dose concentration (μM), respectively. app The calculation was performed for each iteration and then averaged. The permeability coefficients of the compounds in Equation I are provided in Table B1. In this assay, the compounds had a permeability of 8 × 10⁻⁶. -6 A compound is defined as having high permeability if its permeability exceeds 2 × 10⁻⁶ cm / second. -6 cm / sec~8×10 -6 A compound is defined as having moderate permeability if the permeability is 2 × 10⁻⁶ cm / second. -6 A value of less than cm / second is defined as having low permeability.

[0509] The discharge ratio is the average P from the top to the bottom (AB). app Data and mean P from bottom to top (BA) app Calculate from the data. Emission ratio=P app (BA) / P app (AB)

[0510] [Table 6-1]

[0511] [Table 6-2]

[0512] The discharge ratio is the average P from the top to the bottom (AB). app Data and mean P from bottom to top (BA) app Calculate from the data. Emission ratio=P app (BA) / P app (AB)

[0513] Table B2 provides the efflux ratios for the compound of formula I when used in this assay.

[0514] [Table 7-1]

[0515] [Table 7-2]

[0516] (Example C) PK (Ratio of free brain to free plasma) (mouse) The ability of representative compounds to penetrate the blood-brain barrier (BBB) ​​in mice was determined by evaluating the ratio of unbound brain to unbound plasma (also called free brain to free plasma) concentration in male CD1 mice.

[0517] Brain compound levels were generated from PK of orally administered mice using typical sampling times at 2, 4, 8, 12, and 24 hours after oral forced feeding administration of 10 mg / kg. Brain samples were stored at -20±5°C before analysis. The concentration of the test compound in mouse brain homogenate was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after precipitation of proteins with acetonitrile. A 12-point calibration curve in the range of 0.5–10,000 ng / mL was prepared in double series. A solution of the test compound at 400 μg / mL in dimethyl sulfoxide (DMSO) was serially diluted (3-fold) with 100% DMSO, and then 2.5 μL of each standard solution was added to 100 μL of naive male CD-1 mouse brain homogenate. 2.5 μL of DMSO was added to all test samples to mimic the extraction in the standard curve. Both calibration and test brain homogenate samples were spiked with 10 μL of IS (a structural analogue of 1 μg / mL). Brain homogenates were prepared by adding 0.75 mL of 4:1 water:MeOH to each brain sample, followed by homogenization at 6 m / s for 1 minute in a bead crusher tube using MP Fast Prep-24®. Proteins were precipitated from 100 μL of brain homogenate sample by adding 300 μL of acetonitrile. The samples were vortex-mixed for 5 minutes and centrifuged at approximately 1,500 × g for 15 minutes at 4°C in an Allegra X-12R centrifuge (Beckman Coulter, Fullerton, CA; SX4750A rotor). A fixed volume of 100 μL of each supernatant was transferred to a 96-well plate using a 550 μL Personal Pipettor (Apricot Designs, Monrovia, CA) and diluted 1:1 with HPLC-grade water. The resulting plates were sealed in aluminum for LC-MS / MS analysis.

[0518] The ratio of brain to plasma was calculated using the concentration of the compound measured in brain divided by the concentration of the compound measured in plasma. The ratio of brain to plasma was always generated from a single animal and time point. The ratio of free brain to free plasma is given by the following equation: (B / P)*(B fu / P fuThe ratio of brain to plasma was calculated by multiplying the in vitro brain homogenate free fraction by the in vitro plasma free fraction using ).

[0519] Table C provides the ratio of free brain to free plasma for representative compounds of Examples 6, 7, 8, 14, 22, 36, and 46 disclosed herein.

[0520] [Table 8] Synthesis Examples Intermediate 1

[0521] [ka] Methyl(E)-2,6-dichloro-4-(2-(dimethylamino)vinyl)nicotinate Step 1. Preparation of methyl 2,6-dichloro-4-methylnicotinate. To a solution of 2,6-dichloro-4-methylnicotinic acid (1.0 g, 4.9 mmol) in 1:1 MeOH:dioxane (10 mL), (trimethylsilyl)diazomethane (3.3 mL, 2 M in hexane, 6.6 mmol) was added at 0°C. The mixture was removed from the ice bath, stirred for 10 minutes, then concentrated to half the volume and partitioned into water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL), the combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered, and carefully concentrated. The residue was purified by elution with 0-15% ethyl acetate / petroleum ether by column chromatography to obtain methyl 2,6-dichloro-4-methylnicotinate (0.81 g, 76%). 1 H NMR (400 MHz, CDCl3) δ 7.2 (s, 1H), 4.0 (s, 3H), 2.3 (s, 3H) ppm.

[0522] Step 2. Preparation of methyl(E)-2,6-dichloro-4-(2-(dimethylamino)vinyl)nicotinate. To a solution of methyl 2,6-dichloro-4-methylnicotinate (810 mg, 3.68 mmol) in DMF (5 mL), N,N-dimethylformamide dimethylacetal (978 mL, 7.36 mmol) was added, 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 the solid was collected by filtration, washed with water, and dried in vacuum to obtain methyl(E)-2,6-dichloro-4-(2-(dimethylamino)vinyl)nicotinate (764 mg, 75%). 1 H NMR (400 MHz, CDCl3) δ 7.3 (s, 1H), 7.1 (d, 1H), 4.8 (d, 1H), 3.1 (s, 3H), 2.9 (s, 6H) ppm.

[0523] Intermediate 2

[0524] [ka] Methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate 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, and stirring was continued at -78°C for 1 hour. Solid CO2 (155.1 g, 3.53 mol) was added gradually to the reaction mixture, and stirring was continued at -78°C for 2 hours. The reaction mixture was quenched by adding 1 M Na2CO3 (1600 mL), followed by water (500 mL), and stirred for 10 minutes. The aqueous layer was extracted with HCl (300 mL). The pH of the aqueous solution was adjusted with 2N HCl to obtain a solution with pH 2. Next, the aqueous solution was extracted with HCl (3 × 300 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain 4-bromo-2,6-dichloronicotinic acid (540 g, 75%).1 H NMR (400 MHz, DMSO-d6) δ 15.51 - 12.87 (m, 1H), 8.13 (s, 1H) ppm.

[0525] Step 2. Preparation of 4-bromo-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid. A solution of NaOH (4M, 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 all at once. The mixture was stirred for 8 hours and then cooled to 0°C. The reaction mixture was adjusted to pH 1 with HCl (6M) and stirred for 30 minutes. The solid was collected by filtration and dried in vacuum to obtain 4-bromo-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (assuming 100%).

[0526] Step 3. Preparation of methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate. To a mixture of 4-bromo-2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (100 g, 396 mmol) in DMF (800 mL), methyl iodide (168.6 g, 1.19 mol, 73.98 mL) and K2CO3 (164.2 g, 1.19 mol) were added all at once. The mixture was stirred at 25°C for 3 hours, then poured into saturated NH4Cl (1800 mL), and the aqueous phase was extracted with ELISA (2 × 500 mL). The combined organic phase was washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated. The combined residues (5 batches) were purified by elution with 2-100% siRNA / petroleum ether using column chromatography to obtain methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (141.83 g, 24.7%) from the 5 batches. 1 H NMR (400 MHz, CDCl3) δ 6.86 (s, 1H), 3.94 (s, 3H), 3.69 - 3.66 (m, 3H); MS (apci, m / z) = 280.0, 282.0 (M+H).

[0527] Intermediate 3

[0528] [ka] Methyl(Z)-2-chloro-4-(2-ethoxyvinyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate Methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (20.0 g, 71.3 mmol), methanesulfonate (2-dicyclohexylphosphino-2',6'-di-i-propoxy-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-dioxaborolane (14.8 g, 74.9 mmol) were suspended in 1,4-dioxane (700 mL), and K2CO3 (53.5 mL, 107 mmol) (2N aqueous solution) was added. The mixture was stirred at 60°C for 6 hours, and then stirred under an argon atmosphere at ambient temperature for 12 hours. The reaction products were partitioned into water (1500 mL) and ethyl acetate (500 mL). The aqueous layer was extracted with ethyl acetate (2 × 400 mL), the combined organic layer was washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by elution with 0-40-60% ethyl acetate / heptane by column chromatography to obtain methyl(Z)-2-chloro-4-(2-ethoxyvinyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (13.3 g, 68%). 1 H NMR (400 MHz, CDCl3) δ 7.23 (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).

[0529] Intermediate 4

[0530] [ka] Methyl 4-(2-((2-(tert-butoxy)ethoxy)amino)ethyl)-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate 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 at 60°C for 1 hour, then cooled and filtered. The filtrate was concentrated to obtain methyl(E / Z)-4-(2-((2-(tert-butoxy)ethoxy)imino)ethyl)-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (assuming 100%) as a 1:1 isomer mixture. MS(apci, m / z) = 359.1(M+H).

[0531] Step 2. Preparation of methyl 4-(2-((2-(tert-butoxy)ethoxy)amino)ethyl)-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate. 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), sodium borohydride (1.09 g, 17.4 mmol) was added, followed by acetic acid (1.0 mL, 17.4 mmol). The mixture was stirred at ambient temperature for 16 hours, and then partitioned into saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ELISA (2 × 30 mL), the combined organic phase was washed with brine (30 mL), then dried over Na₂SO₄, filtered, and concentrated. The residue was purified by elution with 0-80% ELISA / DCM by column chromatography to obtain 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 (400 MHz, CDCl3) δ 6.43 (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).

[0532] Intermediate 5

[0533] [ka] 2-Chloro-4-ethylaniline Step 1. Preparation of N-(4-ethylphenyl)acetamide. 4-ethylaniline (513 μL, 4.13 mmol) was dissolved in DCM (10.3 mL). Triethylamine (690 μL, 4.95 mmol) was added, and after cooling to 0°C, acetic anhydride (467 μL, 4.95 mmol) was added dropwise. After 30 minutes, the reaction mixture was quenched by adding saturated NaHCO3 (50 mL). The organic layer was 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 smeared with hexane, and the solid was collected by filtration to obtain N-(4-ethylphenyl)acetamide (600 mg, 89%). 1 H NMR (400 MHz, CDCl3) δ 7.40 - 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.

[0534] 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 and then cooled to ambient temperature for 16 hours. The reaction mixture was poured into 2N HCl (4 mL) and stirred for 15 minutes. The mixture was extracted with HCl (10 mL). The organic layer was washed with water (3 × 10 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by elution with 0-25% HCl / hexane by column chromatography to obtain N-(2-chloro-4-ethylphenyl)acetamide (36 mg, 59%). 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​- 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.

[0535] 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, pH was adjusted to 10 by adding 6N NaOH, and then extracted with MTBE (3 × 25 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain 2-chloro-4-ethylaniline (26 mg, 92%). 1 H NMR (400 MHz, CDCl3) δ 7.09 - 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).

[0536] Intermediate 6

[0537] [ka] 4-((difluoromethyl)thio)-2-fluoroaniline 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-fluorobenzenethiol (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 rapidly added, and the solution was stirred at the same temperature for 10 minutes. TBAF (6 mL, 1 N / THF, 6.00 mmol) was rapidly added, and the solution was stirred at the same temperature for 10 minutes. The reaction mixture was quenched with water (50 mL). The mixture was extracted with HCl (2 × 25 mL), the combined organic layer was washed with water (3 × 50 mL) and brine (50 mL), then dried over Na₂SO₄, filtered, and concentrated. The residue was purified by elution with 0-15% ethyl acetate / hexane using column chromatography to obtain 4-((difluoromethyl)thio)-2-fluoroaniline (56 mg, 17%). 1 H NMR (400 MHz, CDCl3) δ 7.25 - 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.

[0538] Intermediate 7

[0539] [ka] 2-Chloro-4-(methylthio)aniline 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-dimethyldisulfane (44 μL, 0.493 mmol) was added, the mixture was sealed, and heated at 65°C for 16 hours. The reaction mixture was diluted with toluene (50 mL), washed with concentrated NH4OH (50 mL), and then washed with 10% citric acid solution (50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by elution with 0-15% toluene / hexane by column chromatography to obtain 2-chloro-4-(methylthio)aniline (116 mg, 68%). 1 H NMR (400 MHz, CDCl3) δ 7.27 - 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).

[0540] Intermediate 8

[0541] [ka] Methyl(E)-2-chloro-4-(2-ethoxyvinyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate Methyl 4-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.0 g, 3.565 mmol), methanesulfonate (2-dicyclohexylphosphino-2',6'-di-i-propoxy-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-dioxaborolane (0.7414 g, 3.743 mmol) were suspended in 1,4-dioxane (35.65 mL), and potassium carbonate (2.674 mL, 2N aqueous solution, 5.35 mmol) was added. After degassing with argon, the mixture was stirred at 60°C for 4 hours. The cooled reaction mixture was partitioned into water (150 mL) and toluene (50 mL). The aqueous layer was washed with toluene (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 elution with 0-40% toluene / heptane by column chromatography to obtain methyl(E)-2-chloro-4-(2-ethoxyvinyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (379 mg, 39%). 1 H NMR (400 MHz, CDCl3) δ 7.27 (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).

[0542] (Example 1)

[0543] [ka] 8-((4-bromo-2-fluorophenyl)amino)-2-cyclopropyl-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione Step 1. Preparation of methyl 2,6-dichloro-4-(2-oxoethyl)nicotinate. A suspension of methyl (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...

Claims

1. structure 【Transformation 3】 A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof that is 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione having the above characteristics.

2. structure 【Chemistry 4】 A pharmaceutical composition comprising a compound which is 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione having the following characteristics.

3. A pharmaceutical composition comprising crystals containing 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.

4. A pharmaceutical composition containing crystals of anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.

5. The pharmaceutical composition according to claim 4, comprising crystals of anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, characterized by having PXRD peaks at 5.0, 8.7, 9.3, 10.8, 14.5, 15.3, 18.8 and 20.5 degrees 2 theta (±0.2 degrees 2 theta).

6. The pharmaceutical composition according to claim 4, comprising crystals of anhydrous 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione, having a PXRD pattern including 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 degrees 2 theta (±0.2 degrees 2 theta).

7. A pharmaceutical composition containing crystals of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione monohydrate.

8. A pharmaceutical composition comprising crystals of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione monohydrate according to claim 7, characterized by having PXRD peaks at 13.7, 18.0, and 18.3 degrees 2 theta (±0.2 degrees 2 theta).

9. A pharmaceutical composition comprising an amorphous solid of 8-((2-fluoro-4-(methylthio)phenyl)amino)-2-(2-hydroxyethoxy)-7-methyl-3,4-dihydro-2,7-naphthyridine-1,6(2H,7H)-dione.

10. A pharmaceutical composition according to any one of claims 1 to 9, for use in treating MEK-related tumors.

11. The pharmaceutical composition according to claim 10, wherein the tumor has a BRAF V600 mutation selected from V600E, V600K, V600D, V600R, and V600S.

12. The pharmaceutical composition according to claim 10, wherein the tumor has the BRAF V600E mutation.

13. The pharmaceutical composition according to claim 10, wherein the tumor is a CNS tumor.

14. The pharmaceutical composition according to claim 13, wherein the CNS tumor is an intracranial tumor.

15. The pharmaceutical composition according to claim 14, wherein the intracranial tumor is a brain tumor.

16. The pharmaceutical composition according to claim 15, wherein the brain tumor is a metastatic brain tumor.

17. The pharmaceutical composition according to claim 16, wherein the metastatic brain tumor is selected from metastatic melanoma, metastatic colorectal cancer, metastatic non-small cell lung cancer, metastatic thyroid cancer, and metastatic ovarian cancer.

18. The pharmaceutical composition according to claim 13, wherein the CNS tumor is intracranial LMD or extracranial LMD.

19. The pharmaceutical composition according to claim 18, wherein LMD is selected from metastatic melanoma, metastatic colorectal cancer, and metastatic non-small cell lung cancer.

20. The pharmaceutical composition according to claim 14, wherein the intracranial tumor is a primary tumor.

21. The pharmaceutical composition according to claim 20, wherein the primary brain tumor is a malignant tumor.

22. The pharmaceutical composition according to claim 21, wherein the primary brain tumor is a grade 2 glioma, a grade 3 glioma, or a grade 4 glioma.

23. The pharmaceutical composition according to claim 20, wherein the primary brain tumor is a benign tumor.

24. The pharmaceutical composition according to claim 10, wherein the tumor has BRAF fusion.

25. The tumor is KIAA11549-BRAF, MKRN1-BRAF, TRIM24-BRAF, AGAP3-BRAF, ZC3HAV1-BRAF, AKAP9-BRAF, CCDC6-BRAF, AGK-BRAF, EPS15-BRAF F, NUP214-BRAF, ARMC10-BRAF, BTF3L4-BRAF, GHR-BRAF, ZC3HAV1-BRAF, ZNF767-BRAF, CCDC91-BRAF, DYNC112-BRAF, ZKSCAN1-BR The pharmaceutical composition according to claim 24, having a BRAF fusion selected from AF, 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.

26. The pharmaceutical composition according to claim 25, wherein the tumor is breast cancer, colorectal cancer, esophageal cancer, glioma, head and neck carcinoma, lung cancer, melanoma, pancreatic cancer, prostate cancer, sarcoma, thyroid cancer, cancer of unknown primary origin, pleural mesothelioma, rectal adenocarcinoma, endometrial cancer, or ovarian serous carcinoma.

27. The pharmaceutical composition according to claim 10, wherein the tumor is a BRAF wild-type tumor.

28. The pharmaceutical composition according to claim 10, for use in combination with one or more further anti-cancer therapies.

29. The pharmaceutical composition according to claim 28, wherein further anti-cancer treatment is selected from one or more anti-cancer agents.

30. The pharmaceutical composition according to claim 29, wherein the anticancer agent is a BRAF inhibitor.

31. The pharmaceutical composition according to claim 30, wherein the BRAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof.

32. 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)aminophenyl)-3-fluoropropane-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-4,5-difluorophenyl)propane-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-4-fluorophenyl)propane-1-sulfonamide; N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide; N-(2-chloro-4-fluoro-3-((5-methyl-3-(methyl-d3)-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-6-yl)oxy]-4-fluorophenyl}propan-1-sulfonamide; N-(3-chloro-4-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)oxy)-5-fluoropyridine-2-yl)propane-1-sulfonamide; and N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6-yl)oxy]-4-fluorophenyl}-3-fluoropropane-1-sulfonamide; The pharmaceutical composition according to claim 30, or selected from pharmaceutically acceptable salts thereof.

33. The pharmaceutical composition according to claim 32, 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.

34. BRAF inhibitors, 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-dihydroquinazolin-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-fluoroazetidine-1-sulfonamide, The pharmaceutical composition according to claim 30, or selected from pharmaceutically acceptable salts thereof.

35. The pharmaceutical composition according to claim 34, wherein the BRAF inhibitor is N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide or a pharmaceutically acceptable salt thereof.

36. The pharmaceutical composition according to claim 29, wherein the anticancer agent is an SHP2 inhibitor.

37. The pharmaceutical composition according to claim 36, wherein the SHP2 inhibitor is (S)-1'-(6-((2-amino-3-chloropyridine-4-yl)thio)-1,2,4-triazine-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine or a pharmaceutically acceptable salt thereof.

38. The pharmaceutical composition according to claim 10, wherein the target is a human.

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