Heterocyclic compounds and methods of use thereof

Abstract

As defined herein, the present invention relates to compounds of formula (I) and pharma- ceutically acceptable salts thereof. The present invention also relates to pharmaceutical compositions comprising compounds of formula (I) and pharma- ceutically acceptable salts thereof, and methods of using the compounds and compositions to inhibit certain protein-protein interactions and to treat cancer.

Description

[Technical Field]

[0001] SUMMARY OF THE INVENTION This specification relates to heterocyclic compounds useful in the treatment of proliferative disorders such as cancer. [Background technology]

[0002] Cancer is characterized by abnormal cell growth and proliferation. Ras proteins are key components of signaling networks important in controlling cell proliferation, differentiation, and survival. See, for example, Fernandes-Medarde and Santos, Genes Cancer, Vol. 2, No. 3, pp. 344-358 (2011). Ras is a GTPase that acts as a molecular switch between an active GTP-bound state and an inactive GDP-bound state—GTP-bound Ras can activate several downstream signaling pathways involved in cell cycle progression, survival, and apoptosis.

[0003] Guanine nucleotide exchange factors (GEFs), such as SOS1, are required for Ras activation by promoting the exchange of GDP (inactive Ras) for GTP (active Ras). SOS1 is itself activated by Ras through an allosteric interaction, which strongly activates the GEF function of SOS1, resulting in a positive feedback loop between SOS1 and Ras. See, for example, Bandaru, et al., Cold Spring Harb. Perspect Med., Vol. 9, No. 2, a031534 (2019). Ras mutations occur in many human cancers, yet no drugs targeting Ras proteins are currently approved. See Hillig, et al., Proc. Nat. Acad. Sci., Vol. 117, No. 7, pp. 2551–2560 (2019). Therefore, there is a need for novel therapeutic agents that disrupt Ras signaling. Summary of the Invention

[0004] In accordance with the present invention, it has been discovered that certain condensed compounds are inhibitors of SOS1 activity and are useful in treating a variety of diseases and disorders, including cancer.

[0005] Thus, formula (I): [ka] [In the formula, R 1 , R 2 , R 3 , X and other variables are as defined herein. or a pharmaceutically acceptable salt thereof.

[0006] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0007] Also provided herein is a method for inhibiting mammalian cell proliferation in vitro or in vivo, comprising contacting the cells with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0008] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0009] Also provided herein is a method for treating SOS1-associated cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0010] Also provided herein is a method of treating a Ras pathway-associated disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a Ras pathway-associated disease or disorder an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] Also provided herein is a method of treating a Ras pathway-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a Ras pathway-associated cancer an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0012] Also provided herein is a method for treating a Ras-related disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a Ras-related disease or disorder an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0013] Also provided herein is a method of treating a Ras tract-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a Ras-associated cancer an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0014] Also provided herein is a method for treating SOS1-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having an SOS1-associated cancer an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0015] 1. A method of treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them; and (b) administering to the subject an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Also provided herein are methods, including:

[0016] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject in whom it has been determined that the cancer is associated with dysregulation of the expression or activity or level of a Ras pathway gene, a Ras pathway protein, or any of them, an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0017] 1. A method of treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or levels of the Ras gene, the Ras protein, or any of them; and (b) administering to the subject an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Also provided herein are methods, including:

[0018] Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in whom it has been determined that the cancer is associated with dysregulation of the expression or activity or level of a Ras gene, a Ras protein, or any of them, an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0019] Also provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in whom it has been determined that the cancer is associated with dysregulation of the expression or activity or level of the SOS1 gene, the SOS1 protein, or any of them, an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0020] 1. A method of treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the expression or activity or levels of the SOS1 gene, the SOS1 protein, or any of them; and (b) administering to the subject an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Also provided herein are methods, including:

[0021] Also provided herein is a method of inhibiting mammalian cell proliferation, comprising contacting a mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] Also provided herein is a method of inhibiting Ras pathway activity in a mammalian cell, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0023] Also provided herein is a method of inhibiting SOS1 activity in a mammalian cell, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0024] Also provided herein is a method of inhibiting Ras activity in a mammalian cell, comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0025] Also provided herein is a method for inhibiting SOS1-Ras protein-protein interaction in a mammalian cell, the method comprising contacting the mammalian cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0026] Also provided herein is a method of inhibiting metastasis in a subject having certain cancers and in need of treatment, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0027] There is also provided herein a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer.

[0028] Also provided herein is a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a Ras pathway-associated disease or disorder.

[0029] Also provided herein is a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a Ras pathway-associated cancer.

[0030] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating cancer and / or inhibiting metastasis associated with certain cancers.

[0031] Also provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibiting SOS1-Ras protein-protein interaction in mammalian cells.

[0032] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting SOS1-Ras protein-protein interaction in mammalian cells.

[0033] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a Ras pathway-associated disease or disorder.

[0034] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a Ras pathway-associated cancer.

[0035] Also provided herein are methods for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0036] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof obtained by the processes for preparing compounds defined herein.

[0037] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims.

[0038] Detailed Description Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art can also be used.Materials, methods and examples are only illustrative and are not intended to be limiting.All publications, patent applications, patents, sequences, entire databases and other references mentioned herein are incorporated herein by reference in their entirety.In case of discrepancies, the present specification, including definitions, shall prevail.

[0039] definition As used herein, the term "compound" refers to all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structure. Compounds herein identified by name or structure as being in a particular tautomeric form actually include other tautomeric forms unless otherwise indicated.

[0040] The term "tautomer" as used herein refers to a compound that differs significantly in structure in the arrangement of atoms, but exists in easy and rapid equilibrium, and it should be understood that the compounds provided herein may be represented as various tautomers, and when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the name of the compound does not exclude any tautomer. Examples of tautomeric forms include the following: [ka]

[0041] Certain compounds provided herein may contain one or more asymmetric centers and may therefore be prepared and isolated as mixtures of isomers, such as racemic mixtures, or in enantiomerically pure form.

[0042] The term "halo" refers to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0043] The term "C1-C6 alkyl" refers to a straight or branched saturated hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.

[0044] The term "C1-C6 haloalkyl" as defined herein refers to a C1-C6 alkyl group substituted with at least one halogen atom, for example, independently selected from fluorine, chlorine, bromine, and iodine. The halogen atom can be located at any position on the alkyl group. For example, C1-C6 haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, for example, 1-chloroethyl and 2-chloroethyl, trichloroethyl, for example, 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, for example, 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, for example, 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl.

[0045] The term "C1-C6 alkoxy," as defined herein, refers to a C1-C6 alkyl group attached to a molecule through an oxygen. It includes moieties in which the alkyl portion can be straight or branched, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0046] The term "C1-C6 haloalkoxy" as defined herein refers to a C1-C6 alkoxy group substituted with at least one halogen atom independently selected from, for example, fluorine, chlorine, bromine, and iodine. The halogen atom can be located at any position on the alkyl group. For example, C1-C6 haloalkoxy can refer to fluoromethoxy (e.g., 1-fluoromethoxy, 1,1-difluoromethoxy, and 1,1,1-trifluoromethoxy), fluoroethoxy (e.g., 2-fluoroethoxy, 1,2,2-trifluoroethoxy, and 2,2,2-trifluoroethoxy), or chloroethoxy (e.g., 1-chloroethoxy, 2-chloroethoxy, 1,2,2-trichloroethoxy, and 2,2,2-trichloroethoxy).

[0047] The term "C1-C6 hydroxyalkyl" as defined herein refers to a C1-C6 alkyl group substituted with one or more hydroxyl groups. The hydroxyl groups can be located at any position on the hydrocarbon chain. For example, C1-C6 hydroxyalkyl can refer to hydroxymethyl, hydroxyethyl (e.g., 1-hydroxyethyl or 2-hydroxyethyl), and 2-hydroxyisopropyl.

[0048] The term "C1-C6 alkoxyalkyl," as defined herein, refers to a C1-C6 alkyl group substituted with one or more C1-C6 alkoxy groups, wherein the alkoxy group is attached to the alkyl group through an oxygen. This includes moieties in which the alkyl portion of the C1-C6 alkyl or C1-C6 alkoxy can independently be straight or branched chain, for example, methoxyethyl, ethoxyethyl, or 1,3-dimethoxypropyl.

[0049] As used herein, the term "cyano" refers to the -CN radical.

[0050] As used herein, the term "nitro" refers to the -NO2 radical.

[0051] As used herein, the term "hydroxyl" refers to the --OH radical.

[0052] As used herein, the term "amino" refers to the -NH2 radical.

[0053] As used herein, the term "heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic group in which at least one ring in the system is aromatic; and one or more carbon atoms in at least one ring in the system is replaced with a heteroatom independently selected from N, O, and S. Non-limiting examples of heteroaryl groups include furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine.

[0054] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic carbon group having 3 to 10 carbon atoms, e.g., C3-C 10 Cycloalkyl groups and C3-C6 cycloalkyl groups. Bicyclic cycloalkyl groups include fused, spiro, and bridged ring systems. Non-limiting examples of cycloalkyl groups include phenyl, 2,3-dihydro-1H-indene, cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl.

[0055] The term "heterocyclyl" refers to a non-aromatic saturated or partially unsaturated hydrocarbon monocyclic or bicyclic ring system having 3 to 10 ring atoms, with at least one heteroatom in the ring selected from N, O, and S. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. Heterocyclyl groups are sometimes referred to as "5- to 10-membered heterocyclyl groups," which are ring systems containing 5, 6, 7, 8, 9, or 10 atoms, at least one of which is a heteroatom. Heterocyclyl groups can contain, for example, 1, 2, 3, or more heteroatoms. In some embodiments, heterocyclyl groups have 1 or 2 independently selected heteroatoms. Heterocycles can further contain one or more carbonyl or thiocarbonyl functionalities, such that oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates, are included in the definition. Heterocyclyl groups can be attached to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. Representative heterocyclyl groups include, but are not limited to, 1,3-dioxolane, 1,4-dioxolane, maleimide, succinimide, dioxopiperazine, hydantoin, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, azetidine, oxetane, and 2-azaspiro[3.3]heptanyl.

[0056] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation inherent in the ring itself; for example, one or more double or triple bonds between constituent ring atoms), but the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0057] The term "oxo" as used herein refers to an "=O" group attached to a carbon atom.

[0058] As used herein, the symbols [ka] indicates the point of attachment of the atom or molecule to the indicated atom or group in the remainder of the molecule.

[0059] The compounds of formula (I) (e.g., formula (Ia) or (Ib)) include pharmaceutically acceptable salts thereof. Additionally, the compounds of formula (I) also include other salts of such compounds, which need not be pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and / or purifying the compounds of formula (I) and / or for separating the enantiomers of the compounds of formula (I).

[0060] It is further understood that the compounds of formula (I) or salts thereof may be isolated in the form of solvates, and therefore, all such solvates are included within the scope of the present invention. For example, the compounds of formula (I) and their salts may exist in the form of solvates and solvates with pharmaceutically acceptable solvents such as water, ethanol, etc.

[0061] In some embodiments, the compounds of Formula (I) include the compounds of Examples 1-182 and stereoisomers and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the compounds of Examples 1-182 are in free base form. In some embodiments, the compounds of Examples 1-182 are in the form of pharmaceutically acceptable salts.

[0062] The term "pharmaceutically acceptable salt" refers to a compound that does not cause significant irritation to the organism to which it is administered and does not impair the biological activity and properties of the compound. In some embodiments, pharmaceutically acceptable salts can be obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some embodiments, pharmaceutically acceptable salts can be obtained by reacting a compound having an acidic group described herein with a base to form an alkali metal salt such as an ammonium salt, a sodium salt, or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, a salt with an organic base such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt with an amino acid such as arginine or lysine, or by other predetermined methods. Pharmacologically acceptable salts are not particularly limited as long as they can be used in medicine. Examples of salts of the compounds described herein with bases include salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, for example, with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0063] Protecting groups may be temporary substituents intended to protect potentially reactive functional groups from undesired chemical transformations. The particular protecting group used is within the skill of one in the art. The protecting group of choice can be determined by several considerations, including, but not limited to, the functional group to be protected, other functional groups present in the molecule, the reaction conditions for each step of the synthetic sequence, other protecting groups present in the molecule, functional groups tolerant to the conditions required for removal of the protecting group, and reaction conditions for the pyrolysis of the compounds provided herein. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).

[0064] Nitrogen protecting groups can be temporary substituents to protect the amine moiety from undesired chemical transformations. Examples of the moiety formed when such protecting groups are combined with an amine include, but are not limited to, allylamine, benzylamine (e.g., benzylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, and tritylamine), acetylamide, trichloroacetamide, trifluoroacetamide, pent-4-enamide, phthalimide, carbamate (e.g., methyl carbamate, t-butyl carbamate, benzyl carbamate, allyl carbamate, 2,2,2-trichloroethylcarbamate, and 9-fluorenylmethyl carbamate), imine, and sulfonamide (e.g., benzenesulfonamide, p-toluenesulfonamide, and p-nitrobenzenesulfonamide).

[0065] Oxygen protecting groups can be temporary substituents to protect hydroxyl moieties from undesired chemical transformations. Examples of moieties formed when such protecting groups are combined with hydroxyl include, but are not limited to, esters (e.g., acetyl, t-butyl carbonyl, and benzoyl), benzyls (e.g., benzyl, p-methoxybenzyl, and 2,4-dimethoxybenzyl and trityl), carbonates (e.g., methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate, and benzyl carbonate), ketals and acetals, and ethers.

[0066] The compounds provided herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, particularly when referred to in connection with a compound according to Formula (I), includes all naturally occurring or synthetically produced isotopes and isotopic mixtures of that atom, in either natural abundance or isotopically enriched form. For example, unless otherwise indicated, when referring to hydrogen, it is 1 H, 2 H, 3 H or mixtures thereof; when referring to carbon, it is 11 C. 12 C. 13 C. 14 C or mixtures thereof; when referring to nitrogen, it is 13 N, 14 N, 15 N or mixtures thereof; when referring to oxygen, it is 14 O. 15 O. 16 O. 17 O. 18 Fluorocarbons are understood to refer to fluorocarbons or mixtures thereof; when referring to fluorocarbons, it is ... 18 F, 19The term "radioactive" refers to a compound having one or more isotopes of one or more atoms, including radioactive compounds in which one or more non-radioactive atoms are replaced with one of its radioactively enriched isotopes, and is understood to refer to F or mixtures thereof. For example, in deuterated alkyl and deuterated alkoxy groups, one or more hydrogen atoms are specifically replaced with deuterium (H). Because some of these isotopes are radioactive, the compounds provided herein also include compounds having one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds in which one or more non-radioactive atoms are replaced with one of their radioactively enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All radioactive variants of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0067] The efficacy of a test compound to act as an inhibitor of SOS1-Ras (e.g., KRas (e.g., KRasG12C)) interaction can be demonstrated by the biological assays described herein. IC for inhibiting SOS1-Ras interaction 50 The values ​​are shown in Table A and are the K D The values ​​are shown in Table B.

[0068] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) permeability. Such compounds can cross the blood-brain barrier and inhibit SOS1 activity in the brain and / or other CNS structures. In some embodiments, the compounds provided herein can cross the blood-brain barrier in an effective amount. For example, cancers (e.g., Ras pathway-related cancers (e.g., SOS1-related cancers, Ras-related cancers (e.g., KRas-related cancers, HRas-related cancers and / or NRas-related cancers), EGFR-related cancers, ErbB2-related cancers, ErbB3-related cancers, ErbB4-related cancers, NF1-related cancers, PDGFR-A-related cancers, PDGFR-B-related cancers, FGFR1-related cancers, FGFR2-related cancers, FGFR3-related cancers, IGF1R-related cancers, INSR-related cancers, ALK-related cancers, ROS-related cancers, TrkA-related cancers) The treatment of subjects with cancers such as TrkB-related cancer, TrkC-related cancer, RET-related cancer, c-MET-related cancer, VEGFR1-related cancer, VEGFR2-related cancer, VEGFR3-related cancer, AXL-related cancer, SHP2-related cancer, RAF-related cancer (for example, BRAF-related cancer), PI3K-related cancer, AKT-related cancer, mTOR-related cancer, MEK-related cancer, ERK-related cancer, or a combination thereof, for example, Ras pathway-related brain or CNS cancer, can include administering (for example, orally administering) compound to subjects.In such an embodiment, the compounds provided herein are useful for treating primary brain tumors or metastatic brain tumors.For example, Ras pathway-related primary brain tumors or metastatic brain tumors.

[0069] The compound of formula (I) or a pharmaceutically acceptable salt thereof is useful in treating diseases and disorders that can be treated with an SOS1 inhibitor, such as hematological cancers, solid tumors, Ras pathway-related diseases or disorders (e.g., SOS1-related diseases or disorders, Ras-related diseases or disorders (e.g., KRas-related diseases or disorders, HRas-related diseases or disorders, and / or NRas-related diseases or disorders), including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), LEOPARD syndrome, capillary malformation-cerebral venous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Regius syndrome, and hereditary gingival fibromatosis, EGFR-related diseases or disorders, ErbB2-related diseases or disorders, ErbB3-related diseases or disorders, ErbB4-related diseases or disorders, NF1-related diseases or disorders, PDGFR-A-related diseases or disorders, PDGFR-B-related diseases or disorder, an FGFR1-related disease or disorder, an FGFR2-related disease or disorder, an FGFR3-related disease or disorder, an IGF1R-related disease or disorder, an INSR-related disease or disorder, an ALK-related disease or disorder, a ROS-related disease or disorder, a TrkA-related disease or disorder, a TrkB-related disease or disorder, a TrkC-related disease or disorder, a RET-related disease or disorder, a c-MET-related disease or disorder, a VEGFR1-related disease or disorder, a VEGFR2-related disease or disorder, a VEGFR3-related disease or disorder, an AXL-related disease or disorder, an SHP2-related disease or disorder, a RAF-related disease or disorder (e.g., a BRAF-related disease or disorder), a PI3K-related disease or disorder, an AKT-related disease or disorder, an mTOR-related disease or disorder, a MEK-related disease or disorder, an ERK-related disease or disorder, or a combination thereof.

[0070] The compound of formula (I) or a pharmaceutically acceptable salt thereof is useful for treating diseases and disorders that can be treated with an SOS1 inhibitor, such as Ras pathway-related cancers (e.g., SOS1-related cancers, Ras-related cancers (e.g., KRas-related cancers, HRas-related cancers, and / or NRas-related cancers), EGFR-related cancers, ErbB2-related cancers, ErbB3-related cancers, ErbB4-related cancers, NF1-related cancers, PDGFR-A-related cancers, PDGFR-B-related cancers, FGFR1-related cancers, FGFR2-related cancers, and the like, including hematological cancers and solid tumors. In some embodiments, the compounds are useful for treating a cancer associated with a tumour, such as a thyroid cancer, ...

[0071] In some embodiments, the SOS1 inhibitor has a dissociation constant (K) with SOS1 protein of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, as measured in an assay described herein. D In some embodiments, the SOS1 inhibitor may exhibit a dissociation constant (K) with SOS1 protein of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as measured in the assays provided herein. D In some embodiments, the SOS1 inhibitor may exhibit an inhibitory activity (IC) of SOS1-KRas (e.g., a G12C mutant of KRas) protein-protein interaction of less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM, as measured in an assay described herein. 50In some embodiments, the SOS1 inhibitor may exhibit an inhibitory activity (IC) of SOS1-KRas (e.g., a G12C mutant of KRas) protein-protein interaction of less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM, as measured in the assays provided herein. 50 ) can be shown.

[0072] As used herein, the term "treat" or "treatment" refers to curative or palliative treatment. Beneficial or desirable clinical results include, but are not limited to, total or partial alleviation of symptoms associated with a disease or disorder or condition, reduction in the extent of the disease, a stabilized (i.e., not worsening) disease state, delay or slowing of disease progression, improvement or palliation and remission (partial or complete) of the disease state (e.g., one or more symptoms of the disease), which may be detectable or undetectable. "Treatment" can also mean prolonging survival compared to expected survival if not receiving treatment.

[0073] As used herein, the term "subject" refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans.In some embodiments, the subject is human.In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease or disorder to be treated and / or prevented.

[0074] In some embodiments, the subject has (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit) a gene or genes in the Ras pathway (e.g., SOS1, Ras (e.g., KRas, HRas and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2 , VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), Ras pathway proteins (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEG Cancers associated with dysregulation of expression or activity or levels of any of the following: Ras pathway-associated cancers (e.g., SOS1-associated cancers, Ras-associated cancers (e.g., KRas-associated cancers, HRas-associated cancers, and / or NRas-associated cancers), EGFR-associated cancers, ErbB2-associated cancers, ErbB3-associated cancers, ErbB4-associated cancers, NF1-associated cancers, PDGFR-A-associated cancers, PDGFR-B-associated cancers, PDGFR-C-associated cancers, PDGFR-D-associated cancers, PDGFR-E-associated cancers, PDGFR-F ... or a combination thereof).In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of a Ras pathway gene, a Ras pathway protein, or any of them (e.g., as determined using a regulatory agency-approved assay or kit). The subject may have a tumor that is positive for dysregulated expression or activity or level of a Ras pathway gene, a Ras pathway protein, or any of them (e.g., identified as positive by a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that has dysregulated expression or activity or level of a Ras pathway gene, a Ras pathway protein, or any of them (e.g., identified as such using a regulatory agency-approved, e.g., FDA-approved kit or assay). In some embodiments, the subject is suspected of having a Ras pathway-related cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor that has dysregulated expression or activity or level of a Ras pathway gene, a Ras pathway protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer that has been determined to be associated with dysregulation of the expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them (Ras pathway-associated cancer) based on histological examination.

[0075] In some embodiments, the subject has been identified or diagnosed with cancer (Ras-associated cancer) with dysregulated expression or activity or level of Ras gene, Ras protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of Ras gene, Ras protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for dysregulated expression or activity or level of Ras gene, Ras protein, or any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have dysregulated expression or activity or level of Ras gene, Ras protein, or any of them (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having Ras-associated cancer. In some embodiments, the subject has clinical records showing that the subject has a tumor with dysregulation of expression or activity or level of Ras gene, Ras protein, or any of them (and optionally, clinical records show that the subject should be treated with any of the compositions provided herein).In some embodiments, the subject is a pediatric subject.In some embodiments, the subject has been identified or diagnosed with cancer that is determined to be associated with dysregulation of expression or activity or level of Ras gene, Ras protein, or any of them (Ras-related cancer) based on histological examination.

[0076] In some embodiments, the subject has been identified or diagnosed as having a cancer (KRas-associated cancer) with dysregulated expression or activity or level of KRas gene, KRas protein, or any of them (e.g., as determined by using a regulatory agency-approved assay or kit).In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of KRas gene, KRas protein, or any of them (e.g., as determined by using a regulatory agency-approved assay or kit).The subject may have a tumor that is positive for dysregulated expression or activity or level of KRas gene, KRas protein, or any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved assay or kit).The subject may have a tumor that is positive for dysregulated expression or activity or level of KRas gene, KRas protein, or any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved kit or assay).In some embodiments, the subject is suspected of having a KRas-associated cancer. In some embodiments, the subject has clinical records showing that the subject has a tumor with dysregulation of expression or activity or level of KRas gene, KRas protein, or any of them (and optionally, clinical records show that the subject should be treated with any of the compositions provided herein).In some embodiments, the subject is a pediatric subject.In some embodiments, the subject has been identified or diagnosed with cancer that is determined to be associated with dysregulation of expression or activity or level of KRas gene, KRas protein, or any of them (KRas-related cancer) based on histological examination.

[0077] In some embodiments, the subject has been identified or diagnosed with a cancer (HRas-associated cancer) having dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (e.g., as identified using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an HRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or level of the HRas gene, HRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer that has been determined to be associated with dysregulated expression or activity or level of the HRas gene, HRas protein, or any of them (HRas-associated cancer) based on histological examination.

[0078] In some embodiments, the subject has been identified or diagnosed as having cancer (NRas-associated cancer) with dysregulated expression or activity or level of NRas gene, NRas protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of NRas gene, NRas protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for dysregulated expression or activity or level of NRas gene, NRas protein, or any of them (e.g., identified as positive ... dysregulated expression or activity or level of NRas gene, NRas protein, or any of them (e.g., identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having NRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or level of the NRas gene, NRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer that is determined to be associated with dysregulated expression or activity or level of the NRas gene, NRas protein, or any of them (NRas-associated cancer) based on histological examination.

[0079] In some embodiments, the subject has been identified or diagnosed with a cancer (SOS1-associated cancer) with dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an SOS1-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer that has been determined to be associated with dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (SOS1-associated cancer) based on histological examination.

[0080] The term "pediatric subject" used herein refers to a subject under 21 years old at the time of diagnosis or treatment.The term "child" can be further divided into various subgroups, including neonates (up to 1 month old); infants (1 to 2 years old); children (2 to 12 years old); and adolescents (12 to 21 years old (excluding the 22nd birthday)).Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is from birth to the first 28 days, from 29 days to under 2 years of age, from 2 to under 12 years of age, or from 12 to 21 years of age (up to but not including the 22nd birthday). In some embodiments, the pediatric subject is from birth to the first 28 days, from 29 days to under 1 year of age, from 1 to 4 months of age, from 3 to 7 months of age, from 3 to under 1 year of age, from 1 to under 2 years of age, from 2 to under 3 years of age, from 2 to under 7 years of age, from 3 to under 5 years of age, from 5 to under 10 years of age, from 6 to under 13 years of age, from 10 to under 15 years of age, or from 15 to under 22 years of age.

[0081] In certain embodiments, the compounds of Formula (I) or pharmaceutically acceptable salts thereof are useful for preventing diseases and disorders (e.g., autoimmune diseases, inflammatory diseases, and cancer) defined herein. As used herein, the term "prevent" refers to preventing the onset, recurrence, or spread of a disease or condition defined herein, or a symptom thereof, in whole or in part.

[0082] In certain embodiments, the compounds of Formula (I) or pharmaceutically acceptable salts thereof are useful for preventing diseases and disorders as defined herein, e.g., Ras pathway-associated diseases or disorders (e.g., autoimmune diseases, inflammatory diseases, and cancer). As used herein, the term "preventing" means preventing the onset, recurrence, or spread of a disease or condition as defined herein, or a symptom thereof, in whole or in part.

[0083] Abnormal cell growth and spread are hallmarks of cancer. One pathway through which this can occur is through Ras family protein signaling. Human Ras proteins (e.g., KRas (V-Ki-Ras2, Kirsten rat sarcoma 2 viral oncogene homolog), HRas (V-Ha-Ras, Harvey rat sarcoma viral oncogene homolog), and / or NRas (neuroblastoma RAS viral (V-Ras) oncogene homolog; sometimes referred to as KRAS, HRAS, and NRAS, or K-Ras, H-Ras, and N-Ras, respectively) are membrane-bound guanosine triphosphate (GTP) / guanosine diphosphate (GDP)-binding (G) proteins involved in many oncogenic signaling cascades. Each of these proteins is approximately 21 kD in size. KRas has two common isoforms, known as KRas4A and KRas4B.

[0084] Mature Ras proteins are typically attached to cell membranes via post-translational modifications such as prenylation (e.g., farnesylation of the "CAAX box," where C represents cysteine, A represents an aliphatic amino acid, and X represents methionine, serine, leucine, or glutamine). In the inactive state, Ras proteins are bound to GDP. See, e.g., Adjei, J. Nat'l. Cancer Inst. 93.14 (2001): 1062-1074.

[0085] Activation of Ras proteins can be initiated through multiple types of cell surface receptors, including receptor tyrosine kinases (TKIs) (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3, AXL), T cell receptors, B cell receptors, monocyte colony-stimulating factor receptors, G-protein-coupled receptors (GPCRs), and integrin family proteins. Activation of one of these types of cell surface receptors generally directly or indirectly results in the activation of one or more guanine nucleotide exchange factors (GEFs), which promote the release of GDP from Ras proteins and allow GTP to bind. Non-limiting examples of GEFs include SOS (Son of Sevenless homolog) protein and RASGRF1 (Ras protein-specific guanine nucleotide-releasing factor 1; sometimes also referred to as Cdc25). For example, activation, dimerization, and autophosphorylation of EGFR can lead to binding to the SH2 domain of the adaptor protein growth factor receptor-bound protein 2 (GRB2), which then binds to SOS proteins (e.g., SOS1 or SOS2, sometimes also called SOS-1 and SOS-2, respectively), thereby colocalizing the SOS proteins with Ras family proteins to the plasma membrane.For example, Xuehua et al., Proc. Nat. Acad. Sci. Nov. 2017, 114 (47) E10092-E10101; Vetter and Wittinghofer, Science 294.5545 (2001): 1299-1304; Downward, Nat. Coumoul, Biochem. Pharmacol. 82.9 (2011): 1049-1056. Kortum, et al. Proc. Nat. Acad. Sci. 108.30 (2011): 12407-12412; U.S. Application Publication Nos. 2019 / 0358230 and 2019 / 0194192; and PCT Publication Nos. WO2018 / 172250 and WO2019 / 201848.

[0086] Upon activation by binding to GTP, Ras proteins bind to and activate numerous downstream effectors, including RAF family proteins, phosphatidylinositol 3-kinase (PI3K), and RAL family proteins. See, for example, Gurung and Bhattacharjee. Oncology & Hematology Review, 2015;11(2):147-52 (2015). For example, signal transduction via the Ras-RAF-MAPK pathway has been implicated in many cancers, including, but not limited to, pancreatic cancer, thyroid cancer (e.g., papillary thyroid carcinoma), colon cancer, lung cancer (e.g., non-small cell lung cancer), melanoma, cholangiocarcinoma, small intestine cancer, endometrial cancer, ovarian cancer, cervical cancer, prostate cancer, soft tissue cancer, peritoneal cancer, gastric cancer, liver cancer, urinary tract cancer, breast cancer, and combinations thereof. See, e.g., Kinsey, et al. Nat. Medicine 25.4 (2019): 620-627; Roberts and Der. Oncogene 26.22 (2007): 3291-3310; Santarpia, et al. Expert Opinion on Therapeutic Targets 16.1 (2012): 103-119. As another example, signaling through the mammalian target of rapamycin (mTOR) pathway plays a role in many cancers, including, but not limited to, melanoma, ovarian cancer, cervical cancer, endometrial cancer, breast cancer, prostate cancer, brain cancer (e.g., glioblastoma), lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, bladder cancer, colon cancer, head and neck cancer, leukemia, thyroid cancer, lymphoma, intestinal cancer, gastric cancer, and combinations thereof. For example, Chappell, et al. Oncotarget 2.3 (2011): 135; Vara, et al. Cancer Treatment Reviews 30.2 (2004): 193-204; Hennessy, et al. Nat. Rev. Drug Disc. 4.12 (2005): 988-1004; Osaki, et al. Apoptosis 9.6 (2004): 667-676; see Luo, et al. Cancer Cell 4.4 (2003): 257-262.

[0087] Although Ras proteins have intrinsic GTPase activity, it is typically not physiologically relevant. Instead, hydrolysis of bound GTP is catalyzed by GTPase-activating proteins (GAPs), such as those involved in neurofibromatosis type 1 (NF1) or p120. GAP The binding of α-glucan is enhanced (e.g., by about 5 orders of magnitude). See, e.g., Adjei, Journal of the National Cancer Institute 93.14 (2001): 1062-1074; Downward, Nature Reviews Cancer 3.1 (2003): 11-22; Scheffzek, et al. Science 277.5324 (1997): 333-339.

[0088] It is estimated that activating mutations in Ras family proteins (especially mutations at G12, G13 and / or Q61, for example) are present in up to approximately 30% of all human cancers. Generally, activating mutations in Ras family proteins make Ras proteins insensitive to the activity of GAPs. For example, see Santarpia, et al. Expert Opinion on Therapeutic Targets 16.1 (2012): 103-119. Typical and non-limiting examples of Ras mutations are shown in Table 1 (KRas mutation), 2 (HRas mutation) and 3 (NRas mutation).

[0089] As used herein, the term "Ras pathway-associated disease or disorder" refers to cancer associated with or involving dysregulation of the expression, activity, or levels of a gene in the Ras pathway, a protein in the Ras pathway, or any of them (e.g., one or more) (e.g., any type of dysregulation of the expression, activity, or levels of a gene in the Ras pathway, a protein in the Ras pathway, or any of them described herein). Non-limiting examples of Ras pathway-associated diseases or disorders include, for example, neurofibromatosis type 1 (NF1), Noonan syndrome (NS), LEOPARD syndrome, capillary malformation-cerebral venous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Regius syndrome, hereditary gingival fibromatosis, and cancer.

[0090] In some embodiments, the Ras pathway-related disease or disorder is a Ras pathway-related cancer, such as a KRas-related cancer, an HRas-related cancer, an NRas-related cancer, an SOS1-related cancer, an EGFR-related cancer, an ErbB2-related cancer, an ErbB3-related cancer, an ErbB4-related cancer, an NF1-related cancer, a PDGFR-A-related cancer, a PDGFR-B-related cancer, an FGFR1-related cancer, an FGFR2-related cancer, an FGFR3-related cancer, an IGF1R-related cancer, an INSR-related cancer, an ALK-related cancer, a ROS-related cancer, a TrkA-related cancer, a TrkB-related cancer, a TrkC-related cancer, a RET-related cancer, a c-MET-related cancer, a VEGFR1-related cancer, a VEGFR2-related cancer, a VEGFR3-related cancer, an AXL-related cancer, an SHP2-related cancer, a RAF-related cancer (e.g., a BRAF-related cancer), a PI3K-related cancer, an AKT-related cancer, an mTOR-related cancer, a MEK-related cancer, an ERK-related cancer, or a combination thereof.

[0091] As used herein, the term "Ras pathway-associated cancer" refers to cancers associated with or having dysregulation of the expression or activity or levels of a gene in the Ras pathway, a protein in the Ras pathway, or any of them (e.g., one or more) (e.g., any type of dysregulation of the expression or activity or levels of a gene in the Ras pathway, a protein in the Ras pathway, or any of them described herein). Non-limiting examples of Ras pathway-associated cancers are described herein. In some embodiments, the Ras pathway-related cancer may be a KRas-related cancer, an HRas-related cancer, an NRas-related cancer, an SOS1-related cancer, an EGFR-related cancer, an ErbB2-related cancer, an ErbB3-related cancer, an ErbB4-related cancer, an NF1-related cancer, a PDGFR-A-related cancer, a PDGFR-B-related cancer, an FGFR1-related cancer, an FGFR2-related cancer, an FGFR3-related cancer, an IGF1R-related cancer, an INSR-related cancer, an ALK-related cancer, a ROS-related cancer, a TrkA-related cancer, a TrkB-related cancer, a TrkC-related cancer, a RET-related cancer, a c-MET-related cancer, a VEGFR1-related cancer, a VEGFR2-related cancer, a VEGFR3-related cancer, an AXL-related cancer, a SHP2-related cancer, a RAF-related cancer (e.g., a BRAF-related cancer), a PI3K-related cancer, an AKT-related cancer, an mTOR-related cancer, a MEK-related cancer, an ERK-related cancer, or a combination thereof.

[0092] As used herein, the term "Ras-related cancer" refers to cancer that is associated with or has dysregulation of the expression or activity or level of Ras gene, Ras protein, or any of them (for example, one or more) (for example, any type of dysregulation of the expression or activity or level of Ras gene, Ras protein, or any of them).Non-limiting examples of Ras-related cancer are described herein.In some embodiments, Ras-related cancer can be KRas-related cancer, HRas-related cancer, NRas-related cancer, or a combination thereof.

[0093] The phrase "dysregulated expression or activity or levels of a Ras gene, a Ras protein, or any of them" refers to a genetic mutation that results in the expression of a fusion protein (e.g., a Ras (e.g., KRas, NRas, or HRas) gene translocation, a mutation in a Ras gene that results in the expression of a Ras protein containing at least one amino acid deletion compared to the wild-type Ras protein, a mutation in a Ras gene that results in the expression of a Ras protein with one or more point mutations compared to the wild-type Ras protein, a mutation in a Ras gene that results in the expression of a Ras protein with at least one inserted amino acid compared to the wild-type Ras protein, a gene duplication that results in an increased level of a Ras protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of a Ras protein in a cell), an alternatively spliced ​​form of a Ras "Aberrant expression" refers to increased expression (e.g., increased levels) of wild-type Ras protein in mammalian cells due to mRNA (e.g., resulting in a Ras protein having at least one amino acid deletion or insertion compared to the wild-type Ras protein), or abnormal cell signaling and / or impaired autocrine / paracrine signaling (e.g., compared to control non-cancer cells). As another example, dysregulated expression, activity, or levels of a Ras gene, Ras protein, or any of them can be a mutation in a Ras gene encoding a Ras protein that is constitutively active or has increased activity compared to a protein encoded by a Ras gene that does not contain the mutation. In some embodiments of any of the methods described herein, dysregulated expression, activity, or levels of a Ras gene, Ras protein, or any of them can be selected from the group consisting of a G12 mutation, a G13 mutation, a Q61 mutation, and combinations thereof.

[0094] Table 1 lists some non-limiting exemplary KRas fusions. In some embodiments of any of the methods described herein, the dysregulation of the expression or activity or level of the KRas gene, KRas protein, or any of them may be selected from the group consisting of a G12 mutation (e.g., G12I, G12A, G12C, G12D, G12E, G12F, G12L, G12N, G12R, G12S, G12T, G12V, G12W, or G12Y), a G13 mutation (e.g., G13A, G13C, G13D, G13E, G13F, G13I, G13M, G13N, G13P, G13R, G13S, G13V, or G13Y), a Q61 mutation (e.g., Q61D, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R), and combinations thereof.

[0095] Some non-limiting exemplary HRas mutations are listed in Table 2. In some embodiments of any of the methods described herein, the dysregulation of the expression or activity or level of the HRas gene, HRas protein, or any of them may be selected from the group consisting of a G12 mutation (e.g., G12A, G12C, G12D, G12R, G12S, G12V), a G13 mutation (e.g., G13A, G13C, G13D, G13R, G13S, G13V), a Q61 mutation (e.g., Q61H, Q61K, Q61L, Q61P, Q61R, Q61*), and combinations thereof.

[0096] Some non-limiting exemplary HRas mutations are listed in Table 3. In some embodiments of any of the methods described herein, the dysregulation of the expression or activity or level of the HRas gene, HRas protein, or any of them may be selected from the group consisting of a G12 mutation (e.g., G12A, G12C, G12D, G12R, G12S, G12V, G12W, G12N), a G13 mutation (e.g., G13A, G13C, G13D, G13R, G13S, G13V), a Q61 mutation (e.g., Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, Q61E, Q61N), and combinations thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 2] [Table 3] [Table 4]

[0097] However, Ras proteins are often considered "undruggable," and no direct Ras inhibitors have been approved by the U.S. Food and Drug Administration. Therefore, other targets in the Ras signaling pathway, including both upstream and downstream targets of Ras family proteins, have been targeted to suppress aberrant signaling through the Ras signaling pathway. For example, Cox, et al. Nat. Rev. Drug Disc. 13.11 (2014): 828-851; Khan, et al. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1867.2 (2020): 118570; Kessler, et al. Proc. Nat. Acad. Sci. 116.32 (2019): 15823-15829; Dang, et al. Nat. Rev. Cancer 17.8 (2017): 502; Baker and Der, Nature 497.7451 (2013): 577-578.

[0098] Guanine nucleotide exchange factors that promote the exchange of Ras family protein-bound GDP for GTP may be suitable targets for reducing signaling through the pathway. Inhibition of GEFs may promote an inactive (GDP-bound) state of Ras family proteins, thus reducing signaling through the pathway. For example, Evelyn, et al. Chemistry & Biology 21.12 (2014): 1618-1628; Hillig, et al. Proc. Nat. Acad. Sci. 116.7 (2019): 2551-2560; Patgiri, et al. Nat. See al. Proc. Nat. Acad. Sci. 109.14 (2012): 5299-5304; Winter, et al. J. Med. Chem. 58.5 (2015): 2265-2274.

[0099] SOS1 is a central "catalytic" core of approximately 500 residues (SOS cat), which is sufficient for Ras-activating activity. SOS1 has a primary (sometimes referred to as the "catalytic" site) Ras-binding site (e.g., containing a Cdc25 homology domain) that can bind to and distort the protein's nucleotide-binding site, thereby facilitating the release of a bound nucleotide (e.g., GDP) and providing another nucleotide (e.g., GTP). SOS1 can bind two Ras molecules in a ternary complex, in which binding of the Ras·GTP complex to a second (sometimes referred to as the "allosteric" site) site on SOS1 further activates the catalytic activity of SOS1 in a positive feedback-type mechanism. See, e.g., Margarit, et al. Cell 112.5 (2003): 685-695; Freedman, et al. Proc. Nat. Acad. Sci. 103.45 (2006): 16692-16697. Furthermore, small molecule binders of SOS1 have been shown to modulate its GEF activity. See, for example, Burns, et al. Proc. Nat. Acad. Sci. 111.9 (2014): 3401-3406. In some cases, small molecule binders of SOS1 can negatively regulate its GEF activity with Ras protein; such molecules are herein referred to as "SOS1 inhibitors" and can also be referred to as inhibiting "SOS1 activity." Some SOS1 inhibitors have been shown to bind proximal to the primary Ras binding site, for example, causing the side chain of Tyr884 to shift, reducing the favorable stacking interaction with Arg73 of KRas. Furthermore, the anti-proliferative activity of such SOS1 inhibitors has been shown. See, e.g., Hillig, et al., Proc. Nat. Acad. Sci. 116.7 (2019): 2551-2560; U.S. Patent Application Publication Nos. 2019 / 0358230 and 2019 / 0194192; and PCT Publication Nos. WO 2018 / 172250 and WO 2019 / 201848.

[0100] As used herein, the term "SOS1-associated cancer" refers to cancers associated with or having dysregulation of the expression, activity, or levels of the SOS1 gene, SOS1-GEF (also referred to herein as the SOS1 protein), or any of them (e.g., one or more) (e.g., any type of dysregulation of the expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them described herein). Non-limiting examples of SOS1-associated cancers are described herein.

[0101] The phrase "dysregulated expression or activity or levels of the SOS1 gene, SOS1 protein, or any of them" refers to a genetic mutation (e.g., an SOS1 gene translocation resulting in the expression of a fusion protein, a mutation in the SOS1 gene resulting in the expression of an SOS1 protein containing at least one amino acid deletion compared to the wild-type SOS1 protein, a mutation in the SOS1 gene resulting in the expression of an SOS1 protein having one or more point mutations compared to the wild-type SOS1 protein, a mutation in the SOS1 gene resulting in the expression of an SOS1 protein having at least one inserted amino acid compared to the wild-type SOS1 protein, a gene duplication resulting in an increased level of SOS1 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) resulting in an increased level of SOS1 protein in a cell), an alternatively spliced ​​form of SOS1 " refers to increased expression (e.g., increased levels) of wild-type SOS1 protein in mammalian cells due to mRNA (e.g., resulting in a Ras protein having a deletion of at least one amino acid in the SOS1 protein compared to the wild-type SOS1 protein, or an SOS1 protein having an insertion of at least one amino acid in the SOS1 protein compared to the wild-type SOS1 protein), or abnormal cell signaling and / or impaired autocrine / paracrine signaling (e.g., compared to control non-cancer cells). As another example, dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them can be a mutation in the SOS1 gene encoding an SOS1 protein that is constitutively active or has increased activity compared to a protein encoded by an SOS1 gene that does not contain the mutation. Non-limiting examples of SOS1 protein point mutations / insertions / deletions are described in Table 4. Non-limiting exemplary SOS1 fusions are listed in Table 4A. [Table 5-1] [Table 5-2] [Table 5-3]

[0102] The term "wild-type" refers to a nucleic acid (e.g., SOS1 gene or mRNA) or protein (e.g., SOS1 protein) found in a subject who does not have a disease or disorder associated with the nucleic acid or protein (e.g., an SOS1-associated disease or disorder), e.g., a cancer associated with the nucleic acid or protein (and optionally does not have an increased risk of developing a disease or disorder associated with the nucleic acid or protein and / or is not suspected of having a disease or disorder associated with the nucleic acid or protein), or found in cells or tissues derived from a subject who does not have a disease associated with the nucleic acid or protein, e.g., a cancer associated with the nucleic acid or protein (and optionally does not have an increased risk of developing a disease or disorder associated with the nucleic acid or protein and / or is not suspected of having a disease or disorder associated with the nucleic acid or protein).

[0103] The term "regulatory authority" refers to a national agency that approves the medical use of pharmaceuticals in that country. For example, a non-limiting example of a regulatory authority is the United States Food and Drug Administration (FDA).

[0104] compound Formula (I): [ka] [During the ceremony, X is phenyl, naphthyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, each of which is selected from 1 to 3 independently selected R A optionally substituted with; R 1 is C1-C6 alkyl, -(C1-C6 alkyl)-NR B R C , C1-C6 hydroxyalkyl or 5-6 membered heteroaryl; R 2represents hydrogen, halogen, cyano, hydroxyl, -NR D R E , C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 3-10 membered cycloalkyl or heterocyclyl, C(O)C1-C6 alkyl, C1-C6 hydroxycycloalkyl optionally substituted with 1-3 fluoro, C1-C6 hydroxyheterocyclyl optionally substituted with 1-3 fluoro, or 3-10 membered heterocyclyl optionally substituted with amino; R 3 teeth, (A) hydroxyl, cyano, C1-C6 alkyl or C3-C8 cycloalkyl optionally substituted with 1 to 3 fluoro, C3-C6 cycloalkyl, 5-10 membered heteroaryl optionally substituted with 1 to 3 fluoro, 3-10 membered -CH2-heterocyclyl substituted with 1 to 3 fluoro, C1-C6 haloalkyl, C1-C6 hydroxyalkyl-C(O)NR F R G or C1-C6 alkyl, or (B) —C(O)C-C cycloalkyl or —C(O)NR, optionally substituted independently with one or more halogen, C-C alkyl, C-C haloalkyl, —C(O)C-C alkyl, halogen, C-C alkyl, or C-C alkoxy. F R G 3- to 10-membered heterocyclyl optionally substituted by and; Each R A are independently one or more of halogen, cyano, nitro, -(C1-C6 alkyl) p -NR H R IC1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl optionally substituted with 1-3 fluoro, C1-C6 alkoxyalkyl optionally substituted independently with one or more of 1-3 fluoro or C1-C6 alkyl, C1-C6 haloalkyl optionally substituted with 3-10 membered heterocyclyl, —CH2C(O)NR optionally substituted with 1-3 fluoro F R G , 5-6 membered -CH2-heteroaryl and -(C1-C6 alkyl) substituted with 1-3 fluoro p -NR J R K 3 to 10-membered cycloalkyl optionally substituted with Each R B , R C , R D , R E , R F , R G , R H , R I , R J , R K are independently selected from hydrogen and C1-C6 alkyl, or R B and R C can be taken together with the atoms to which they are attached to form a 5- to 10-membered heterocyclyl optionally substituted with one or more of halogen, C1-C6 alkyl, and C1-C6 alkoxy; p is 0 or 1. or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, a compound of formula (I): [ka] [During the ceremony, X is phenyl, naphthyl, 3- to 10-membered cycloalkyl, or 5- to 10-membered heteroaryl, each of which is independently selected from 1 to 3 R A optionally substituted with; R 1is C1-C6 alkyl, -(C1-C6 alkyl)-NR B R C , C1-C6 hydroxyalkyl or 5-6 membered heteroaryl; R 2 represents hydrogen, halogen, cyano, hydroxyl, -NR D R E , C1-C6 alkyl, C1-C6 alkoxy optionally substituted with 3-10 membered cycloalkyl, 3-10 membered heterocyclyl optionally substituted with C(O)C1-C6 alkyl or amino; R 3 teeth, (A) Hydroxyl, cyano, 5-10 membered heteroaryl, C1-C6 haloalkyl, -C(O)NR F R G or C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, or (B) Halogen, C1-C6 alkyl, —C(O)C1-C6 alkyl, or —C(O)NR F R G 3- to 10-membered heterocyclyl optionally substituted with and; Each R A are independently halogen, cyano, nitro, -(C1-C6 alkyl) p -NR H R I C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl optionally substituted with 1-3 fluoro, C1-C6 alkoxyalkyl optionally substituted with 1-3 fluoro, C1-C6 haloalkyl optionally substituted with 3-10 membered heterocyclyl, and -(C1-C6 alkyl) p -NR J R K 3 to 10-membered cycloalkyl optionally substituted with Each R B , R C , R D , R E , R F , R G , RH , R I , R J , R K are independently selected from hydrogen and C1-C6 alkyl or R B and R C can be taken together with the atoms to which they are attached to form a 5- to 10-membered heterocyclyl optionally substituted with one or more of halogen, C1-C6 alkyl, and C1-C6 alkoxy; p is 0 or 1. or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, R 1 is C1-C6 alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl (straight or branched chain), or hexyl (straight or branched chain). 1 is methyl or ethyl. In some embodiments, R 1 is methyl.

[0107] In some embodiments, R 1 -(C1-C6 alkyl)-NR B R C For example, methylamino, ethylamino, dimethylamino(ethyl), and the like.

[0108] In some embodiments, each R B and R C and R are both hydrogen. B and R C is independently C1-C6 alkyl. In some embodiments, R B and R C is hydrogen and R B and R C The other is C1-C6 alkyl.

[0109] In some embodiments, R 1is a 5- to 6-membered heteroaryl. In some embodiments, R 1 is a 5-membered heteroaryl, e.g., furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, thiazole, or triazole. 1 is a 5-membered heteroaryl, e.g., pyridine, pyridazine, pyrimidine, pyrazine. In some embodiments, R 1 is an oxazole.

[0110] In some embodiments, R 1 is C1-C6 hydroxyalkyl. In some embodiments, R 1 is ethoxy.

[0111] In some embodiments, R 2 is halogen. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo.

[0112] In some embodiments, R 2 is hydrogen.

[0113] In some embodiments, R 2 is cyano.

[0114] In some embodiments, R 2 is hydroxyl.

[0115] In some embodiments, R 2 Ha-NR D R E is.

[0116] In some embodiments, R 2 is C1-C6 alkoxy optionally substituted with 3-10 membered cycloalkyl. In some embodiments, R 2is methoxy. In some embodiments, R 2 is cyclopropylmethoxy. In some embodiments, R 2 is C(O)C1-C6 alkyl. In some embodiments, R 2 is acetyl. In some embodiments, R 2 is a 3- to 10-membered heterocyclyl optionally substituted with amino.

[0117] In some embodiments, each R D and R E are both hydrogen (e.g., R 2 is amino). In some embodiments, each R D and R E is independently C1-C6 alkyl. In some embodiments, R D and R E is hydrogen and R D and R E The other is C1-C6 alkyl.

[0118] In some embodiments, R 2 is C1-C6 alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl (straight or branched chain), or hexyl (straight or branched chain). 2 is methyl.

[0119] In some embodiments, R 2 is C1-C6 alkoxy, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, iso-butoxy, t-butoxy, pentyl (straight or branched chain), or hexyl (straight or branched chain). In some embodiments, R 2 is methoxy.

[0120] In some embodiments, R 3is hydroxyl, cyano, 5-10 membered heteroaryl, C1-C6 haloalkyl, -C(O)NR F R G or C-C cycloalkyl optionally substituted with C-C alkyl. In some embodiments, R 3 is hydroxyl, cyano, 5-10 membered heteroaryl, C1-C6 haloalkyl, -C(O)NR F R G or C-C cycloalkyl substituted with C-C alkyl. In some embodiments, R 3 is a C-C cycloalkyl substituted with a C-C alkyl. In some embodiments, R 3 is a C-C cycloalkyl substituted with methyl. In some embodiments, R 3 is a C-C cycloalkyl substituted with hydroxylmethyl. In some embodiments, R 3 is unsubstituted C-C cycloalkyl. In some embodiments, R 3 is cyclopropyl, cyclobutyl, or bicyclopentyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl. In some embodiments, R 3 is bicyclopentyl.

[0121] In some embodiments, R 3 is a C-C cycloalkyl optionally substituted with cyano. In some embodiments, R 3 is a C3-C6 cycloalkyl optionally substituted with a 5-10 membered heteroaryl. In some embodiments, R 3 is C-C cycloalkyl optionally substituted with C-C haloalkyl. In some embodiments, R 3 is -C(O)NR F R G is a C3-C6 cycloalkyl optionally substituted with

[0122] In some embodiments, R 3 teeth [ka] is selected from.

[0123] In some embodiments, R 3 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)C1-C6 alkyl or -C(O)NR F R G In some embodiments, R 3 is halogen, C1-C6 alkyl, -C(O)C1-C6 alkyl or -C(O)NR F R G In some embodiments, R 3 is a 3-10 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R 3 is a 3- to 6-membered heterocyclyl optionally substituted with C1-C6 haloalkyl or —C(O)C1-C6 cycloalkyl optionally substituted with halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0124] In some embodiments, R 3 is a 6-10 membered heterocyclyl substituted with C1-C6 alkyl. In some embodiments, R 3 is a 6-10 membered heterocyclyl substituted with C1-C6 haloalkyl. 3 is a 3- to 10-membered heterocyclyl substituted with halogen. In some embodiments, R 3 is a 6- to 10-membered heterocyclyl substituted with methyl. In some embodiments, R 3 is a 3-10 membered heterocyclyl substituted with -C(O)C1-C6 alkyl. In some embodiments, R 3is a 6-10 membered heterocyclyl substituted with -C(O)C1-C6 alkyl. In some embodiments, R 3 is a 6- to 10-membered heterocyclyl substituted with acetyl. In some embodiments, R 3 is a 3- to 6-membered heterocyclyl optionally substituted with —C(O)C-C cycloalkyl optionally substituted with halogen, C-C alkyl, or C-C alkoxy. 3 is -C(O)NR F R G In some embodiments, R 3 is -C(O)NR F R G is a 6- to 10-membered heterocyclyl substituted with

[0125] In some embodiments, each R F and R G and R are both hydrogen. F and R G is independently C1-C6 alkyl. In some embodiments, R F and R G is hydrogen and R F and R G The other is C1-C6 alkyl.

[0126] In some embodiments, R 3 is C1-C6 alkyl, -C(O)C1-C6 alkyl or -C(O)NR F R G In some embodiments, R is 2-oxaspiro[3.3]heptane, piperidine, or tetrahydropyran, optionally substituted with 3 is C1-C6 alkyl, -C(O)C1-C6 alkyl or -C(O)NR F R GIn some embodiments, R is a 2-oxaspiro[3.3]heptane, piperidine, or tetrahydropyran substituted with 3 is unsubstituted 2-oxaspiro[3.3]heptane, piperidine, or tetrahydropyran. In some embodiments, R 3 is tetrahydropyran.

[0127] In some embodiments, R 3 teeth [ka] is selected from.

[0128] In some embodiments, R 3 teeth [ka] In some embodiments, R 3 teeth, [ka] is.

[0129] In some embodiments, X is selected from 1 to 3 independently selected R A R is phenyl optionally substituted with A The group can be located at any of the five available positions on the phenyl ring.

[0130] In some embodiments, X is one R A one R is phenyl substituted with A The group can be in the ortho, meta, or para position relative to the bond that attaches X to the rest of the molecule. In some embodiments, X is selected from two independently selected R A Two independently selected R A The groups can be in the ortho, meta, or para position relative to each other. In some embodiments, X is selected from three independently selected R AThree independently selected R A The groups can be located at any combination of the five available positions on the phenyl ring. In some embodiments, X is unsubstituted phenyl.

[0131] In some embodiments, X is: [ka] is selected from.

[0132] In some embodiments, X is: [ka] is selected from.

[0133] In some embodiments, X is: [ka] In some embodiments, X is: [ka] In some embodiments, X is: [ka] In some embodiments, X is: [ka] is.

[0134] In some embodiments, X is: [ka] is.

[0135] In some embodiments, X is selected from 1 to 3 independently selected R AIn some embodiments, X is naphthyl optionally substituted with one R A In some embodiments, X is a naphthyl substituted with two independently selected R A In some embodiments, X is a naphthyl substituted with three independently selected R A naphthyl substituted with R A The group can be present on one ring (e.g., the ring with a bond to the rest of the compound or the ring without a bond to the rest of the compound) or on both rings. In some embodiments, the naphthyl is attached to the -CH(CH3)NH- moiety at the position of the naphthyl attached to the fused carbon.

[0136] In some embodiments, X is unsubstituted naphthyl. [ka] is.

[0137] In some embodiments, X is selected from 1 to 3 independently selected R A In some embodiments, X is a 3- to 10-membered cycloalkyl optionally substituted with one selected R A In some embodiments, X is a 3- to 10-membered cycloalkyl optionally substituted with two independently selected R A In some embodiments, X is a 3- to 10-membered cycloalkyl substituted with three independently selected R A In some embodiments, X is a 3-, 4-, 5-, 6-, 9-, or 10-membered cycloalkyl.

[0138] In some embodiments, X is [ka] is.

[0139] In some embodiments, X is selected from 1 to 3 independently selected R A In some embodiments, X is a 5- to 10-membered heteroaryl or a 3- to 10-membered heterocyclyl optionally substituted with one selected R A In some embodiments, X is a 5- to 10-membered heteroaryl optionally substituted with two independently selected R A In some embodiments, X is a 5- to 10-membered heteroaryl substituted with three independently selected R A In some embodiments, X is a 6-, 9-, or 10-membered heteroaryl.

[0140] In some embodiments, X is pyridine, pyrazine, pyrimidine, indole, indazole, benzimidazole, thiophene, or pyrrolopyrimidine. In some embodiments, X is pyridine.

[0141] In some embodiments, each R A are independently halogen, cyano, nitro, -(C1-C3 alkyl) p -NR H R I C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl optionally substituted with 3-10 membered heterocyclyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl optionally substituted with 1-3 fluoro, -(C1-C6 alkyl) p -NR J R K and C1-C3 alkoxyalkyl optionally substituted with 1 to 3 fluoro.

[0142] In some embodiments, each R A are independently cyano, -(C1-C3 alkyl) p -NR H R I; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl optionally substituted with 3-10 membered heterocyclyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl optionally substituted with 1-3 fluoro and C1-C3 alkoxyalkyl optionally substituted with 1-3 fluoro.

[0143] In some embodiments, each R A are independently cyano, -(C1-C3 alkyl) p -NR H R I ; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl optionally substituted with 3-10 membered heterocyclyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl substituted with 1-3 fluoro, and C1-C3 alkoxyalkyl substituted with 1-3 fluoro.

[0144] In some embodiments, each R A are independently cyano, -(C1-C3 alkyl) p -NR H R I ; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl optionally substituted with 3-10 membered heterocyclyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl and C1-C3 alkoxyalkyl.

[0145] In some embodiments, p is 0. In some embodiments, p is 1.

[0146] In some embodiments, each R H and R I are both hydrogen.

[0147] In some embodiments, each R H and R I is independently C1-C6 alkyl. In some embodiments, R H and RI is hydrogen and R H and R I The other is C1-C6 alkyl.

[0148] In some embodiments, R A is R A -(C1-C3 alkyl) p -NR H R I If p is 0, then R D and R E may be an amino where both are hydrogen.

[0149] In some embodiments, each R A is independently selected from cyano, C1-C3 alkyl, and C1-C3 haloalkyl optionally substituted with 3- to 10-membered heterocyclyl.

[0150] In some embodiments, each R A are independently C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, -(C1-C6 alkyl) optionally substituted with cyano, methyl, methoxy, 3- to 10-membered heterocyclyl. p -NR J R K and C1-C3 alkoxyalkyl optionally substituted with 1-3 fluoro, 3-10 membered cycloalkyl optionally substituted with 1-3 fluoro, 5-6 membered -CH2-heteroaryl and C1-C3 alkoxyalkyl.

[0151] In some embodiments, each R Ais independently selected from fluoro, chloro, cyano, nitro, —(C-C alkyl)-NH, —NH(amino), —(C-C alkyl)-NHMe, —NHMe, —(C-C alkyl)-N(Me), —N(Me), methyl, methoxy, trifluoromethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoroethan-1-ol, 1,1-difluoroethyl-2-ol, and methoxyethyl.

[0152] In some embodiments, each R A is independently selected from cyano, —(C1-C3 alkyl)-NH2, —NH2, —(C1-C3 alkyl)-N(Me)2, —N(Me)2, methyl, methoxy, trifluoromethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoroethan-1-ol, 1,1-difluoroethyl-2-ol, and methoxyethyl.

[0153] In some embodiments, each R A are independently C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, -(C1-C6 alkyl) optionally substituted with cyano, amino, methyl, methoxy, 3- to 10-membered heterocyclyl. p -NR J R K and C1-C3 alkoxyalkyl, optionally substituted with 3-10 membered cycloalkyl.

[0154] In some embodiments, each R A is independently selected from cyano, methyl, fluoro, methoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy, and hydroxyethyl.

[0155] In some embodiments, each R Ais independently selected from cyano, methyl, difluoromethyl, and trifluoromethyl.

[0156] In some embodiments, each R A is independently selected from cyano and methyl.

[0157] In some embodiments, each R A is independently selected from amino and methyl.

[0158] In some embodiments, each R A is independently selected from methyl and trifluoromethyl.

[0159] In some embodiments, at least one R A is methyl. In some embodiments, at least one R A is difluoromethyl. In some embodiments, at least one R A is trifluoromethyl. In some embodiments, at least one R A is amino. In some embodiments, one R A is methyl. In some embodiments, one R A is trifluoromethyl. In some embodiments, one R A is an amino.

[0160] In some embodiments, one R A is amino and one R A is trifluoromethyl. In some embodiments, one R A is methyl and one R A is trifluoromethyl. In some embodiments, one R A is fluoro and one R A is difluoromethyl.

[0161] In some embodiments, R B and R Ctogether with the atoms to which they are attached represent a 5- to 10-membered heterocyclyl optionally substituted with one or more of halogen, C1-C6 alkyl, and C1-C6 alkoxy. In some embodiments, R B and R C may be taken together with the atoms to which they are attached to form a 5- to 10-membered heterocyclyl optionally substituted with one or more of one or more halogens. B and R C together with the atoms to which they are attached form a 5-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. B and R C together with the atoms to which they are attached form a 5- to 10-membered heterocyclyl optionally substituted with C1-C6 alkoxy.

[0162] In some embodiments, X is [ka] is.

[0163] In some embodiments, X is [ka] is.

[0164] In some embodiments, X is [ka] is.

[0165] In some embodiments, X is [ka] is.

[0166] In some embodiments, X is unsubstituted phenyl, unsubstituted naphthyl, or unsubstituted 5-10 membered heteroaryl.

[0167] In some embodiments, the compound has Formula (Ia): [ka] [During the ceremony, R 2 is hydrogen, methyl, methoxy, amino or halogen; R 3 is a C3-C6 cycloalkyl optionally substituted with hydroxyl or C1-C6 alkyl, a 3- to 10-membered heterocyclyl optionally substituted with C1-C6 alkyl, —C(O)C1-C6 alkyl, or —C(O)NR F R G and; Each R A1 are independently halogen, cyano, nitro, -(C1-C6 alkyl) p -NR H R I selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl optionally substituted with 1-3 fluoro, and C1-C6 alkoxyalkyl optionally substituted with 1-3 fluoro; or When present, two adjacent R A1 together with the atom to which they are attached form a 5- to 6-membered heteroaryl or phenyl, wherein said 5- to 6-membered heteroaryl and phenyl are each independently selected from 1 to 3 R A2 optionally substituted with; Each R A2 are independently halogen, cyano, nitro, -(C1-C6 alkyl) o -NR J R Kselected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl optionally substituted with 1-3 fluoro, and C1-C6 alkoxyalkyl optionally substituted with 1-3 fluoro; Each R F , R G , R H , R I , R J and R K is independently selected from hydrogen and C1-C6 alkyl; o is 0 or 1; p is 0 or 1; q is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is methyl. In some embodiments, R 2 is methoxy. In some embodiments, R 2 is amino. In some embodiments, R 2 is halogen, such as fluoro, chloro, or bromo. 2 is chloro. In some embodiments, R 2 is bromo.

[0169] In some embodiments, R 3 , R B and R C is as described for formula (I).

[0170] In some embodiments, the compound has Formula (Ib): [ka] [During the ceremony, A is a bond, -C(R 3A )(R 3B)- or -CH2OCH2-; R 2 is hydrogen, methyl, methoxy, amino or halogen; Each R A1 are independently halogen, cyano, nitro, -(C1-C6 alkyl) p -NR H R I selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl optionally substituted with 1-3 fluoro, and C1-C6 alkoxyalkyl optionally substituted with 1-3 fluoro; or When present, two adjacent R A1 together with the atom to which they are attached form a 5- to 6-membered heteroaryl or phenyl, wherein said 5- to 6-membered heteroaryl and phenyl are each independently selected from 1 to 3 R A2 optionally substituted with; Each R A2 are independently halogen, cyano, nitro, -(C1-C6 alkyl) o -NR J R K selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl optionally substituted with 1-3 fluoro, and C1-C6 alkoxyalkyl optionally substituted with 1-3 fluoro; R 3A and R 3B is independently selected from H and hydroxyl; R 3C is H, C1-C6 alkyl, or —C(O)C1-C6 alkyl; Each R H , R I , R J and R K is independently selected from hydrogen and C1-C6 alkyl; o is 0 or 1; p is 0 or 1; q is 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is methyl. In some embodiments, R 2 is methoxy. In some embodiments, R 2 is amino. In some embodiments, R 2 is halogen, such as fluoro, chloro, or bromo. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo.

[0172] In some embodiments, A is a bond.

[0173] In some embodiments, A is -C(R 3A )(R 3B In some embodiments, R 3A and R 3B is independently selected from hydrogen and hydroxyl. In some embodiments, R 3A and R 3B and R are both hydrogen. 3A and R 3B is hydrogen and R 3A and R 3B The other is a hydroxyl.

[0174] In some embodiments, A is —CH 2 OCH 2 —.

[0175] In some embodiments, q is 1. In some embodiments, q is 2.

[0176] In some embodiments, [ka] teeth [ka] is selected from.

[0177] In some embodiments, [ka] teeth [ka] is selected from.

[0178] In some embodiments, [ka] teeth [ka] is selected from.

[0179] In some embodiments, [ka] teeth [ka] is.

[0180] In some embodiments, [ka] teeth [ka] is.

[0181] In some embodiments, [ka] teeth [ka] is.

[0182] In some embodiments, [ka] teeth [ka] is.

[0183] In some embodiments, each R A1 are independently halogen, cyano, nitro, -(C1-C3 alkyl) p -NR H R I ; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl optionally substituted with 1 to 3 fluoro, and C1-C3 alkoxyalkyl optionally substituted with 1 to 3 fluoro.

[0184] In some embodiments, each R A1 are independently cyano, -(C1-C3 alkyl) p -NR H R I ; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl optionally substituted with 1 to 3 fluoro, and C1-C3 alkoxyalkyl optionally substituted with 1 to 3 fluoro.

[0185] In some embodiments, each R A1 are independently cyano, -(C1-C3 alkyl) p -NR H R I; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl substituted with 1 to 3 fluoro, and C1-C3 alkoxyalkyl substituted with 1 to 3 fluoro.

[0186] In some embodiments, each R A1 are independently cyano, -(C1-C3 alkyl) p -NR H R I ; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl and C1-C3 alkoxyalkyl.

[0187] In some embodiments, p is 0. In some embodiments, p is 1.

[0188] In some embodiments, each R H and R I and R are both hydrogen. H and R I is independently C1-C6 alkyl. In some embodiments, R H and R I is hydrogen and R H and R I The other is C1-C6 alkyl.

[0189] In some embodiments, each R A1 is independently selected from cyano, amino, methyl, methoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, and C1-C3 alkoxyalkyl.

[0190] In some embodiments, each R A1 is independently selected from cyano, amino, methyl, methoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, and C1-C3 alkoxyalkyl.

[0191] In some embodiments, each R A1 is independently selected from cyano, amino, methyl, methoxy, trifluoromethyl, trifluoromethoxy, and hydroxyethyl.

[0192] In some embodiments, each R A1 is independently selected from cyano, amino, methyl and trifluoromethyl.

[0193] In some embodiments, each R A1 is independently selected from cyano and methyl.

[0194] In some embodiments, each R A1 is independently selected from amino and methyl.

[0195] In some embodiments, each R A1 is independently selected from methyl and trifluoromethyl.

[0196] In some embodiments, at least one R A1 is methyl. In some embodiments, at least one R A1 is trifluoromethyl. In some embodiments, at least one R A1 is amino. In some embodiments, one R A1 is methyl and one R A1 is trifluoromethyl.

[0197] In some embodiments, when present, two adjacent R A1 together with the atom to which they are attached form a 5- to 6-membered heteroaryl or phenyl, wherein said 5- to 6-membered heteroaryl and phenyl are each independently selected from 1 to 3 R A2 may be optionally substituted with

[0198] In some embodiments, when present, two adjacent R A1 together with the atom to which they are attached form a 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is selected from 1 to 3 independently selected R A2 may be optionally substituted with

[0199] In some embodiments, the 5- to 6-membered heteroaryl is selected from two independently selected R A2 is replaced by .

[0200] In some embodiments, the 5- to 6-membered heteroaryl is pyrazolyl. A2 is bonded to the N1 position of the pyrazolyl, and other R A2 is attached to the C3 position of the pyrazolyl.

[0201] In some embodiments, when present, two adjacent R A1 together with the atom to which they are attached form a phenyl, wherein said phenyl is selected from 1 to 3 independently selected R A2 may be optionally substituted with

[0202] In some embodiments, the phenyl is unsubstituted (eg, when q is 0).

[0203] In some embodiments, each R A2 are independently halogen, cyano, nitro, -(C1-C3 alkyl) o -NR J R K ; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl optionally substituted with 1 to 3 fluoro, and C1-C3 alkoxyalkyl optionally substituted with 1 to 3 fluoro.

[0204] In some embodiments, each R A2 are independently cyano, -(C1-C3 alkyl)o -NR J R K ; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl optionally substituted with 1 to 3 fluoro, and C1-C3 alkoxyalkyl optionally substituted with 1 to 3 fluoro.

[0205] In some embodiments, each R A2 are independently cyano, -(C1-C3 alkyl) o -NR J R K ; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl substituted with 1 to 3 fluoro, and C1-C3 alkoxyalkyl substituted with 1 to 3 fluoro.

[0206] In some embodiments, each R A2 are independently cyano, -(C1-C3 alkyl) o -NR J R K ; selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl and C1-C3 alkoxyalkyl.

[0207] In some embodiments, o is 0. In some embodiments, o is 1.

[0208] In some embodiments, each R J and R K and R are both hydrogen. J and R K is independently C1-C6 alkyl. In some embodiments, R J and R K is hydrogen and R J and R K The other is C1-C6 alkyl.

[0209] In some embodiments, each R A2 is independently selected from cyano, amino, methyl, methoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, and C1-C3 alkoxyalkyl.

[0210] In some embodiments, each R A2 is independently selected from cyano, amino, methyl, methoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, and C1-C3 alkoxyalkyl.

[0211] In some embodiments, each R A2 is independently selected from cyano, amino, methyl, methoxy, trifluoromethyl, trifluoromethoxy, and hydroxyethyl. A2 is independently selected from cyano, amino, methyl, and trifluoromethyl. A2 is independently selected from cyano and methyl. In some embodiments, each R A is independently selected from amino and methyl. In some embodiments, each R A2 is independently selected from methyl and trifluoromethyl.

[0212] In some embodiments, at least one R A2 is methyl. In some embodiments, at least one R A2 is trifluoromethyl. In some embodiments, at least one R A is amino. In some embodiments, one R A2 is methyl and one R A2 is trifluoromethyl.

[0213] In some embodiments, A is a bond. [ka] teeth [ka] is.

[0214] In some embodiments, A is a bond. [ka] teeth [ka] is.

[0215] In some embodiments, A is —CH—; [ka] teeth [ka] is.

[0216] In some embodiments, A is —CH—; [ka] teeth [ka] is.

[0217] In some embodiments, A is —CH—O—CH—; [ka] teeth [ka] is.

[0218] In some embodiments, A is —CH—O—CH—; [ka] teeth [ka] is.

[0219] In some embodiments, A is a bond, —CH—, or —CH—O—CH—; [ka] teeth [ka] is.

[0220] Treatment method Cancer (e.g., Ras pathway-associated cancer (e.g., SOS1-associated cancer, Ras-associated cancer (e.g., KRas-associated cancer, HRas-associated cancer, and / or NRas-associated cancer), EGFR-associated cancer, ErbB2-associated cancer, ErbB3-associated cancer, ErbB4-associated cancer, NF1-associated cancer, PDGFR-A-associated cancer, PDGFR-B-associated cancer, FGFR1-associated cancer, FGFR2-associated cancer, FGFR3-associated cancer, IGF1R-associated cancer, INSR-associated cancer, ALK-associated cancer, ROS-associated cancer, TrkA-associated cancer, TrkB Provided herein is a method for treating a subject with a cancer (e.g., a BRAF-associated cancer, a PI3K-associated cancer, an AKT-associated cancer, an mTOR-associated cancer, a MEK-associated cancer, an ERK-associated cancer, or a combination thereof), comprising administering to a subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the cancer is a Ras pathway-associated cancer. In some embodiments, the cancer is a Ras-associated cancer. In some embodiments, the cancer is a KRas-associated cancer. In some embodiments, the cancer is an HRas-associated cancer. In some embodiments, the cancer is an NRas-associated cancer. In some embodiments, the cancer is an SOS1-associated cancer.

[0221] For example, a Ras pathway-associated cancer (e.g., an SOS1-associated cancer, a Ras-associated cancer (e.g., a KRas-associated cancer, an HRas-associated cancer, and / or an NRas-associated cancer), an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an IGF1R-associated cancer, an INSR-associated cancer, an ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c - A method of treating a MET-associated cancer, a VEGFR1-associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL-associated cancer, a SHP2-associated cancer, a RAF-associated cancer (e.g., a BRAF-associated cancer), a PI3K-associated cancer, an AKT-associated cancer, an mTOR-associated cancer, a MEK-associated cancer, an ERK-associated cancer, or a combination thereof, comprising: a) detecting an expression of a Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGF R-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), Ras pathway proteins (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, PDGFR-C, PDGFR-D, PDGFR-E, PDGFR-F ... B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or dysregulation of expression or activity or levels of any thereof; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.In some embodiments, the Ras pathway gene, Ras pathway protein, or dysregulation of the expression or activity or level of any thereof comprises one or more fusion proteins.

[0222] For example, provided herein is a method for treating Ras-related cancer in a subject who needs treatment, comprising: a) detecting the dysregulation of Ras gene, Ras protein or any of their expression or activity or level in the sample from the subject; And b) administering an effective amount of the compound of formula (I) or its pharmaceutically acceptable salt.In some embodiments, the dysregulation of Ras gene, Ras protein or any of their expression or activity or level comprises one or more fusion proteins.

[0223] For example, provided herein is a method for treating KRas-related cancer in a subject who needs treatment, comprising: a) detecting the dysregulation of KRas gene, KRas protein or any of their expression or activity or level in a sample from the subject; And b) administering an effective amount of the compound of formula (I) or its pharmaceutically acceptable salt.In some embodiments, the dysregulation of KRas gene, KRas protein or any of their expression or activity or level comprises one or more fusion proteins.

[0224] For example, provided herein are methods for treating HRas-associated cancer in a subject in need thereof, comprising: (a) detecting dysregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them in a sample from the subject; and (b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them comprises one or more fusion proteins.

[0225] For example, provided herein is a method for treating NRas-associated cancer in a subject in need of treatment, comprising: a) detecting NRas gene, NRas protein, or any of them in a sample from the subject, and b) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the NRas gene, NRas protein, or any of them in the sample comprises one or more fusion proteins.

[0226] For example, provided herein is a method for treating SOS1-associated cancer in a subject in need thereof, comprising: a) detecting dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them comprises one or more fusion proteins.

[0227] 1. A method of treating cancer in a subject in need thereof, comprising: (a) detecting a Ras pathway-associated cancer (e.g., an SOS1-associated cancer, a Ras-associated cancer (e.g., a KRas-associated cancer, an HRas-associated cancer, and / or an NRas-associated cancer), an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an IGF1R-associated cancer, an INSR-associated cancer, an ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer) in the subject; Also provided herein are methods comprising (a) detecting a cancer of interest in a subject, including (i) a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c-MET-associated cancer, a VEGFR1-associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL-associated cancer, a SHP2-associated cancer, a RAF-associated cancer (e.g., a BRAF-associated cancer), a PI3K-associated cancer, an AKT-associated cancer, an mTOR-associated cancer, a MEK-associated cancer, an ERK-associated cancer, or a combination thereof; and (b) administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least part of their tumor removed or has undergone radiation therapy.In some embodiments, the subject has a genetic abnormality associated with a Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), a Ras pathway protein (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, The presence of a Ras pathway-associated cancer is determined in a subject or a biopsy sample from the subject by using a regulatory-approved, for example, FDA-approved, test or assay for identifying dysregulation of the expression or activity or level of any of the following: ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof, or any of the above. In some embodiments, the test or assay is provided as a kit.

[0228] Also provided herein are methods for treating cancer in a subject in need thereof, comprising: (a) detecting a Ras-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, for example, has undergone at least partial tumor resection or radiation therapy. In some embodiments, the subject is determined to have a Ras-associated cancer in the subject or a biopsy sample from the subject using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression or activity or level of a Ras gene, a Ras protein, or any of them, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit.

[0229] Also provided herein are methods for treating cancer in a subject in need thereof, comprising: (a) detecting KRas-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, for example, has undergone at least partial tumor resection or radiation therapy. In some embodiments, the subject is determined to have KRas-associated cancer in the subject or a biopsy sample from the subject using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression or activity or level of the KRas gene, KRas protein, or any of them, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit.

[0230] Also provided herein are methods for treating cancer in a subject in need thereof, comprising: (a) detecting an HRas-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is determined to have an HRas-associated cancer in the subject or in a biopsy sample from the subject using a regulatory agency-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0231] Also provided herein are methods for treating cancer in a subject in need thereof, comprising: (a) detecting an NRas-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of the tumor removed or has undergone radiation therapy. In some embodiments, the subject is determined to have an NRas-associated cancer in the subject or in a biopsy sample from the subject using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression, activity, or level of the NRas gene, NRas protein, or any of them, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0232] Also provided herein are methods for treating cancer in a subject in need thereof, comprising: (a) detecting SOS1-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, for example, has had at least a portion of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is determined to have SOS1-associated cancer in the subject or in a biopsy sample from the subject using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression or activity or level of the SOS1 gene, SOS1 protein, or any of them, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0233] 1. A method of treating cancer in a subject in need thereof, comprising: determining a gene encoding a Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof); a Ras pathway protein (e.g., SOS1, Ras (e.g., KRas, HRas, and / or Also provided herein are methods comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression or activity or levels of a gene encoding a gene encoding a tumour (e.g., NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of their tumor removed or has undergone radiation therapy.In some embodiments, the subject has identified a Ras pathway-associated cancer (e.g., SOS1-associated cancer, Ras-associated cancer (e.g., KRas-associated cancer, HRas-associated cancer, and / or NRas-associated cancer), EGFR-associated cancer, ErbB2-associated cancer, ErbB3-associated cancer, ErbB4-associated cancer, or ErbB5-associated cancer) in the subject or a biopsy sample from the subject using a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of expression or activity or levels of a Ras pathway gene, Ras pathway protein, or any thereof, or by performing any of the non-limiting examples of assays described herein. The patient is determined to have a bB4-related cancer, an NF1-related cancer, a PDGFR-A-related cancer, a PDGFR-B-related cancer, an FGFR1-related cancer, an FGFR2-related cancer, an FGFR3-related cancer, an IGF1R-related cancer, an INSR-related cancer, an ALK-related cancer, a ROS-related cancer, a TrkA-related cancer, a TrkB-related cancer, a TrkC-related cancer, a RET-related cancer, a c-MET-related cancer, a VEGFR1-related cancer, a VEGFR2-related cancer, a VEGFR3-related cancer, an AXL-related cancer, a SHP2-related cancer, a RAF-related cancer (e.g., a BRAF-related cancer), a PI3K-related cancer, an AKT-related cancer, an mTOR-related cancer, a MEK-related cancer, an ERK-related cancer, or a combination thereof. In some embodiments, the test or assay is provided as a kit.

[0234] Also provided herein are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of a Ras gene, a Ras protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, for example, has had at least a portion of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is determined to have a Ras-associated cancer in the subject or a biopsy sample from the subject using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression, activity, or level of a Ras gene, a Ras protein, or any of them, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit.

[0235] Also provided herein are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of the KRas gene, KRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, for example, has had at least a portion of the tumor removed or has undergone radiation therapy. In some embodiments, the subject is determined to have a KRas-associated cancer in the subject or a biopsy sample from the subject using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression, activity, or level of the KRas gene, KRas protein, or any of them, or by performing any of the non-limiting examples of the assays described herein. In some embodiments, the test or assay is provided as a kit.

[0236] Also provided herein are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is determined to have an HRas-associated cancer in the subject or in a biopsy sample from the subject using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0237] Also provided herein are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of the NRas gene, NRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, for example, has had at least part of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is determined to have an NRas-associated cancer in the subject or a biopsy sample from the subject using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression, activity, or level of the NRas gene, NRas protein, or any of them, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0238] A method for treating cancer in a subject in need of treatment comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with an anti-cancer treatment, for example, has had at least part of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is determined to have an SOS1-associated cancer in the subject or a biopsy sample from the subject using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them, or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0239] If the subject is a candidate for a Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR 3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), Ras pathway proteins (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, Also provided herein are methods of treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of their tumor removed or has undergone radiation therapy.In some embodiments, the subject has a Ras pathway-associated cancer (e.g., an SOS1-associated cancer, a Ras-associated cancer (e.g., a KRas-associated cancer, an HRas-associated cancer, and / or an NRas-associated cancer), an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an IGF1R-associated cancer, an INSR-associated cancer, an ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a T The subject may be suspected of having rkB-related cancer, TrkC-related cancer, RET-related cancer, c-MET-related cancer, VEGFR1-related cancer, VEGFR2-related cancer, VEGFR3-related cancer, AXL-related cancer, SHP2-related cancer, RAF-related cancer (e.g., BRAF-related cancer), PI3K-related cancer, AKT-related cancer, mTOR-related cancer, MEK-related cancer, ERK-related cancer, or a combination thereof), a subject showing one or more symptoms of Ras pathway-related cancer, or a subject at increased risk of developing Ras pathway-related cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory-approved assay, for example, an FDA-approved kit. In some embodiments, the assay is liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0240] Also provided herein are methods of treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is suspected of having a Ras-associated cancer, is exhibiting one or more symptoms of a Ras-associated cancer, or is at increased risk of developing a Ras-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit.In some embodiments, the assay is a liquid biopsy.Further non-limiting assays that can be used in these methods are described herein.Further assays are also known in the art.

[0241] Also provided herein are methods of treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the KRas gene, KRas protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or levels of the KRas gene, KRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is suspected of having a KRas-associated cancer, is exhibiting one or more symptoms of a KRas-associated cancer, or is at increased risk of developing a KRas-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit.In some embodiments, the assay is a liquid biopsy.Further non-limiting assays that can be used in these methods are described herein.Further assays are also known in the art.

[0242] Also provided herein are methods of treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is suspected of having an HRas-associated cancer, is exhibiting one or more symptoms of an HRas-associated cancer, or is at increased risk for developing an HRas-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit.In some embodiments, the assay is a liquid biopsy.Further non-limiting assays that can be used in these methods are described herein.Further assays are also known in the art.

[0243] Also provided herein are methods of treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is suspected of having an NRas-associated cancer, is exhibiting one or more symptoms of an NRas-associated cancer, or is at increased risk of developing an NRas-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit.In some embodiments, the assay is a liquid biopsy.Further non-limiting assays that can be used in these methods are described herein.Further assays are also known in the art.

[0244] Also provided herein are methods of treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with an anti-cancer treatment, e.g., has had at least a portion of a tumor removed or has undergone radiation therapy. In some embodiments, the subject is suspected of having an SOS1-associated cancer, is exhibiting one or more symptoms of an SOS1-associated cancer, or is at increased risk of developing an SOS1-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit.In some embodiments, the assay is a liquid biopsy.Further non-limiting assays that can be used in these methods are described herein.Further assays are also known in the art.

[0245] The presence of a Ras pathway gene, Ras pathway protein, or dysregulation of expression or activity or levels of any thereof identifies the subject as having a Ras pathway-associated cancer, if the subject has a Ras pathway protein (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGF, VEGF-related cancer, or a Ras pathway gene, Ras pathway protein, or dysregulation of expression or activity or levels of any thereof identifies the subject as having a Ras pathway-associated cancer. GFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), Ras pathway proteins (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, a Ras pathway-associated cancer (e.g., SOS1-associated cancer, Ras-associated cancer (e.g., KRas-associated cancer, HRas-associated cancer, and / or NRas-associated cancer), EGFR-associated cancer, ErbB2-associated cancer, or a combination thereof) in a subject identified or diagnosed as having a Ras pathway-associated cancer through the process of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression or activity or levels of any of SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof; Related cancers, ErbB3-related cancers, ErbB4-related cancers, NF1-related cancers, PDGFR-A-related cancers, PDGFR-B-related cancers, FGFR1-related cancers, FGFR2-related cancers, FGFR3-related cancers, IGF1R-related cancers, INSR-related cancers, ALK-related cancers, ROS-related cancers, TrkA-related cancers, TrkB-related cancers, TrkC-related cancers, RET-related cancers, c-MET-related cancers, VEGFR1-related cancers, VEGFR2-related cancers, VEGFR3-related cancers, AXL-related cancers, SHP2-related cancers, RAF-related cancers (e.g., BRAF-related cancers), PI3K-related cancers, AKT-related cancers, mTOR-related cancers, MEK-related cancers, ERK-related cancers,Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a Ras pathway-associated cancer (or a combination thereof). Also provided herein is a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a Ras pathway-associated cancer in a subject identified or diagnosed as having a Ras pathway-associated cancer through a process of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them, where the presence of dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them identifies the subject as having a Ras pathway-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, should be administered if performing the assay determines that the subject has dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0246] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating Ras-related cancer in a subject identified or diagnosed as having a Ras-related cancer through a process of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them, when the presence of dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them identifies the subject as having a Ras-related cancer. Also provided herein is a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating Ras-related cancer in a subject identified or diagnosed as having a Ras-related cancer through a process of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them, when the presence of dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them identifies the subject as having a Ras-related cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that if the subject is determined to have a dysregulated expression or activity or level of a Ras gene, a Ras protein, or any of them by performing the assay, the subject should be administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, for example, an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0247] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a KRas-associated cancer in a subject identified or diagnosed as having a KRas-associated cancer through a process of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the KRas gene, KRas protein, or any of them, where the presence of dysregulated expression, activity, or levels of the KRas gene, KRas protein, or any of them identifies the subject as having a KRas-associated cancer. Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a KRas-associated cancer in a subject identified or diagnosed as having a KRas-associated cancer through a process of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the KRas gene, KRas protein, or any of them, where the presence of dysregulated expression, activity, or levels of the KRas gene, KRas protein, or any of them identifies the subject as having a Ras-associated cancer. Also provided herein is a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a KRas-associated cancer in a subject identified or diagnosed as having a KRas-associated cancer through a process of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the KRas gene, KRas protein, or any of them, where the presence of dysregulated expression, activity, or levels of the KRas gene, KRas protein, or any of them identifies the subject as having a Ras-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that if the subject is determined to have dysregulated expression or activity or level of the KRas gene, KRas protein, or any of them by performing the assay, the subject should be administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, for example, an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0248] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an HRas-associated cancer in a subject identified or diagnosed as having an HRas-associated cancer through the process of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them, where the presence of dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them identifies the subject as having an HRas-associated cancer. Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in treating an HRas-associated cancer in a subject identified or diagnosed as having an HRas-associated cancer through the process of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them, where the presence of dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them identifies the subject as having a Ras-associated cancer. Also provided herein is a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HRas-associated cancer in a subject identified or diagnosed as having an HRas-associated cancer through the process of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them, where the presence of dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them identifies the subject as having a Ras-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical records (e.g., a computer-readable medium) that if the subject is determined to have dysregulated expression, activity, or level of the HRas gene, HRas protein, or any of them by performing the assay, the subject should be administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0249] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an NRas-associated cancer in a subject identified or diagnosed as having an NRas-associated cancer through the process of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them, where the presence of dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them identifies the subject as having an NRas-associated cancer. Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in treating an NRas-associated cancer in a subject identified or diagnosed as having an NRas-associated cancer through the process of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them, where the presence of dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them identifies the subject as having an NRas-associated cancer. Also provided herein is a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an NRas-associated cancer in a subject identified or diagnosed as having an NRas-associated cancer through the process of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them, where the presence of dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them identifies the subject as having an NRas-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that if the subject is determined to have dysregulated expression, activity, or level of the NRas gene, NRas protein, or any of them by performing the assay, the subject should be administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., an FDA-approved kit. In some embodiments, the assay is a liquid biopsy.

[0250] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an SOS1-associated cancer in a subject identified or diagnosed as having an SOS1-associated cancer through the process of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them, where the presence of dysregulated expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them identifies the subject as having an SOS1-associated cancer. Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in treating an SOS1-associated cancer in a subject identified or diagnosed as having an SOS1-associated cancer through the process of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them, where the presence of dysregulated expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them identifies the subject as having an SOS1-associated cancer. Also provided herein is a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an SOS1-associated cancer in a subject identified or diagnosed as having an SOS1-associated cancer through the process of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them, where the presence of dysregulated expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them identifies the subject as having an SOS1-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry or break-apart FISH analysis.In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit.In some embodiments, the assay is liquid biopsy.

[0251] In any embodiment of the methods or uses described herein, the subject has been identified or diagnosed with cancer having dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them. In any embodiment of the methods or uses described herein, the subject has been identified or diagnosed with cancer having dysregulated expression or activity or levels of a Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), a Ras pathway protein, or any of them. In one embodiment of the methods or uses described herein, the subject may have a tumor positive for a Ras pathway gene, a Ras pathway protein, or dysregulation of the expression or activity or levels of any of them. In another embodiment of the methods or uses described herein, the subject may have a tumor positive for a Ras pathway gene, a Ras pathway protein, or dysregulation of the expression or activity or levels of any of them. In embodiments of any of the methods or uses described herein, the subject may be one whose tumor has a Ras pathway gene, a Ras pathway protein, or dysregulated expression or activity or levels of any thereof.In embodiments of any of the methods or uses described herein, the subject has a Ras pathway-associated cancer (e.g., SOS1-associated cancer, Ras-associated cancer (e.g., KRas-associated cancer, HRas-associated cancer, and / or NRas-associated cancer), EGFR-associated cancer, ErbB2-associated cancer, ErbB3-associated cancer, ErbB4-associated cancer, NF1-associated cancer, PDGFR-A-associated cancer, PDGFR-B-associated cancer, FGFR1-associated cancer, FGFR2-associated cancer, FGFR3-associated cancer, IGF-1-associated cancer, or a combination thereof). The subject is suspected of having cancers such as 1R-related cancer, INSR-related cancer, ALK-related cancer, ROS-related cancer, TrkA-related cancer, TrkB-related cancer, TrkC-related cancer, RET-related cancer, c-MET-related cancer, VEGFR1-related cancer, VEGFR2-related cancer, VEGFR3-related cancer, AXL-related cancer, SHP2-related cancer, RAF-related cancer (for example, BRAF-related cancer), PI3K-related cancer, AKT-related cancer, mTOR-related cancer, MEK-related cancer, ERK-related cancer, or a combination thereof. In some embodiments, provided herein is a method for treating Ras pathway-related cancer in a subject in need of treatment, comprising: a) detecting the dysregulation of expression or activity or level of Ras pathway genes, Ras pathway proteins, or any of them in a sample from the subject; and b) administering an effective amount of a compound of formula (I) or its pharmaceutically acceptable salt. In some embodiments, the dysregulation of expression or activity or level of Ras pathway genes, Ras pathway proteins, or any of them comprises one or more Ras pathway protein point mutations / insertions / deletions.

[0252] In any embodiment of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with dysregulated expression, activity, or level of the Ras gene, Ras protein, or any of them. In any embodiment of the methods or uses described herein, the subject has a tumor that is positive for dysregulated expression, activity, or level of the Ras gene, Ras protein, or any of them. In any embodiment of the methods or uses described herein, the subject may have a tumor that is positive for dysregulated expression, activity, or level of the Ras gene, Ras protein, or any of them. In any embodiment of the methods or uses described herein, the subject may have a tumor that is positive for dysregulated expression, activity, or level of the Ras gene, Ras protein, or any of them. In any embodiment of the methods or uses described herein, the subject may have a tumor that is positive for dysregulated expression, activity, or level of the Ras gene, Ras protein, or any of them. In any embodiment of the methods or uses described herein, the subject is suspected of having a Ras-related cancer. In some embodiments, provided herein is a method for treating a Ras-related cancer in a subject in need of treatment, comprising: a) detecting dysregulated expression, activity, or level of the Ras gene, Ras protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression or activity or levels of the Ras gene, Ras protein, or any thereof comprises one or more Ras pathway protein point mutations / insertions / deletions.

[0253] In any embodiment of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with dysregulated expression, activity, or level of the KRas gene, KRas protein, or any of them. In any embodiment of the methods or uses described herein, the subject has a tumor that is positive for dysregulated expression, activity, or level of the KRas gene, KRas protein, or any of them. In any embodiment of the methods or uses described herein, the subject may have ... is suspected of having a KRas-related cancer. In some embodiments, provided herein is a method for treating KRas-related cancer in a subject who needs treatment, comprising: a) detecting the dysregulation of KRas gene, KRas protein, or any of their expression or activity or level in a sample from the subject; and b) administering an effective amount of a compound of formula (I) or its pharmaceutically acceptable salt.In some embodiments, the dysregulation of KRas gene, KRas protein, or any of their expression or activity or level comprises one or more KRas pathway protein point mutations / insertions / deletions.Non-limiting examples of KRas protein point mutations / insertions / deletions are listed in Table 1.

[0254] In any embodiment of the methods or uses described herein, the subject has been identified or diagnosed with a cancer having dysregulated expression, activity, or level of the HRas gene, HRas protein, or any of them. In any embodiment of the methods or uses described herein, the subject has a tumor that is positive for dysregulated expression, activity, or level of the HRas gene, HRas protein, or any of them. In any embodiment of the methods or uses described herein, the subject may have ... some embodiments of the methods or uses described herein, the subject is suspected of having an HRas-associated cancer. In some embodiments, provided herein is a method for treating an HRas-associated cancer in a subject in need of treatment, comprising: a) detecting dysregulated expression, activity, or level of the HRas gene, HRas protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression or activity or level of the HRas gene, HRas protein, or any of them comprises one or more HRas pathway protein point mutations / insertions / deletions. Non-limiting examples of HRas protein point mutations / insertions / deletions are listed in Table 2.

[0255] In any embodiment of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with dysregulated expression, activity, or level of the NRas gene, NRas protein, or any of them. In any embodiment of the methods or uses described herein, the subject has a tumor that is positive for dysregulated expression, activity, or level of the NRas gene, NRas protein, or any of them. In any embodiment of the methods or uses described herein, the subject may have ... some embodiments of the methods or uses described herein, the subject is suspected of having an NRas-associated cancer. In some embodiments, provided herein is a method for treating an NRas-associated cancer in a subject in need of treatment, comprising: a) detecting dysregulated expression, activity, or level of the NRas gene, NRas protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression or activity or level of the NRas gene, NRas protein, or any of them comprises one or more NRas pathway protein point mutations / insertions / deletions. Non-limiting examples of NRas protein point mutations / insertions / deletions are listed in Table 3.

[0256] In any embodiment of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them. In any embodiment of the methods or uses described herein, the subject has a tumor that is positive for dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them. In any embodiment of the methods or uses described herein, the subject may be a subject with a tumor that is positive for dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them. In any embodiment of the methods or uses described herein, the subject may be a subject whose tumor has dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them. In any embodiment of the methods or uses described herein, the subject is suspected of having an SOS1-associated cancer. In some embodiments, provided herein is a method for treating SOS1-associated cancer in a subject in need of treatment, comprising: a) detecting dysregulation of the expression or activity or level of SOS1 gene, SOS1 protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression or activity or level of SOS1 gene, SOS1 protein, or any of them comprises one or more SOS1 protein point mutations / insertions / deletions. Non-limiting examples of SOS1 protein point mutations / insertions / deletions are listed in Table 4.

[0257] In some embodiments, the Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), a Ras pathway protein (e.g., SOS1, Ras (e.g., KRa Cancers with dysregulated expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them (e.g., EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or any of them are determined using a regulatory agency-approved, for example, FDA-approved, assay or kit. In some embodiments, tumors with dysregulated expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them are determined using a regulatory agency-approved, for example, FDA-approved, assay or kit.

[0258] In some embodiments, the cancer that has dysregulated expression or activity or level of Ras gene, Ras protein or any of them is determined by using regulatory agency approved, for example, FDA approved, assay or kit.In some embodiments, the tumor that has dysregulated expression or activity or level of Ras gene, Ras protein or any of them is determined by regulatory agency approved, for example, FDA approved, assay or kit.

[0259] In some embodiments, the cancer that has KRas gene, KRas protein or any of them is dysregulated in expression or activity or level is determined by using regulatory agency approved, for example, FDA approved, assay or kit.In some embodiments, the tumor that has KRas gene, KRas protein or any of them is dysregulated in expression or activity or level is determined by regulatory agency approved, for example, FDA approved, assay or kit.

[0260] In some embodiments, cancers with dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them are determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, tumors with dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them are determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.

[0261] In some embodiments, the cancer that has dysregulated expression or activity or level of NRas gene, NRas protein, or any of them is determined using a regulatory agency approved, for example, FDA approved, assay or kit.In some embodiments, the tumor that has dysregulated expression or activity or level of NRas gene, NRas protein, or any of them is determined using a regulatory agency approved, for example, FDA approved, assay or kit.

[0262] In some embodiments, cancers with dysregulated expression or activity or levels of the SOS1 gene, SOS1 protein, or any of them are determined using a regulatory agency-approved, for example, FDA-approved, assay or kit. In some embodiments, tumors with dysregulated expression or activity or levels of the SOS1 gene, SOS1 protein, or any of them are determined using a regulatory agency-approved, for example, FDA-approved, assay or kit.

[0263]

[0023] In any of the embodiments of the methods or uses described herein, the subject is diagnosed with a leukemia or encephalopathy, including a leukemia or encephalopathy, in which the subject has a leukemia or encephalopathy, or ... or have clinical records indicating that the subject has a tumor with dysregulation of expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof). Also provided herein are methods of treating a subject, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to a subject with clinical records indicating that the subject has dysregulation of expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them.

[0264] In any embodiment of the methods or uses described herein, the subject has clinical records showing that the subject has a tumor with dysregulated expression or activity or level of Ras gene, Ras protein, or any of them.Also provided herein is a method for treating a subject, comprising administering to a subject with clinical records showing that the subject has dysregulated expression or activity or level of Ras gene, Ras protein, or any of them an effective amount of the compound of formula (I) or its pharmaceutically acceptable salt.

[0265] In any embodiment of the methods or uses described herein, the subject has clinical records showing that the subject has a tumor with dysregulated expression or activity or level of KRas gene, KRas protein, or any of them.Also provided herein is a method for treating a subject, comprising administering to a subject with clinical records showing that the subject has dysregulated expression or activity or level of KRas gene, KRas protein, or any of them, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0266] In any embodiment of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor with dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them. Also provided herein is a method of treating a subject, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject with clinical records indicating that the subject has dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them.

[0267] In any embodiment of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor with dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them. Also provided herein is a method of treating a subject, comprising administering to a subject with clinical records indicating that the subject has dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0268] In any embodiment of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor with dysregulated expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them. Also provided herein is a method of treating a subject, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject with clinical records indicating that the subject has a tumor with dysregulated expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them.

[0269] In some embodiments, the methods provided herein involve targeting a Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), a Ras pathway protein (e.g., SOS1, Ras, The method also includes performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of a Ras pathway gene, a Ras pathway protein, or any of a combination thereof (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof). In some such embodiments, the method also includes administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject determined to have dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of a combination thereof. In some embodiments, the method includes determining that the subject has a dysregulated expression or level of a Ras pathway gene, a Ras pathway protein, or any of them by an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the method comprises carrying out an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or level of Ras gene, Ras protein, or any of them.In some such embodiments, the method also comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject who is determined to have dysregulated expression or activity or level of Ras gene, Ras protein, or any of them.In some embodiments, the method comprises determining that the subject has dysregulated expression or level of Ras gene, Ras protein, or any of them by an assay carried out on a sample obtained from the subject.In such embodiments, the method also comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the method comprises performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulated expression or level of KRas gene, KRas protein, or any of them.In some such embodiments, the method also comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject who is determined to have a dysregulated expression or activity or level of KRas gene, KRas protein, or any of them.In some embodiments, the method comprises determining that the subject has a dysregulated expression or level of KRas gene, KRas protein, or any of them by performing an assay on a sample obtained from the subject.In such embodiments, the method also comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the method comprises performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of the HRas gene, HRas protein, or either thereof. In some such embodiments, the method also comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to have dysregulated expression, activity, or levels of the HRas gene, HRas protein, or either thereof. In some embodiments, the method comprises determining that the subject has dysregulated expression or levels of the HRas gene, HRas protein, or either thereof by an assay performed on a sample obtained from the subject. In such embodiments, the method also comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the method comprises performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or level of NRas gene, NRas protein, or any of them.In some such embodiments, the method also comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject who is determined to have dysregulated expression or activity or level of NRas gene, NRas protein, or any of them.In some embodiments, the method comprises determining that the subject has dysregulated expression or level of NRas gene, NRas protein, or any of them by an assay performed on a sample obtained from the subject.In such embodiments, the method also comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the method comprises performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of the SOS1 gene, SOS1 protein, or any of them. In some such embodiments, the method also comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to have dysregulated expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them. In some embodiments, the method comprises determining that the subject has dysregulated expression or levels of the SOS1 gene, SOS1 protein, or any of them by an assay performed on a sample obtained from the subject. In such embodiments, the method also comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0275] In any embodiment of the methods or uses described herein, the cancer (e.g., a Ras pathway-associated cancer (e.g., an SOS1-associated cancer, a Ras-associated cancer (e.g., a KRas-associated cancer, an HRas-associated cancer, and / or an NRas-associated cancer), an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an I ... GF1R-associated cancer, INSR-associated cancer, ALK-associated cancer, ROS-associated cancer, TrkA-associated cancer, TrkB-associated cancer, TrkC-associated cancer, RET-associated cancer, c-MET-associated cancer, VEGFR1-associated cancer, VEGFR2-associated cancer, VEGFR3-associated cancer, AXL-associated cancer, SHP2-associated cancer, RAF-associated cancer (e.g., BRAF-associated cancer), PI3K-associated cancer, AKT-associated cancer, mTOR-associated cancer, MEK-associated cancer, ERK-associated cancer, or a combination thereof) is a hematological cancer. Examples of hematological cancers (e.g., hematological cancers that are Ras pathway-associated cancers) include, for example, leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, specify juvenile myelomonocytic leukemia (JMML), and hairy cell leukemia) and lymphomas (e.g., non-Hodgkin's lymphoma, Hodgkin's disease, cutaneous T-cell lymphoma, and Burkitt's lymphoma).

[0276] In any embodiment of the methods or uses described herein, the cancer (e.g., a Ras pathway-associated cancer (e.g., an SOS1-associated cancer, a Ras-associated cancer (e.g., a KRas-associated cancer, an HRas-associated cancer, and / or an NRas-associated cancer), an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an I ... GF1R-associated cancer, INSR-associated cancer, ALK-associated cancer, ROS-associated cancer, TrkA-associated cancer, TrkB-associated cancer, TrkC-associated cancer, RET-associated cancer, c-MET-associated cancer, VEGFR1-associated cancer, VEGFR2-associated cancer, VEGFR3-associated cancer, AXL-associated cancer, SHP2-associated cancer, RAF-associated cancer (e.g., BRAF-associated cancer), PI3K-associated cancer, AKT-associated cancer, mTOR-associated cancer, MEK-associated cancer, ERK-associated cancer, or a combination thereof)) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are Ras pathway-associated cancers) are, for example, thyroid cancer (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma), lung cancer (e.g., non-small cell lung carcinoma, small cell lung carcinoma, bronchial adenoma, and pleuropulmonary blastoma), pancreatic cancer, ductal carcinoma of the pancreas, bile duct cancer, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ), gastric cancer, small intestine cancer, colon cancer, colorectal cancer, peritoneal cancer, ovarian cancer, uterine cancer, liver cancer, endometrial cancer, prostate cancer (including benign prostatic hyperplasia), testicular cancer, bladder cancer, urinary tract cancer, cervical cancer, head and neck cancer, brain cancer (e.g., glioblastoma, brainstem and hypothalamic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, and ependymoma), squamous cell carcinoma, and melanoma.

[0277] In some embodiments, the subject is a human.

[0278] The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may also be used to treat Ras pathway-related cancers (e.g., SOS1-related cancers, Ras-related cancers (e.g., KRas-related cancers, HRas-related cancers, and / or NRas-related cancers), EGFR-related cancers, ErbB2-related cancers, ErbB3-related cancers, ErbB4-related cancers, NF1-related cancers, PDGFR-A-related cancers, PDGFR-B-related cancers, FGFR1-related cancers, FGFR2-related cancers, FGFR3-related cancers, IGF1-related cancers, and the like. R-associated cancer, INSR-associated cancer, ALK-associated cancer, ROS-associated cancer, TrkA-associated cancer, TrkB-associated cancer, TrkC-associated cancer, RET-associated cancer, c-MET-associated cancer, VEGFR1-associated cancer, VEGFR2-associated cancer, VEGFR3-associated cancer, AXL-associated cancer, SHP2-associated cancer, RAF-associated cancer (e.g., BRAF-associated cancer), PI3K-associated cancer, AKT-associated cancer, mTOR-associated cancer, MEK-associated cancer, ERK-associated cancer, or a combination thereof.

[0279] Thus, also provided herein is a method for treating a subject diagnosed or identified as having a Ras pathway-associated cancer, e.g., any of the exemplary Ras pathway-associated cancers described herein, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) is selected from the compounds of Examples 1 to 85, or a pharmaceutically acceptable salt thereof.

[0280] Thus, also provided herein is a method for treating a subject diagnosed or identified as having a Ras pathway-associated cancer, e.g., any of the exemplary Ras pathway-associated cancers described herein, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) is selected from the compounds of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0281] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful for treating Ras-associated cancers.

[0282] Therefore, also provided herein is a method for treating a subject diagnosed or identified as having a Ras-associated cancer, e.g., any of the exemplary Ras-associated cancers described herein, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) is selected from the compounds of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0283] Therefore, also provided herein is a method for treating a subject diagnosed or identified as having a Ras-associated cancer, e.g., any of the exemplary Ras-associated cancers described herein, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) is selected from the compounds of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0284] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in the treatment of KRas-associated cancers.

[0285] Thus, also provided herein is a method for treating a subject diagnosed or identified as having a KRas-associated cancer, e.g., any of the exemplary KRas-associated cancers described herein, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) is selected from the compounds of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0286] Thus, also provided herein is a method for treating a subject diagnosed or identified as having a KRas-associated cancer, e.g., any of the exemplary KRas-associated cancers described herein, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) is selected from the compounds of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0287] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in the treatment of HRas-associated cancers.

[0288] Thus, also provided herein is a method for treating a subject diagnosed or identified as having an HRas-associated cancer, e.g., any of the exemplary HRas-associated cancers described herein, comprising administering to the subject an effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from the compounds of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0289] Thus, also provided herein is a method for treating a subject diagnosed or identified as having an HRas-associated cancer, e.g., any of the exemplary HRas-associated cancers described herein, comprising administering to the subject an effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from the compounds of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0290] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in the treatment of NRas-associated cancers.

[0291] Therefore, also provided herein is a method for treating a subject diagnosed or identified as having an NRas-associated cancer, e.g., any of the exemplary NRas-associated cancers described herein, comprising administering to the subject an effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is a compound of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0292] Therefore, also provided herein is a method for treating a subject diagnosed or identified as having an NRas-associated cancer, e.g., any of the exemplary NRas-associated cancers described herein, comprising administering to the subject an effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is a compound of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0293] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in the treatment of SOS1-associated cancers.

[0294] Therefore, also provided herein is a method for treating a subject diagnosed or identified as having an SOS1-associated cancer, e.g., any of the exemplary SOS1-associated cancers described herein, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) is a compound of Examples 1-182, or a pharmaceutically acceptable salt thereof.

[0295] Ras pathway proteins (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), Ras pathway genes (e.g., SOS1, Ras (e.g., , KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or any (e.g., one or more) of these may contribute to tumorigenesis. For example, the fusion protein may have increased activity compared to a wild-type Ras pathway protein (e.g., increased Ras activation and / or increased GEF activity due to more favorable binding to SOS1), increased expression (e.g., increased levels) of a wild-type Ras pathway protein in mammalian cells may result from aberrant cell signaling and / or dysregulation of autocrine / paracrine signaling (e.g., compared to control non-cancerous cells), and Ras pathway mRNA splice variants may also result in dysregulation of the Ras pathway.

[0296] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) permeability.Such compounds can cross the blood-brain barrier and inhibit Ras pathway (for example, SOS1, Ras (for example, KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (for example, BRAF), PI3K, AKT, mTOR, MEK, ERK, or combinations thereof) activity in the brain and / or other CNS structures.In some embodiments, the compounds provided herein can cross the blood-brain barrier in an effective amount. For example, treating a subject with cancer (e.g., a Ras pathway-related cancer, such as a Ras pathway-related brain or CNS cancer) can include administering (e.g., orally administering) a compound to the subject. In some such embodiments, the compounds provided herein are useful for treating primary brain tumors or metastatic brain tumors. For example, the compounds can be used to treat one or more of gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendroglioma, ependymoma, and mixed glioma, meningioma, medulloblastoma, ganglioglioma, schwannoma (schwannoma), and craniopharyngioma (see the tumors listed in DN et al. Acta Neuropathol 131(6), 803-820 (June 2016)). In some embodiments, the brain tumor is a primary brain tumor.In some embodiments, the subject has previously been treated with another anti-cancer agent, for example, another Ras pathway inhibitor (e.g., a compound other than the compound of general formula (I) or another Ras pathway gene or protein (e.g., an inhibitor of Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or a combination thereof). In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the subject has previously been treated with another anti-cancer agent, for example, another Ras pathway inhibitor (e.g., a compound other than a compound of general formula (I) or another Ras pathway gene or protein (e.g., Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or a combination thereof).

[0297] The ability of the compounds described herein to cross the BBB can be demonstrated by assays known in the art. Such assays include BBB models such as transwell systems, hollow fiber (dynamic in vitro BBB) models, other microfluidic BBB systems, BBB spheroid platforms, and other cell aggregation-based BBB models. See, for example, Cho et al. Nat Commun. 2017; 8: 15623; Bagchi, et al. Drug Des Devel Ther. 2019; 13: 3591-3605; Gastfriend, et al. Curr Opin Biomed Eng. 2018 Mar; 5: 6-12; and Wang et al. Biotechnol Bioeng. 2017 Jan; 114(1): 184-194. In some embodiments, the compounds described herein are fluorescently labeled, and the fluorescent label can be detected using a microscope (e.g., a confocal microscope). In some such embodiments, the ability of a compound to penetrate a model surface barrier can be represented by fluorescence intensity at a given depth below the surface. In some assays, such as calcein-AM-based assays, the fluorescent label is non-fluorescent until it penetrates viable cells, is hydrolyzed by intracellular esterases, and produces a fluorescent compound that is retained by the cell and can be quantified spectrophotometrically. Non-limiting examples of fluorescent labels that can be used in the assays described herein include Cy5, rhodamine, infrared IRDye® CW-800 (LICOR #929-71012), near-infrared IRDye® 650 (LICOR #929-70020), sodium fluorescein (Na—F), Lucifer Yellow (LY), 5′-carboxyfluorescein, and calcein-acetoxymethyl ester (calcein-AM). In some embodiments, a BBB model (e.g., a tissue or cell aggregate) can be sectioned and a compound described herein can be detected in one or more sections using mass spectrometry (e.g., MALDI-MSI analysis).In some embodiments, the ability of the compounds described herein to cross the BBB via transcytosis, such as receptor-mediated transport (RMT), carrier-mediated transport (CMT), or active efflux transport (AET), can be demonstrated by assays known in the art. See, for example, Wang, et al. Drug Deliv. 2019; 26(1): 551-565. In some embodiments, the assay for determining whether a compound can be effluxed by P-glycoprotein (Pgp) comprises a monolayer efflux assay, measuring the movement of the compound through Pgp by measuring the movement of digoxin, a model Pgp substrate (see, for example, Doan et al. 2002. J Pharmacol Exp Ther. 303(3):1029-1037). Another in vivo assay for identifying compounds that cross the blood-brain barrier involves a phage-based system (see, e.g., Peng et al. 2019. ChemRxiv. Preprint doi.org / 10.26434 / chemrxiv.8242871.v1). In some embodiments, the binding of the compounds described herein to brain tissue is quantified. For example, a brain tissue binding assay can be performed using equilibrium dialysis, and the fraction of the compounds described herein that do not bind to brain tissue can be analyzed by LC-MS / MS (Cyprotex: Brain Tissue Binding Assay). www.cyprotex.com / admepk / protein_binding / brain-tissue-binding / ) can be detected using

[0298] In some embodiments, the subject has (e.g., as identified using a regulatory agency-approved, e.g., FDA-approved, assay or kit) a gene encoding a Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), The subject has been identified or diagnosed with a cancer having dysregulated expression or activity or level of a Ras pathway protein (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or any of them (Ras pathway-related cancer). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of a Ras pathway gene, a Ras pathway protein, or any of them (e.g., as determined using a regulatory agency-approved assay or kit). The subject can have tumor that is positive for the dysregulation of Ras pathway gene, Ras pathway protein or any of their expression or activity or level (for example, by using regulatory agency approved, for example, FDA approved, assay or kit, it is identified as positive).The subject can have tumor that is positive for the dysregulation of Ras pathway gene, Ras pathway protein or any of their expression or activity or level (for example, by using regulatory agency approved, for example, FDA approved, assay or kit, it is identified as such).In some embodiments, the subject is suspected to have Ras pathway-related cancer.In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0299] In some embodiments, the subject has been identified or diagnosed with cancer (Ras-associated cancer) with dysregulated expression or activity or level of Ras gene, Ras protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of Ras gene, Ras protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for dysregulated expression or activity or level of Ras gene, Ras protein, or any of them (e.g., identified as positive ... dysregulated expression or activity or level of Ras gene, protein, or any of them (e.g., identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a Ras-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of a Ras gene, a Ras protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0300] In some embodiments, the subject has been identified or diagnosed with a cancer (KRas-associated cancer) with dysregulated expression or activity or level of the KRas gene, KRas protein, or any of them (e.g., as determined using a regulatory-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of the KRas gene, KRas protein, or any of them (e.g., as determined using a regulatory-approved, e.g., FDA-approved, assay or kit). For example, the subject has a tumor that is positive for a mutation listed in Table 1. The subject may have a tumor that is positive for dysregulated expression or activity or level of the KRas gene, KRas protein, or any of them (e.g., identified as positive using a regulatory-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for dysregulated expression or activity or level of the KRas gene, KRas protein, or any of them (e.g., identified as positive using a regulatory-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the KRas gene, KRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0301] In some embodiments, the subject has been identified or diagnosed with a cancer (HRas-associated cancer) having dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (e.g., as identified using a regulatory-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (e.g., as determined using a regulatory-approved, e.g., FDA-approved, assay or kit). For example, the subject has a tumor that is positive for a mutation listed in Table 2. The subject may have a tumor that is positive for dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (e.g., identified as positive using a regulatory-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor whose tumor has dysregulated expression or activity or levels of the HRas protein, or any of them (e.g., whose tumor is so identified using a regulatory-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an HRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0302] In some embodiments, the subject has been identified or diagnosed with a cancer (NRas-associated cancer) with dysregulated expression or activity or level of the NRas gene, NRas protein, or any of them (e.g., as determined using a regulatory-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of the NRas gene, NRas protein, or any of them (e.g., as determined using a regulatory-approved, e.g., FDA-approved, assay or kit). For example, the subject has a tumor that is positive for a mutation listed in Table 3. The subject may have a tumor that is positive for dysregulated expression or activity or level of the NRas gene, NRas protein, or any of them (e.g., identified as positive using a regulatory-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that is positive for dysregulated expression or activity or level of the NRas gene, NRas protein, or any of them (e.g., identified as positive using a regulatory-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an NRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has dysregulation of the expression or activity or levels of the NRas gene, NRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0303] In some embodiments, the subject has been identified or diagnosed with a cancer (SOS1-associated cancer) with dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (e.g., as identified using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (e.g., as identified using a regulatory agency-approved, e.g., FDA-approved, assay or kit). For example, the subject has a tumor that is positive for the mutations listed in Table 4. The subject has a tumor that is positive for dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an SOS1-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has dysregulated expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0304]

[0023] In any embodiment of the methods or uses described herein, a sample from the subject is used to determine whether the subject has a Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or a Ras pathway protein (e.g., SOS1, RAS, EGFR ... Assays used to determine whether a patient has dysregulation of expression or activity or levels of a gene encoding a marker for a tumor (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or any of them can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assay is typically carried out, for example, by using at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment.Assay can utilize other detection methods known in the art for detecting the dysregulation of the expression or activity or level of Ras pathway gene, Ras pathway protein or any of them.In some embodiments, sample is biological sample or biopsy sample from subject (for example, biopsy sample fixed with paraffin).In some embodiments, the subject is a subject suspected of having a Ras pathway-associated cancer, a subject with one or more symptoms of a Ras pathway-associated cancer, and / or a subject at increased risk of developing a Ras pathway-associated cancer.

[0305] In some embodiments, the Ras pathway gene (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), a Ras pathway protein (e.g., SOS1, Ras (e.g., KRas), , HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or dysregulation of the expression or activity or levels of any of them can be identified using liquid biopsy (variously referred to as fluid biopsy or fluid-phase biopsy). See, e.g., Karachialiou et al., "Real-time liquid biopsies become a reality in cancer treatment," Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect tumor burden and / or dysregulation of expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them. Liquid biopsies can be performed on biological samples that are relatively easily obtained from a subject (e.g., by simple blood sampling), and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulation of expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them.In some embodiments, liquid biopsy can be used to detect the presence of dysregulated expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them at an earlier stage than conventional methods. In some embodiments, the biological samples used in liquid biopsy can include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage, bile, lymph, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (for example, using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to detect dysregulated expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them.

[0306] In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs).In some embodiments, liquid biopsy can be used to detect cell-free DNA.In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can identify Ras pathway genes (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, and others). , ERK, or a combination thereof), Ras pathway proteins (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), or dysregulation of the expression or activity or levels of any of them.

[0307] In some embodiments, the ctDNA that originates from a single gene can be detected using liquid biopsy.In some embodiments, the ctDNA that originates from multiple genes (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more or any number of genes between these numbers) can be detected using liquid biopsy. In some embodiments, ctDNA from multiple genes is obtained from a variety of commercially available test populations (e.g., Ras pathway genes (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof), Ras pathway proteins (e.g., NF1, NF2, NF3, NF4, NF5, NF6, NF7, NF8, NF9, NF10, NF11, NF12, NF13, NF14, NF15, NF16, NF17, NF18, NF19, NF20, NF21, NF22, NF23, NF24, NF25, NF26, NF27, NF28, NF29, NF30, NF31, NF32, NF33, NF34, NF35, NF36, NF37, NF38, NF39, NF40, NF41, NF42, NF43, NF44, NF45, NF46, NF47, NF48, NF49, NF50, NF51, NF52, NF53, NF54, NF55, NF56, NF57, NF58, NF59, NF59, NF5 For example, SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof) or a commercially available test population designed to detect dysregulation of the expression or activity or levels of any of them. Liquid biopsies can be used to detect dysregulation of the expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them, including, but not limited to, point mutations or single nucleotide variants (SNVs), copy number variants (CNVs), gene fusions (e.g., translocations or rearrangements), insertions, deletions, or any combination thereof.In some embodiments, liquid biopsy can be used to detect germline mutations. In some embodiments, liquid biopsy can be used to detect somatic mutations. In some embodiments, liquid biopsy can be used to detect primary genetic mutations (e.g., primary mutations or primary fusions associated with the early development of a disease, e.g., cancer). In some embodiments, dysregulated expression, activity, or levels of a Ras pathway gene, Ras pathway protein, or any of them identified using liquid biopsy are also present in cancer cells present in a subject (e.g., in a tumor). In some embodiments, dysregulated expression, activity, or levels of any of the Ras pathway genes, Ras pathway proteins, or any of them described herein can be detected using liquid biopsy. In some embodiments, genetic mutations identified by liquid biopsy can be used to identify a subject as a candidate for a particular treatment. For example, detecting dysregulated expression, activity, or levels of a Ras pathway gene, Ras pathway protein, or any of them in a subject can indicate that the subject will respond to a treatment comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0308] Some embodiments of these methods further comprise administering to the subject at least one dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof between the first and second time points.For example, Ras pathway genes (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTO, NF-κB ... a reduction (e.g., 1% to about 99% reduction, 1% to about 95% reduction, 1% to about 90% reduction, 1% to about 85% reduction, 1% to about 80% reduction, 1% to about 75% reduction, 1% to about 70% reduction, 1% to about 65% reduction, 1% to about 60% reduction, 1% to about 55% reduction, 1% to about 50% reduction, 1% to about 45% reduction, 1% to about 50% reduction, 1% to about 60% reduction, 1% to about 70% reduction, 1% to about 80% reduction, 1% to about 9 ... Reduction to approximately 40% reduction, 1% reduction to approximately 35% reduction, 1% reduction to approximately 30% reduction, 1% reduction to approximately 25% reduction, 1% reduction to approximately 20% reduction, 1% reduction to approximately 15% reduction, 1% reduction to approximately 10% reduction, 1% to approximately 5% reduction, approximately 5% to approximately 99% reduction, approximately 10% to approximately 99% reduction, approximately 15% to approximately 99% reduction, approximately 20% to approximately 99% reduction, approximately 25% to approximately 99% reduction, approximately 30% to approximately 99% reduction, approximately 35% to approximately 99% reduction, approximately 40% to approximately 99% reduction, approximately 45% to approximately 99% reduction, approximately 50% to approximately 99% reduction, approximately 55% to approximately 99% reduction, approximately 60% to approximately 99% reduction, approximately 65% A reduction of about 70% to about 99%, about 75% to about 95%, about 80% to about 99%, about 90% to about 99%, about 95% to about 99%, about 5% to about 10%, about 5% to about 25%, about 10% to about 30%, about 20% to about 40%, about 25% to about 50%, about 35% to about 55%, about 40% to about 60%, about 50% to about 75%, about 60% to about 80%, or about 65% to about 85% indicates that a compound of Formula (I) or a pharmaceutically acceptable salt thereof is effective in a subject. In some embodiments, AF is reduced such that levels are below the detection limit of the instrument.Alternatively, an increase in the dysregulated allele frequency (AF) of Ras pathway genes in cfDNA obtained from the subject at a second time point compared with the dysregulated allele frequency (AF) of Ras pathway genes in cfDNA obtained from the subject at a first time point indicates that the compound of formula (I) or its pharmaceutically acceptable salt is not effective in the subject. Some embodiments of these methods further comprise administering an additional dose of the compound of formula (I) or its pharmaceutically acceptable salt to the subject for whom it is determined that the compound of formula (I) or its pharmaceutically acceptable salt is effective. Some embodiments of these methods can further comprise administering a different treatment to the subject for whom it is determined that the compound of formula (I) or its pharmaceutically acceptable salt is not effective (for example, not including administering the compound of formula (I) or its pharmaceutically acceptable salt as a sole treatment).

[0309] In some examples of these methods, the time difference between the first and second time points is about 1 day to about 1 year, about 1 day to about 11 months, about 1 day to about 10 months, about 1 day to about 9 months, about 1 day to about 8 months, about 1 day to about 7 months, about 1 day to about 6 months, about 1 day to about 5 months, about 1 day to about 4 months, about 1 day to about 3 months, about 1 day to about 10 weeks, about 1 day to about 2 months, about 1 day to about 6 weeks, about 1 day to about 1 month, about 1 day to about 25 days, about 1 day to about 20 days, about 1 day to about 15 days, about 1 day to about 10 days, about 1 day to about 5 days, about 2 days to about 1 year, about 5 days to about 1 year, about 10 days to about 1 year, about 15 days to about 1 year, about 20 days to about 1 year, about 25 ... The period may be one year, about 1 month to about 1 year, about 6 weeks to about 1 year, about 2 months to about 1 year, about 3 months to about 1 year, about 4 months to about 1 year, about 5 months to about 1 year, about 6 months to about 1 year, about 7 months to about 1 year, about 8 months to about 1 year, about 9 months to about 1 year, about 10 months to about 1 year, about 11 months to about 1 year, about 1 day to about 7 days, about 1 day to about 14 days, about 5 to about 10 days, about 5 to about 20 days, about 10 to about 20 days, about 15 days to about 1 month, about 15 days to about 2 months, about 1 week to about 1 month, about 2 weeks to about 1 month, about 1 month to about 3 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 8 months, or about 7 months to about 9 months. In some embodiments of these methods, the subject may have previously been identified as having a cancer with a dysregulated Ras pathway gene (e.g., any of the examples of dysregulated Ras pathway genes described herein). In some embodiments of these methods, the subject may have previously been identified as having any type of cancer described herein. In some embodiments of these methods, the subject may have one or more metastases (e.g., one or more brain metastases).

[0310] In some of the above embodiments, the cfDNA comprises ctDNA, such as Ras pathway-associated (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof)-associated) ctDNA. For example, the cfDNA is ctDNA, such as Ras pathway-associated ctDNA. In some embodiments, at least some portion of the cfDNA is determined to be Ras pathway-associated ctDNA, e.g., a sequenced and / or quantified amount of total cfDNA is determined to have a Ras pathway fusion and / or Ras pathway overexpression.

[0311] Use in combination In the field of medical oncology, it is common practice to use a combination of different forms of treatment to treat each subject with cancer. In clinical oncology, in addition to the compositions described herein, other components of such combination treatments or therapies include, for example, surgery, radiation therapy, and chemotherapeutic agents, such as other Ras pathway inhibitors (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-M The compound of formula (I) or its pharmaceutically acceptable salt may be an inhibitor of ET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof, a kinase inhibitor, a signal transduction inhibitor, and / or a monoclonal antibody. For example, the surgical procedure may be an open surgery or a minimally invasive surgery. Thus, the compound of formula (I) or its pharmaceutically acceptable salt may also be useful as an adjuvant to cancer treatment. For example, they may be used in combination with one or more additional therapies or It may be used in combination with a therapeutic agent, for example, a chemotherapeutic agent that acts by the same or a different mechanism of action. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof may be used before administering an additional therapeutic agent or additional therapy. For example, a subject in need of treatment may be administered one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof for a period of time, and then undergo at least partial tumor resection. In some embodiments, treatment with one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) before at least partial tumor resection. In some embodiments, a subject in need of treatment may be administered one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof for a period of time under one or more cycles of radiation therapy. In some embodiments, treatment with one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) before one or more cycles of radiation therapy.

[0312] As used herein, "Ras pathway targeted therapeutic agent" includes any compound that exhibits inactivation activity of any protein in the Ras pathway (e.g., active site (e.g., competitive) inhibition, allosteric inhibition, dimerization inhibition, expression inhibition, protein-protein interaction inhibition, and induction of degradation). Non-limiting examples of proteins in the Ras pathway include one of the proteins in the Ras-RAF-MAPK pathway or the PI3K / AKT pathway, such as Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof. In some embodiments, the Ras pathway-targeted therapeutic agent can be selective for a protein in the Ras pathway. For example, a Ras pathway-targeted therapeutic agent may be selective for a Ras protein (e.g., KRas, HRas, and / or NRas, or a mutant thereof); such an agent is also referred to as a "Ras modulator." In some embodiments, a Ras modulator is a covalent inhibitor. In some embodiments, a Ras pathway-targeted therapeutic agent may be selective for a particular Ras protein (e.g., KRas, HRas, or NRas) or a mutant thereof (e.g., a G12 mutant, a G13 mutant, or a Q61 mutant). Non-limiting examples of KRas targeted therapeutics (e.g., KRas inhibitors (KRas G12C inhibitors)) include AMG510, ARS-3248, ARS1620, SML-8-73-1, SML-10-70-1, VSA9, AA12, MRTX-849, MRTX849, LY3499446, JNJ-74699157, ARS853, AZD4785, and JNJ-74699157.

[0313] The compound of Formula (I) or a pharmaceutically acceptable salt thereof can be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapeutic agents that act via the same or different mechanisms of action. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be used before the administration of an additional therapeutic agent or additional therapy. For example, a subject in need of treatment can be administered one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof for a period of time, and at least a portion of the tumor can be resected. In some embodiments, treatment with one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) before at least a portion of the tumor is resected. In some embodiments, a subject in need of treatment can be administered one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof for a period of time, under one or more cycles of radiation therapy. In some embodiments, treatment with one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof reduces tumor size (e.g., tumor burden) before one or more cycles of radiation therapy.

[0314] In some embodiments, the one or more additional therapies or therapeutic agents are independently selected from the group consisting of an EGFR inhibitor (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, and olmutinib), an ErbB2 / Her2 inhibitor (e.g., afatinib, lapatinib, trastuzumab, and pertuzumab), an ALK inhibitor (e.g., crizotinib, alectinib, entrectinib, brigatinib), a ROS1 inhibitor (e.g., crizotinib, entrectinib, lorlatinib, ceritinib, and merestinib), a M EK inhibitors (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib), RAS (KRas, HRas, and / or NRas) inhibitors (e.g., MRTX849, LY3499446, JNJ-74699157, AMG10, and AZD4785), Bcr-Abl inhibitors (e.g., imatinib, dasatinib, nilotinib), FGFR1, 2, or 3 inhibitors (e.g., nintedanib), MET inhibitors (e.g., capmatinib), AXL inhibitors (e.g., sitravatinib), RET inhibitors (e.g., sunitinib and cel percatinib), ERK inhibitors (e.g., ulixertinib), Shp2 inhibitors (e.g., RLY-1971, RMC-4630, TNO155, and JAB-3068), Bcl-2 inhibitors (e.g., ABT-263, obatoclax, ABT-737, and navitoclax), mTOR inhibitors (e.g., everolimus and tacrolimus), Trk inhibitors (e.g., larotrectinib and entrectinib), checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and and pidilizumab) or other immunotherapies (e.g., monoclonal antibodies), PARP inhibitors (e.g., olaparib), PI3K inhibitors (e.g., buparlisib), BET inhibitors (e.g., GSK1210151A), Raf inhibitors (e.g., encorafenib), MCL-1 inhibitors (e.g., AZD5991), AKT inhibitors (e.g., miltefosine), PDK1 inhibitors (e.g., GSK2334470) and other chemotherapeutic agents, such as taxanes (e.g., paclitaxel and docetaxel), platinum-based agents (e.g., cisplatin and carboplatin),The inhibitor is selected from cytotoxic agents (e.g., 5-fluorouracil, capecitabine, floxuridine, cytarabine, and gemcitabine), farnesyltransferase inhibitors, topoisomerase inhibitors (e.g., topotecan and irinotecan), DNA synthesis inhibitors (e.g., capecitabine (Xeloda®) and gemcitabine hydrochloride (Gemzar®)), alkylating agents (e.g., temozolomide (Temodar® and Temodal®), dactinomycin (actinomycin-D, also known as Cosmegen®), carmustine (BiCNU®), bendamustine (Treanda®), and lomustine (CeeNU®)), and cytotoxic agents (e.g., vincristine, cytarabine, and pemetrexed).

[0315] Epidermal growth factor receptor (EGFR) inhibitors, such as osimertinib (AZD9291, merelectinib, TAGRISSO®), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA®, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®) , vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITA®, HM61713, BI-1482694), nacotinib (ASP8273), nilotinib (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010, AC0010MA) EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumumab, MDX447, depatuxizumab (humanized mAb806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylalkanenin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, vallitinib (ASL AN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, modotuximab (TAB-H49), futuximab (992DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG595, BDTX-189, avatinib, disruptin, CL-387785, EGFRBi-modified autologous T cells and EGFR CAR-T therapy. In some embodiments, the EGFR targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0316] Human epidermal growth factor receptor 2 (HER2 receptor) (also called Neu, ErbB-2, CD340, or p185) inhibitors, such as trastuzumab (e.g., TRAZIMERA TM , HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA®),TM ), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S-22261 1 and AEE-788.

[0317] In some embodiments, the FGFR inhibitor is selected from infigratinib, AZD4547, erdafitinib (JNJ-42756493), nintedanib, dovitinib, ponatinib, and TAS120.

[0318] In some embodiments, the ALK inhibitor is selected from alectinib, crizotinib (XALKORI®), ceritinib, AP26113, ASP3026, TSR-011, PF-06463922, X-396, and CEP-37440.

[0319] In some embodiments, the ROS1 inhibitor is selected from crizotinib (XALKORI®), ceritinib, lorlatinib, brigatinib, cabozantinib, and repotrectinib.

[0320] In some embodiments, the mTOR inhibitor is selected from everolimus, tacrolimus rapamycin, perifosine, and temsirolimus.

[0321] In some embodiments, the Trk inhibitor is selected from larotrectinib, lestaurtinib, and entrectinib.

[0322] In some embodiments, the RET inhibitor is selected from sunitinib (Sutent®), selpercatinib (RETEVMO®), vandetanib (Caprelsa®), motesanib (AMG706), sorafenib, regorafenib, and danusertib.

[0323] In some embodiments, the MET inhibitor is selected from capmatinib, tepotinib, savolitinib, crizotinib, cabozantinib, tivantinib, bozitinib, merestinib, glesatinib, sitravatinib, onartuzumab, and emibetuzumab.

[0324] In some embodiments, the AXL inhibitor is selected from sitravatinib, bemcentinib, duvelmatinib, DS-1205, SLC-391, INCB081776, ONO-7475, and BA3011.

[0325] In some embodiments, the Shp2 inhibitor is selected from TNO155, BBP-398, JAB-3068, RMC-4360, and RLY-1971.

[0326] In some embodiments, the RAF inhibitor is a BRAF inhibitor, such as vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), encorafenib (BRAFTOVI®), BMS-908662, sorafenib, LGX818, PLX3603, RAF265, RO5185426, GSK2118436, ARQ736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, and LXH254.

[0327] In some embodiments, the PI3K inhibitor is buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPA®, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), selavelisib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG511, CH5132799, GSK1059615, GDC -0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319 and GSK2636771.

[0328] In some embodiments, the AKT inhibitor is miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, MK-2206, epagliflozin, erlotinib, erlotinib, erlotinib-120 ... Selected from delfosine, miltefosine, perifosine, erucylphosphocholine, elfosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine, API-1, ARQ092, BAY1125976, 3-oxo-tirucalic acid, lactoquinomycin, GSK2141795, ONC201, triciribine, A674563 and AT7867.

[0329] In some embodiments, the MEK inhibitor is selected from trametinib (MEKINIST®), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), and hypothemycin.

[0330] In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, L Selected from TT-462, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-oxozeaenol, 5-iodotubercidin, GDC0994 and ONC201.

[0331] In some embodiments, PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.

[0332] In some embodiments, the RAS inhibitor is MRTX849, LY3499446, JNJ-74699157, AMG510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

[0333] In some embodiments, the PDK-1 inhibitor is selected from GSK2334470, JX06, SNS-510, and AR-12.

[0334] In some embodiments, the BET inhibitor is selected from GSK1210151A, GSK525762, OTX-015, TEN-010, CPI-203, CPI-0610, Orinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1, and MS645.

[0335] In some embodiments, the MCL-1 inhibitor is AZD5991.

[0336] In some embodiments, the Bcl-2 protein family inhibitor is selected from ABT-263, tetrocarcin A, antimycin, gossypol ((-)BL-193), obatoclax, HA14-1, oblimersen (Genasense®); (-)-gossypol acetate (AT-101); ABT-737, and navitoclax.

[0337] In some embodiments, the Bcr / Abl kinase inhibitor is selected from imatinib (Gleevec®), inilotinib, nilotinib (Tasigna®), dasatinib (BMS-345825), ponatinib (SKI-606), ponatinib (AP24534), bafetinib (INNO406), danusertib (PHA-739358), AT9283, saracatinib (AZD0530), and PF-03814735.

[0338] In some embodiments, the checkpoint inhibitor is selected from ipilimumab (YERVOY®), pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), IMP701 (LAG525), CPI-444, MBG453, enoblitzumab, JNJ-61610588, and indoximod. See, e.g., Marin-Acevedo, et. al., J Hematol Oncol. 11: 39 (2018).

[0339] In some embodiments, the other immunotherapy is an antibody therapy (e.g., a monoclonal antibody). In some embodiments, the antibody therapy is bevacizumab (Mvasti TM , Avastin®), trastuzumab (Herceptin®), rituximab (MabThera TM , Rituxan®), edrecolomab (Panorex®), daratumab (Darzalex®), olaratumab (Lartruvo®), TM ), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, dinutuximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti®), TM ), necitumumab (Portrazza TM), cirumutuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, urelumab, pidilizumab, and amatuxamab.

[0340] In some embodiments, the other chemotherapeutic agent is an anthracycline, an alkylating agent, a taxane, a platinum-based agent, eribulin (HALAVEN®), or a combination thereof. TM ), farnesyltransferase inhibitors, topoisomerase inhibitors, DNA synthesis inhibitors and cytotoxic agents.

[0341] In some embodiments, the taxane is selected from paclitaxel, docetaxel, cabazitaxel, abraxane, and taxotere.

[0342] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0343] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedoplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.

[0344] In some embodiments, the farnesyltransferase inhibitor is selected from lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0345] In some embodiments, the topoisomerase inhibitor is a topoisomerase I inhibitor (e.g., irinotecan (Camptosar®), topotecan (Hycamtin®), and 7-ethyl-10-hydroxycamptothecin (SN38)) or a topoisomerase II inhibitor (e.g., etoposide (Toposar®, VePesid®, and Etopophos®), teniposide (VM-26, Vumon®), and tafluposide).

[0346] In some embodiments, the DNA synthesis inhibitor is selected from capecitabine (Xeloda®), gemcitabine hydrochloride (Gemzar®), nelarabine (Arranon® and Atriance®), and sapacitabine.

[0347] In some embodiments, the alkylating agent is temozolomide (Temodar® and Temodal®), dactinomycin (actinomycin-D, also known as Cosmegen®), melphalan (Alkeran®), altretamine (Hexalen®), carmustine (BiCNU®), bendamustine (Treanda®), busulfan (Busulfex® and Myleran®), lomustine (CeeNU®), or fluconazole (Fentan®). The antihistamines are selected from the group consisting of fluticasone (fluticasone), chlorambucil (Leukeran®), cyclophosphamide (Cytoxan® and Neosar®), dacarbazine (DTIC-Dome®), altretamine (Hexalen®), ifosfamide (Ifex®), prednummustine, procarbazine (Matulane®), mechlorethamine (Mustargen®), streptozocin (Zanosar®), and thiotepa (thioplex®).

[0348] In some embodiments, the cytotoxic agent is selected from bleomycin, cytarabine, dacarbazine, methotrexate, mitomycin C, pemetrexed, and vincristine.

[0349] Also provided herein are: (i) a pharmaceutical combination for treating cancer in a subject in need thereof, comprising (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate, or sequential use for treating cancer, wherein the amounts of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the amounts of the additional therapeutic agent are both effective for treating cancer; (ii) a pharmaceutical composition comprising such a pharmaceutical combination; (iii) the use of such a combination for the manufacture of a medicament for treating cancer; and (iv) a commercial package or article of manufacture comprising such a combination as a combination product for simultaneous, separate, or sequential use; for use in a method for treating cancer in a subject in need thereof. In some embodiments, the cancer is a Ras pathway-associated cancer (e.g., an SOS1-associated cancer, a Ras-associated cancer (e.g., a KRas-associated cancer, an HRas-associated cancer, and / or an NRas-associated cancer), an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an IGF1R-associated cancer, an INSR-associated cancer, an ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c-MET-associated cancer, a VEGFR1-associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL-associated cancer, an SHP2-associated cancer, a RAF-associated cancer (e.g., a BRAF-associated cancer), a PI3K-associated cancer, an AKT-associated cancer, an mTOR-associated cancer, a MEK-associated cancer, an ERK-associated cancer, or a combination thereof).

[0350] The term "pharmaceutical combination" as used herein refers to a mixture or combination of more than one active ingredient, including fixed and non-fixed combinations of active ingredients.The term "fixed combination" means that the compound of formula (I) or its pharmaceutically acceptable salt and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are both administered to a subject in a single composition or dosage.The term "non-fixed combination" means that the compound of formula (I) or its pharmaceutically acceptable salt and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are formulated as separate compositions or dosages so that they can be administered simultaneously, together or sequentially to a subject in need of treatment, with various time interval restrictions, and wherein such administration provides effective levels of two or more compounds in the subject's body.

[0351] Therefore, also provided herein is a method for treating cancer, comprising (a) administering to a subject in need of treatment a combination pharmaceutical composition for treating cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and (b) an additional therapeutic agent, wherein the compound of formula (I) and the additional therapeutic agent are administered simultaneously, separately, or sequentially, and wherein the amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are both effective for treating cancer.In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously as separate doses.In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered sequentially as separate doses in any order, in a jointly effective amount, for example, in a daily or intermittent dose.In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously as a combined dose. In some embodiments, the cancer is a Ras pathway-associated cancer (e.g., an SOS1-associated cancer, a Ras-associated cancer (e.g., a KRas-associated cancer, an HRas-associated cancer, and / or an NRas-associated cancer), an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an IGF1R-associated cancer, an INSR-associated cancer, an ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c-MET-associated cancer, a VEGFR1-associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL-associated cancer, an SHP2-associated cancer, a RAF-associated cancer (e.g., a BRAF-associated cancer), a PI3K-associated cancer, an AKT-associated cancer, an mTOR-associated cancer, a MEK-associated cancer, an ERK-associated cancer, or a combination thereof).

[0352] Therefore, also provided herein is a method for inhibiting, preventing, promoting prevention, or reducing symptoms of cancer metastasis in a subject in need of treatment, comprising administering to the subject an effective amount of a compound of formula (I) or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof. Such a method can be used to treat one or more of the cancers described herein. See, for example, U.S. Patent Publication No. 2013 / 0029925; International Publication No. WO2014 / 083567; and U.S. Patent No. 8,568,998. See also, e.g., Hezam K et al., Rev Neurosci 2018 Jan 26;29:93-98; Gao L, et al., Pancreas 2015 Jan;44:134-143; Ding K et al., J Biol Chem 2014 Jun 6;289:16057-71; and Amit M et al., Oncogene 2017 Jun 8;36:3232-3239. In some embodiments, the cancer is a Ras pathway-associated cancer (e.g., an SOS1-associated cancer, a Ras-associated cancer (e.g., a KRas-associated cancer, an HRas-associated cancer, and / or an NRas-associated cancer), an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an IGF1R-associated cancer, an INSR-associated cancer, an ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c-MET-associated cancer, a VEGFR1-associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL-associated cancer, an SHP2-associated cancer, a RAF-associated cancer (e.g., a BRAF-associated cancer), a PI3K-associated cancer, an AKT-associated cancer, an mTOR-associated cancer, a MEK-associated cancer, an ERK-associated cancer, or a combination thereof). In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is used in combination with another therapeutic agent, such as an additional therapy or therapeutic agent described herein.

[0353] The term "metastasis" is a term known in the art and refers to the formation of an additional tumor (e.g., a solid tumor) in a subject at a site distant from the primary tumor, wherein the additional tumor contains the same or similar cancer cells as the primary tumor.

[0354] A method for treating a Ras pathway-associated cancer (e.g., SOS1-associated cancer, Ras-associated cancer (e.g., KRas-associated cancer, HRas-associated cancer, and / or NRas-associated cancer), EGFR-associated cancer, ErbB2-associated cancer, ErbB3-associated cancer, ErbB4-associated cancer, NF1-associated cancer, PDGFR-A-associated cancer, PDGFR-B-associated cancer, FGFR1-associated cancer, FGFR2-associated cancer), comprising selecting, identifying, or diagnosing a subject as having a Ras pathway-associated cancer, and administering to the subject selected, identified, or diagnosed as having a Ras pathway-associated cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein are methods for reducing the risk of developing metastasis or further metastasis in a subject with a Ras pathway-associated cancer, including a Ras pathway-associated cancer, an FGFR3-associated cancer, an IGF1R-associated cancer, an INSR-associated cancer, an ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c-MET-associated cancer, a VEGFR1-associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL-associated cancer, a SHP2-associated cancer, a RAF-associated cancer (e.g., a BRAF-associated cancer), a PI3K-associated cancer, an AKT-associated cancer, an mTOR-associated cancer, a MEK-associated cancer, an ERK-associated cancer, or a combination thereof. Also provided herein are methods for reducing the risk of developing metastasis or further metastasis in a subject with a Ras pathway-associated cancer, including administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The risk reduction of metastasis or further metastasis in the subject with Ras pathway-related cancer can be compared with the risk of metastasis or further metastasis in the subject before treatment, or can be compared with the subject or group of subjects with similar or identical Ras pathway-related cancer that have not received treatment or have received different treatment.In some embodiments, the additional therapeutic agent is selected from MRTX849, LY3499446, JNJ-74699157, AMG510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12 and MRTX-849.In some embodiments, the subject has been administered one or more doses of the compound of formula (I) or its pharmaceutically acceptable salt before administering the pharmaceutical composition.

[0355] Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject with a Ras-associated cancer, comprising selecting, identifying, or diagnosing the subject as having a Ras-associated cancer, and administering to the subject selected, identified, or diagnosed with a Ras-associated cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject with a Ras-associated cancer, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduced risk of developing metastasis or further metastasis in a subject with a Ras-associated cancer can be compared to the risk of developing metastasis or further metastasis in the subject before treatment, or can be compared to a subject or population of subjects with a similar or identical Ras-associated cancer that has not received treatment or has received a different treatment. In some embodiments, the additional therapeutic agent is selected from MRTX849, LY3499446, JNJ-74699157, AMG510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12 and MRTX-849. In some embodiments, the subject has been administered one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0356] Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject with a KRas-associated cancer, comprising selecting, identifying, or diagnosing the subject as having a KRas-associated cancer, and administering to the subject selected, identified, or diagnosed with a KRas-associated cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject with a KRas-associated cancer, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduced risk of developing metastasis or further metastasis in a subject with a KRas-associated cancer can be compared to the risk of developing metastasis or further metastasis in the subject before treatment, or can be compared to a subject or population of subjects with a similar or identical KRas-associated cancer that has not received treatment or has received a different treatment. In some embodiments, the additional therapeutic agent is selected from MRTX849, LY3499446, JNJ-74699157, AMG510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12 and MRTX-849. In some embodiments, the subject has been administered one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0357] Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject having an HRas-associated cancer, comprising selecting, identifying, or diagnosing the subject as having an HRas-associated cancer, and administering to the subject selected, identified, or diagnosed with an HRas-associated cancer an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject having an HRas-associated cancer, comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The reduced risk of developing metastasis or further metastasis in a subject having an HRas-associated cancer can be compared to the risk of developing metastasis or further metastasis in the subject before treatment, or can be compared to a subject or population of subjects with a similar or identical HRas-associated cancer that has not received treatment or that has received a different treatment. In some embodiments, the additional therapeutic agent is selected from MRTX849, LY3499446, JNJ-74699157, AMG510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12 and MRTX-849. In some embodiments, the subject has been administered one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0358] Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject with an NRas-associated cancer, comprising selecting, identifying, or diagnosing the subject as having an NRas-associated cancer, and administering to the subject selected, identified, or diagnosed with an NRas-associated cancer an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject with an NRas-associated cancer, comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The reduced risk of developing metastasis or further metastasis in a subject with an NRas-associated cancer can be compared to the risk of developing metastasis or further metastasis in the subject before treatment, or can be compared to a subject or population of subjects with a similar or identical NRas-associated cancer that has not received treatment or that has received a different treatment. In some embodiments, the additional therapeutic agent is selected from MRTX849, LY3499446, JNJ-74699157, AMG510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12 and MRTX-849. In some embodiments, the subject has been administered one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0359] Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject having an SOS1-associated cancer, comprising selecting, identifying, or diagnosing the subject as having an SOS1-associated cancer, and administering to the subject selected, identified, or diagnosed with an SOS1-associated cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for reducing the risk of developing metastasis or further metastasis in a subject having an SOS1-associated cancer, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduced risk of developing metastasis or further metastasis in a subject having an SOS1-associated cancer can be compared to the risk of developing metastasis or further metastasis in the subject before treatment, or can be compared to a subject or population of subjects with a similar or identical SOS1-associated cancer that has not received treatment or that has received a different treatment. In some embodiments, the additional therapeutic agent is selected from MRTX849, LY3499446, JNJ-74699157, AMG510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12 and MRTX-849. In some embodiments, the subject has been administered one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0360] The phrase "risk of developing metastases" refers to the formation of additional tumors (e.g., solid tumors) at sites distant from the primary tumor in a subject, and refers to the risk that a subject with a primary tumor will develop additional tumors (e.g., solid tumors) at sites distant from the primary tumor in the subject over a period of time, wherein the additional tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing metastases in a subject with cancer are described herein.

[0361] The phrase "risk of developing additional metastases" refers to the risk that a subject who has a primary tumor and one or more additional tumors at sites distant from the primary tumor, where the one or more additional tumors contain the same or similar cancer cells as the primary tumor, will develop one or more additional tumors at sites distant from the primary tumor, where the additional tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0362] Treating a subject with cancer with a multikinase inhibitor (MKI) or a target-specific kinase inhibitor (e.g., a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROS1 inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, a RET inhibitor, or a RAS inhibitor) can reduce or eliminate Ras pathway genes (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, S The dysregulation of the expression or activity or levels of proteins involved in the progression of the disease may result in dysregulation of the expression or activity or levels of proteins involved in the progression of the disease, such as HP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof, Ras pathway proteins (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof). See, e.g., Bhinge et al., Oncotarget 8:27155-27165, 2017; Chang et al., Yonsei Med. J. 58:9-18, 2017; and Lopez-Delisle et al., doi: 10.1038 / s41388-017-0039-5, Oncogene 2018.

[0363] Treating a subject having cancer with a combination of an SOS1 inhibitor and a multikinase inhibitor or a target-specific kinase inhibitor (e.g., a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROS1 inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, a RET inhibitor, or a RAS inhibitor) may result in increased therapeutic efficacy compared to treatment of the same or similar subject with an SOS1 inhibitor as monotherapy, or a multikinase inhibitor or a target-specific kinase inhibitor as monotherapy. For example, Tang et al., doi: 10.1038 / modpathol.2017.109, Mod. Pathol. 2017; Andreucci et al., Oncotarget 7:80543-80553, 2017; Nelson-Taylor et al., Mol. Cancer Ther. 16:1623-1633, 2017; and Kato et al., See Clin. Cancer Res. 23:1988-1997, 2017.

[0364] Provided herein are methods for treating a subject having cancer (e.g., any of the cancers described herein) and who has previously been administered a multikinase inhibitor (MKI) or a target-specific kinase inhibitor (e.g., a Ras inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROS1 inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, a RET inhibitor, or a RAS inhibitor) (e.g., as monotherapy), the method comprising administering to the subject (i) an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as monotherapy, or (ii) an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an effective amount of the previously-administered MKI or the previously-administered target-specific kinase inhibitor.

[0365] Also provided herein is a method for inhibiting SOS1 activity in mammalian cells, comprising contacting the mammalian cells with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having mammalian cells with SOS1 activity. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any of the cancers described herein. In some embodiments, the mammalian cancer cell is a Ras pathway-related cancer (e.g., an SOS1-related cancer, a Ras-related cancer (e.g., a KRas-related cancer, an HRas-related cancer, and / or an NRas-related cancer), an EGFR-related cancer, an ErbB2-related cancer, an ErbB3-related cancer, an ErbB4-related cancer, an NF1-related cancer, a PDGFR-A-related cancer, a PDGFR-B-related cancer, an FGFR1-related cancer, an FGFR2-related cancer, an FGFR3-related cancer, an IGF1R-related cancer, an INSR-related cancer, an ALK-related cancer, a ROS-related cancer, a TrkA-related cancer, a TrkB-related cancer, a TrkC-related cancer, a RET-related cancer, a c-MET-related cancer, a VEGFR1-related cancer, a VEGFR2-related cancer, a VEGFR3-related cancer, an AXL-related cancer, an SHP2-related cancer, a RAF-related cancer (e.g., a BRAF-related cancer), a PI3K-related cancer, an AKT-related cancer, an mTOR-related cancer, a MEK-related cancer, an ERK-related cancer, or a combination thereof) cell.

[0366] Also provided herein is a method for inhibiting Ras activity in mammalian cells, comprising contacting the mammalian cells with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having mammalian cells with Ras activity. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any of the cancers described herein. In some embodiments, the mammalian cancer cell is a Ras pathway-related cancer (e.g., an SOS1-related cancer, a Ras-related cancer (e.g., a KRas-related cancer, an HRas-related cancer, and / or an NRas-related cancer), an EGFR-related cancer, an ErbB2-related cancer, an ErbB3-related cancer, an ErbB4-related cancer, an NF1-related cancer, a PDGFR-A-related cancer, a PDGFR-B-related cancer, an FGFR1-related cancer, an FGFR2-related cancer, an FGFR3-related cancer, an IGF1R-related cancer, an INSR-related cancer, an ALK-related cancer, a ROS-related cancer, a TrkA-related cancer, a TrkB-related cancer, a TrkC-related cancer, a RET-related cancer, a c-MET-related cancer, a VEGFR1-related cancer, a VEGFR2-related cancer, a VEGFR3-related cancer, an AXL-related cancer, an SHP2-related cancer, a RAF-related cancer (e.g., a BRAF-related cancer), a PI3K-related cancer, an AKT-related cancer, an mTOR-related cancer, a MEK-related cancer, an ERK-related cancer, or a combination thereof) cell.

[0367] Also provided herein is a method for inhibiting SOS1-Ras (e.g., KRas, HRas, and / or NRas) protein-protein interaction in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell with SOS1-Ras (e.g., KRas, HRAs, and / or NRas) protein-protein interaction. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any of the cancers described herein. In some embodiments, the mammalian cancer cell is a Ras pathway-related cancer (e.g., an SOS1-related cancer, a Ras-related cancer (e.g., a KRas-related cancer, an HRas-related cancer, and / or an NRas-related cancer), an EGFR-related cancer, an ErbB2-related cancer, an ErbB3-related cancer, an ErbB4-related cancer, an NF1-related cancer, a PDGFR-A-related cancer, a PDGFR-B-related cancer, an FGFR1-related cancer, an FGFR2-related cancer, an FGFR3-related cancer, an IGF1R-related cancer, an INSR-related cancer, an ALK-related cancer, a ROS-related cancer, a TrkA-related cancer, a TrkB-related cancer, a TrkC-related cancer, a RET-related cancer, a c-MET-related cancer, a VEGFR1-related cancer, a VEGFR2-related cancer, a VEGFR3-related cancer, an AXL-related cancer, an SHP2-related cancer, a RAF-related cancer (e.g., a BRAF-related cancer), a PI3K-related cancer, an AKT-related cancer, an mTOR-related cancer, a MEK-related cancer, an ERK-related cancer, or a combination thereof) cell.

[0368] Also provided herein is a method for inhibiting Ras pathway activity in mammalian cells, comprising contacting the mammalian cells with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having mammalian cells with Ras pathway activity. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any of the cancers described herein. In some embodiments, the mammalian cancer cell is a Ras pathway-related cancer (e.g., an SOS1-related cancer, a Ras-related cancer (e.g., a KRas-related cancer, an HRas-related cancer, and / or an NRas-related cancer), an EGFR-related cancer, an ErbB2-related cancer, an ErbB3-related cancer, an ErbB4-related cancer, an NF1-related cancer, a PDGFR-A-related cancer, a PDGFR-B-related cancer, an FGFR1-related cancer, an FGFR2-related cancer, an FGFR3-related cancer, an IGF1R-related cancer, an INSR-related cancer, an ALK-related cancer, a ROS-related cancer, a TrkA-related cancer, a TrkB-related cancer, a TrkC-related cancer, a RET-related cancer, a c-MET-related cancer, a VEGFR1-related cancer, a VEGFR2-related cancer, a VEGFR3-related cancer, an AXL-related cancer, an SHP2-related cancer, a RAF-related cancer (e.g., a BRAF-related cancer), a PI3K-related cancer, an AKT-related cancer, an mTOR-related cancer, a MEK-related cancer, an ERK-related cancer, or a combination thereof) cell.

[0369] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" an SOS1 protein with a compound provided herein includes administering a compound provided herein to a subject, e.g., a human having an SOS1 protein, and, for example, introducing a compound provided herein into a sample containing mammalian cells or a purified product containing an SOS1 protein.

[0370] Also provided herein are methods for inhibiting mammalian cell proliferation in vitro or in vivo, which comprise contacting a mammalian cell with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0371] The phrase "effective amount" refers to an amount that, when administered to a subject in need of treatment, (i) effectively treats a Ras pathway-associated disease or disorder (e.g., a Ras pathway-associated cancer (e.g., an SOS1-associated cancer, a Ras-associated cancer (e.g., a KRas-associated cancer, an HRas-associated cancer, and / or an NRas-associated cancer), an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an IGF1R-associated cancer, an INSR-associated cancer, an ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, "TrkC-related cancer, RET-related cancer, c-MET-related cancer, VEGFR1-related cancer, VEGFR2-related cancer, VEGFR3-related cancer, AXL-related cancer, SHP2-related cancer, RAF-related cancer (e.g., BRAF-related cancer), PI3K-related cancer, AKT-related cancer, mTOR-related cancer, MEK-related cancer, ERK-related cancer, or a combination thereof)," (ii) reduce, ameliorate, or eliminate one or more symptoms of the specific disease, condition, or disorder described herein, or (iii) delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein. The amount of the compound of formula (I) or its pharmaceutically acceptable salt corresponding to such an amount varies depending on the specific compound, the disease state and its severity, individual differences (e.g., body weight) of the subject requiring treatment, etc., but can nevertheless be determined appropriately by one skilled in the art.

[0372] Pharmaceutical Composition When used as a pharmaceutical, the compounds of formula (I), including their pharmaceutically acceptable salts, can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods known in the pharmaceutical arts and can be administered by a variety of routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epithelial, ocular, and mucosal delivery, including intranasal, vaginal, and rectal), pulmonary (e.g., inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Oral administration can include dosage forms formulated for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0373] Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable excipients. For example, a pharmaceutical composition prepared using a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is suitable for topical administration. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When used as a diluent, an excipient can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, bottles, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing up to 10% of active compounds, soft gelatin and hard gelatin capsules, suppositories, sterile injection solutions and sterile packaged powders.In some embodiments, the composition can be formulated for oral administration.In some embodiments, the composition is a solid oral formulation.In some embodiments, the composition is formulated as tablets or capsules.

[0374] Further provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.The pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by intimately mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.The carrier can take a variety of forms depending on the desired route of administration (e.g., oral, parenteral).In some embodiments, the composition is a solid oral composition.

[0375] Suitable pharmaceutically acceptable carriers are known in the art, and a description of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0376] Methods for formulating pharmaceutical compositions are described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0377] Any common pharmaceutical medium can be used to prepare compositions for oral administration.Therefore, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc.; for solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or β-lactose, corn syrup, natural and synthetic gums such as acacia and tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Solid oral preparations can also be coated with a substance such as sugar, or enteric-coated to adjust the main absorption site. For parenteral administration, the carrier usually consists of sterile water, and other ingredients may be added to improve solubility or preservation. Injectable suspensions or solutions can also be prepared by utilizing aqueous carriers with suitable additives. The pharmaceutical composition contains the amount of active ingredient required to deliver the effective dose described herein per dosage unit, for example, tablet, capsule, powder, injection, or teaspoonful.

[0378] Compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated into a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human and other subjects, each unit containing a predetermined amount of the active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0379] In some embodiments, compositions containing about 5 mg to about 50 mg of active ingredient are provided herein. Those skilled in the art will understand that this includes compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of active ingredient.

[0380] In some embodiments, provided herein are compositions containing about 50 mg to about 500 mg of active ingredient. Those skilled in the art will understand that this includes compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of active ingredient. In some embodiments, provided herein are compositions containing about 10 mg, about 20 mg, about 80 mg, or about 160 mg of active ingredient.

[0381] In some embodiments, compositions containing about 500 mg to about 1,000 mg of active ingredient are provided herein. Those skilled in the art will understand that this includes compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

[0382] The daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof can vary over a wide range, from 1.0 to 10,000 mg / adult per day or more, or any of the ranges therein. For oral administration, the composition is preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250, and 500 milligrams of active ingredient, with the dosage to be adjusted symptomatically to the subject being treated. An effective amount of the drug is usually supplied at a dosage level of about 0.1 mg / kg to about 1,000 mg / kg body weight per day, or any range therebetween. Preferably, the range is about 0.5 to about 500 mg / kg body weight per day, or any range therebetween. More preferably, the dosage level is about 1.0 to about 250 mg / kg body weight per day, or any range therebetween. More preferably, the dosage level is about 0.1 to about 100 mg / kg body weight / day, or any range therebetween. In one example, the range may be about 0.1 to about 50.0 mg / kg body weight / day, or any amount or range therebetween. In another example, the range may be about 0.1 to about 15.0 mg / kg body weight / day, or any amount or range therebetween. In yet another example, the range may be about 0.5 to about 7.5 mg / kg body weight / day, or any amount or range therebetween. The pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered on a regimen of 1 to 4 times per day or in a single daily dose.

[0383] Active compound can be effective in a wide range of dosage, and generally administered in a pharmaceutically effective amount.The optimal dosage to be administered can be easily determined by those skilled in the art.Therefore, it is understood that the amount of compound actually administered is usually determined by a doctor and varies according to the relevant circumstances, including administration method, strength of the administered preparation, the condition to be treated and the progression of disease state.In addition, factors related to the specific subject to be treated, including subject response, age, body weight, diet, administration time and the severity of the subject's symptoms, will result in the need to adjust dosage.

[0384] In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg, or from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, it may be administered in an amount of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, such administration may be once daily or twice daily (BID).

[0385] Those skilled in the art will appreciate that both in vivo and in vitro testing using appropriate, known and generally accepted cellular and / or animal models will predict the efficacy of a test compound for treating or preventing a given disorder.

[0386] Those skilled in the art will further appreciate that human clinical trials, including first-in-human, dose-ranging and efficacy studies, in healthy subjects and / or subjects with a given disorder can be completed according to methods known in the clinical trial and medical arts.

[0387] Provided herein is a pharmaceutical kit useful for treating diseases or disorders associated with the Ras pathway, such as cancer, comprising one or more containers containing a pharmaceutical composition comprising an effective amount of the compound provided herein.As will be apparent to those skilled in the art, such kits may further comprise, if desired, one or more of various conventional pharmaceutical kit components, such as one or more containers containing one or more pharmaceutically acceptable carriers, additional containers, etc.Instructions such as package inserts or labels indicating the quality of the components to be administered, directions for administration, and / or directions for mixing the components may also be included in the kit. [Example]

[0388] material and method The compounds provided herein, including their salts, can be prepared using known organic synthesis techniques, or can be prepared according to any of a number of possible synthetic routes.

[0389] The reactions to prepare the compounds provided herein can be carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, from the freezing point of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction step, an appropriate solvent for a particular reaction step can be selected by one skilled in the art.

[0390] The preparation of the compounds provided herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. Protecting group chemistry can be found in Protecting Group Chemistry, 1st Ed., Oxford University Press, 2000; March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed., Wiley-Interscience Publication, 2001; and Peturssion, S. et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 74(11), 1297 (1997).

[0391] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible spectroscopy), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preative LC-MS Purification: Improved Compound Specific Method Optimization" KF Blom, et al., J. Combi. Chem. 6(6), 874 (2004)), normal-phase silica chromatography, and supercritical fluid chromatography (SFC).

[0392] All solvents and reagents were obtained from commercial sources and used without further purification unless otherwise noted. Anhydrous solvents were purchased and used as supplied. Reactions were monitored by thin-layer chromatography (TLC) and visualized with a UV lamp (254 nm) and KMnO4 stain. NMR spectra were obtained on a Bruker Neo 400M spectrometer operating at 400 MHz. Chemical shifts are reported in parts per million (δ) from the tetramethylsilane resonance in the indicated solvent. LC-mass spectra were performed using an Agilent 1260-6125B single quadrupole mass spectrometer with a Welch Biomate column (C18, 2.7 μm, 4.6 × 50 mm) or a Waters H-Class SQD2 system. Detection was performed by DAD (254 nm, 210 nm, and 280 nm). Chiral HPLC was performed on a Waters acquity UPC2 system using a base-containing Daicel Chiralpak AD-H (5 μm, 4.6 × 250 mm), Daicel Chiralpak OD-H (5 μm, 4.6 × 250 mm), Daicel Chiralpak IG-3 (3 μm, 4.6 × 150 mm), Chiral Technologies Europe AD-3 (3 μm, 3.0 × 150 mm), and Trefoil™ Technology Trefoil™ AMY1 (2.5 μm, 3.0 × 150 mm). Detection was by DAD (254 nm). Preparative HPLC was performed on a Gilson Trilution LC system using a Welch XB-C18 column (5 μm, 21.2 × 150 mm). Flash chromatography was performed on a Biotage Isolera Prime system using Welch WelFlash flash columns (40-63 μm). Unless otherwise stated, all synthesized compounds were ≥95% pure.

[0393] Abbreviation °C = degrees Celsius 1 H NMR = proton nuclear magnetic resonance spectrum ACN = acetonitrile AcOH = acetic acid BAST = bis(2-methoxyethyl)aminosulfur trifluoride DAST = diethylaminosulfur trifluoride Boc = tert-butoxycarbonyl con.=con. d=double term DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DMF = N,N-dimethylformamide DMF-DMA = dimethylformamide dimethyl acetal DMSO = dimethyl sulfoxide Et = ethyl EtOAc (or EA) = ethyl acetate EtOH = ethanol ESI = electrospray ionization g = grams hr=hour HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC = High-Performance Liquid Chromatography IBX = 2-iodoxybenzoic acid IPA = 2-propanol LCMS = Liquid Chromatography-Mass Spectrum M=mass m / z=mass-to-charge ratio Me = methyl MeCN = acetonitrile MeOH = methanol MeONa = sodium methoxide mg = milligram mL = milliliters mmol = micromolar mol = mole MS = mass spectrum NBS = N-bromosuccinimide obsd. = observed value Pd(OAc)2 = palladium(II) acetate Pd(dppf)Cl2 = (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) chloride Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0) PE = petroleum ether ppm=parts per million rt=room temperature RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl RuPhos-Pd-G3 = (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate s=singlet T3P = propylphosphonic anhydride t=triplet TBAF = tetrabutylammonium fluoride tBu = tert-butyl TEA = triethylamine Tf = trifluoromethanesulfonate TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography XantPhos = (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) XantPhos-Pd-G3 = [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0394] Intermediate 1: 6-Cyclopropyl-2-methyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione [ka] Step A: 3-(tert-butyl) 4-methyl 1-cyclopropyl-6-oxo-1,6-dihydropyridine-3,4-dicarboxylate To a solution of cyclopropanamine (4.53 g, 79.27 mmol, 5.49 mL) in EtOH / HO (450 mL / 4 mL) was added tert-butyl prop-2-ynoate (10 g, 79.27 mmol, 10.88 mL). The mixture was stirred at room temperature for 16 h, after which dimethyl but-2-yndioate (11.26 g, 79.27 mmol, 9.71 mL) was added, and the mixture was stirred at 85 °C for 16 h. The mixture was cooled to room temperature, concentrated, and purified by flash column chromatography (0–25% ethyl acetate in petroleum ether) to give 3-(tert-butyl) 4-methyl 1-cyclopropyl-6-oxo-1,6-dihydropyridine-3,4-dicarboxylate (9.12 g, 31.09 mmol, 39% yield) as a yellow liquid. MS (ESI) + ):294.2[(M+H) + ].

[0395] Step B: 5-(tert-butoxycarbonyl)-1-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid 3-(tert-Butyl) 4-methyl 1-cyclopropyl-6-oxo-1,6-dihydropyridine-3,4-dicarboxylate (3.2 g, 10.90 mmol, 1.0 equiv.) was dissolved in MeOH / HO (24 mL / 6 mL). LiOH (393 mg, 16.4 mmol, 1.5 equiv.) was added to the solution at 0 °C. The solution was then stirred at room temperature for 2 h and concentrated. Ethyl acetate and water were added to the crude mixture. The mixture was adjusted to pH 5-6 by adding 2 M HCl, extracted with ethyl acetate (50 mL × 3), and the combined organic phase was dried and concentrated to give 5-(tert-butoxycarbonyl)-1-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (2.8 g, 10.07 mmol, 98%) as a light yellow solid. MS (ESI) + ):280.2[(M+H) + ].

[0396] Step C: tert-Butyl 4-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl)-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate 5-(tert-Butoxycarbonyl)-1-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (2.9 g, 10.38 mmol) was dissolved in THF (30 mL) and DIPEA (1.61 g, 12.46 mmol), HATU (4.74 g, 12.46 mmol, 1.2 equiv.), and tert-butyl 2-methylhydrazine-1-carboxylate (1.82 g, 12.46 mmol) were added. The solution was stirred at room temperature for 2 h, then concentrated down to low volume and partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (50 mL). The organic phase was washed with brine (30 mL), dried, concentrated, and purified by flash column chromatography (10–100% ethyl acetate in petroleum ether) to give tert-butyl 4-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl)-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate as a white solid (4.14 g, 10.16 mmol, 97% yield). MS (ESI) + ):408.4[(M+H) + ].

[0397] Step D: 6-cyclopropyl-2-methyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione A mixture of tert-butyl 4-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl)-1-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (4.01 g, 9.82 mmol, 1.0 equiv.) and HCl (4 M in 1,4-dioxane, 90 mL) was stirred at room temperature for 30 minutes and then heated at 100° C. for 30 minutes. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (10 mL × 3) to give 6-cyclopropyl-2-methyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione (1.66 g, 7.12 mmol, 73% yield) as a yellow solid. MS (ESI) data + ):234.4[(M+H) + ].

[0398] Example 1: (R)-6-Cyclopropyl-2-methyl-4-((1-(naphthalen-1-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione [ka] Step A: 6-cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl trifluoromethanesulfonate A solution of 6-cyclopropyl-2-methyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione (100 mg, 0.43 mmol) and pyridine (50.87 mg, 643.16 μmol) in DCM (1.5 mL) was cooled to 0 °C under N2. A solution of trifluoromethanesulfonic anhydride (181.46 mg, 643.16 μmol) in DCM (1.5 mL) was added, and the mixture was stirred at 0 °C for 1 h. The mixture was diluted with DCM (20 mL) and quenched with water (5 mL). The organic phase was dried, concentrated, and purified by flash column chromatography (0–100% ethyl acetate in cyclohexane) to give 6-cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl trifluoromethanesulfonate (102 mg, 0.28 mmol, 65% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.04(s, 1H), 7.35(s, 1H), 3.63(s, 3H), 3.59-3.54(m, 1H), 1.35-1.31(m, 2H), 1.01-0.95(m, 2H).

[0399] Step B: (R)-6-Cyclopropyl-2-methyl-4-((1-(naphthalen-1-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione A solution of 6-cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl trifluoromethanesulfonate (30 mg, 0.082 mmol), (R)-1-(naphthalen-1-yl)ethan-1-amine (16.88 mg, 0.098 mmol), CsCO (53.5 mg, 0.16 mmol), and Xantphos (4.75 mg, 0.008 mmol) in 1,4-dioxane (1.0 mL) was degassed with N for 5 min, after which Pd(dba) (7.5 mg, 0.0081 mmol) was added, and the mixture was heated at 100 °C for 20 h. The reaction mixture was concentrated, and the residue was taken up in DMSO and purified by reverse-phase HPLC to give (R)-6-cyclopropyl-2-methyl-4-((1-(naphthalen-1-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (3.1 mg, 0.008 mmol, 9% yield) as a yellow solid. MS (ESI+): 387.3 [(M+H) + ].

[0400] Example 2: (R)-6-Cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethylamino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione [ka] Step A: 6-cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl 2,4,6-triisopropylbenzenesulfonate 6-Cyclopropyl-2-methyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione (400 mg, 1.7 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (658 mg, 5.1 mmol, 3.0 equiv.) were dissolved in DCM (20 mL) and 2,4,6-triisopropylbenzenesulfonyl chloride (566 mg, 1.87 mmol, 1.1 equiv.) was added under N2 at 0 °C. The mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was concentrated, and the crude mixture was washed with saturated sodium bicarbonate solution (50 mL) and extracted with DCM (150 mL). The organic phase was dried over sodium sulfate, concentrated, and purified by flash column chromatography (10–20% ethyl acetate in petroleum ether) to give 6-cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl 2,4,6-triisopropylbenzenesulfonate (560 mg, 1.12 mmol, 66% yield) as a yellow solid. MS (ESI) data. + ):500.5[(M+H) + ].

[0401] Step B: (R)-6-Cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione Under N2, 6-cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl 2,4,6-triisopropylbenzenesulfonate (50 mg, 0.10 mmol, 1.0 equiv.), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (28 mg, 0.12 mmol, 1.2 equiv.), XantPhos Pd G3 (9 mg, 0.01 mmol, 0.1 equiv.), and Cs2CO3 (98 mg, 0.3 mmol, 3.0 equiv.) were dissolved in 1,4-dioxane (2 mL). The mixture was stirred at 100 °C for 16 h. The mixture was cooled, filtered, and concentrated. The crude residue was pre-purified by preparative TLC (3% MeOH in DCM) to give an impure product residue (20 mg, yellow solid). The product was further purified by reverse-phase HPLC to give (R)-6-cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (15 mg, 0.036 mmol, 35% yield) as a yellow solid. MS (ESI) + ):419.2[(M+H) + ]. 1 H NMR (400MHz, DMSO-d6)d ppm:8.74(s, 1H), 7.72(d, J=7.6Hz, 1H), 7.52(d, J=7.4Hz, 1H), 7.35(s, 1H), 7.23(d, J=6.4Hz, 1H), 6.81(s, 1H), 5.3 3-5.07(m, 1H), 3.61-3.45(m, 1H), 3.24(s, 3H), 2.53(s, 3H), 1.46(d, J=6.8Hz, 3H), 1.19-1.11(m, 2H), 1.08(m, 2H).

[0402] Example 3: (R)-8-Bromo-6-cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione [ka] To a solution of (R)-6-cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (300 mg, 0.71 mmol, 1.0 equiv.) and potassium acetate (70 mg, 0.71 mmol, 1.0 equiv.) in acetic acid (10 mL) was added bromine (138 mg, 0.86 mmol, 1.2 equiv.). The mixture was heated at 70° C. and stirred for 2 hours. The mixture was washed with water (30 mL) and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by preparative TLC (3% MeOH in DCM) to give impure product (120 mg). The crude product was further purified by reverse-phase HPLC to give (R)-8-bromo-6-cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (37 mg, 0.072 mmol, 10% yield) as a yellow solid. 1 H NMR (400MHz, DMSO)δppm 8.68(s, 1H), 7.72(d, J=7.8Hz, 1H), 7.52(d, J=7.6Hz, 1H), 7.34(t, J=7.8Hz, 1H), 7.16(d, J=6.2Hz, 1H), 5 .23-5.03(m, 1H), 3.67-3.49(m, 1H), 3.21(s, 3H), 2.53(s, 3H), 1.46(d, J=6.8Hz, 3H), 1.19-1.05(m, 4H). MS measurement value (ESI + ):497.2 / 499.2(7 9 Br / 81 Br)[(M+H) + ].

[0403] Example 4: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione [ka] Step A: 3-(tert-butyl) 4-methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3,4-dicarboxylate Tetrahydro-2H-pyran-4-amine (1 g, 9.88 mmol, 1.0 equiv.) was added dropwise to ethanol / HO (300 mL, V / V = 500 / 1) and tert-butyl propiolate (1.2 g, 9.88 mmol, 1.0 equiv.). The mixture was stirred at room temperature for 24 h. At this time, dimethyl but-2-ynedioate (1.4 g, 9.88 mmol, 1.0 equiv.) was added, and the mixture was heated at reflux for 24 h. The mixture was cooled to room temperature, sodium methoxide (523 mg, 9.88 mmol, 1.0 equiv.) was added, and the mixture was stirred at room temperature for an additional 8 h. The mixture was concentrated and directly purified by flash column chromatography (10-20% ethyl acetate in petroleum ether) to give 3-(tert-butyl) 4-methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3,4-dicarboxylate (2.2 g, 6.53 mmol, 66% yield) as a light yellow solid. MS (ESI) + ):338.3[(M+H) + ].

[0404] Step B: 5-(tert-butoxycarbonyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridine-4-carboxylic acid : 3-(tert-Butyl) 4-methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3,4-dicarboxylate (1.1 g, 3.26 mmol, 1.0 equiv.) was dissolved in MeOH (20 mL) and lithium hydroxide (156 mg, 6.52 mmol, 2.0 equiv.) was added. The mixture was stirred overnight at room temperature and then concentrated. The residue was partitioned between ethyl acetate (50 mL) and 1 M HCl solution (5 mL). The organic phase was dried over sodium sulfate and concentrated to give 5-(tert-butoxycarbonyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridine-4-carboxylic acid (860 mg, 2.66 mmol, 82% yield) as a light yellow solid. MS (ESI) + ):324.3[(M+H) + ].

[0405] Step C: tert-butyl 4-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate A solution of 5-(tert-butoxycarbonyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridine-4-carboxylic acid (700 mg, 2.17 mmol, 1.0 equiv.), HATU (988 mg, 2.60 mmol, 1.2 equiv.), and N,N-diisopropylethylamine (336 mg, 2.6 mmol, 1.2 equiv.) in THF (10 mL) was treated with tert-butyl 2-methylhydrazine-1-carboxylate (380 mg, 2.6 mmol, 1.2 equiv.), and the mixture was stirred at room temperature overnight and then concentrated. The crude residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (50 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, concentrated, and purified by flash column chromatography (1% MeOH in DCM) to give tert-butyl 4-(2-(tert-butoxycarbonyl)-1-methylhydrazine-1-carbonyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (760 mg, 1.68 mmol, 78% yield) as a light yellow solid. MS (ESI) + ):452.3[(M+H) + ].

[0406] Step D: 2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione : 4-(2-(tert-Butoxycarbonyl)-1-methylhydrazine-1-carbonyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (700 mg, 1.55 mmol, 1.0 equiv.) was dissolved in hydrochloric acid (15 mL, 4 M solution in 1,4-dioxane). The mixture was stirred at room temperature for 30 minutes, then heated to 100°C and stirred for 30 minutes. The mixture was cooled to room temperature, and the resulting solid was filtered under reduced pressure to give 2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione (328 mg, 1.18 mmol, 76% yield) as a light yellow solid. MS (ESI) + ):278.1[(M+H) + ].

[0407] Step E: 2-methyl-1,7-dioxo-6-(tetrahydro-2H-pyran-4-yl)-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl 2,4,6-triisopropylbenzenesulfonate 2-Methyl-6-(tetrahydro-2H-pyran-4-yl)-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione (100 mg, 0.44 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (170 mg, 1.32 mmol, 3.0 equiv.) were dissolved in DCM (5 mL) and 2,4,6-triisopropylbenzenesulfonyl chloride (148 mg, 0.48 mmol, 1.1 equiv.) was added under N at 0 °C. The mixture was allowed to warm to room temperature, stirred for 2 h, and concentrated. The crude mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and DCM (150 mL). The organic phase was dried, concentrated, and purified by flash column chromatography (10–20% ethyl acetate and 1% DCM in petroleum ether) to give 2-methyl-1,7-dioxo-6-(tetrahydro-2H-pyran-4-yl)-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl 2,4,6-triisopropylbenzenesulfonate (159 mg, 0.29 mmol, 66% yield) as a yellow solid. MS (ESI) data. + ):544.5[(M+H) + ].

[0408] Step F: (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione Under N2, 2-methyl-1,7-dioxo-6-(tetrahydro-2H-pyran-4-yl)-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl 2,4,6-triisopropylbenzenesulfonate (100 mg, 0.18 mmol, 1.0 equiv.), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (43 mg, 0.216 mmol, 1.2 equiv.), XantPhos Pd G3 (15.13 mg, 0.018 mmol, 0.1 equiv.), and Cs2CO3 (180 mg, 0.55 mmol, 2.0 equiv.) were dissolved in 1,4-dioxane (8 mL). The mixture was stirred at 100 °C for 16 h. The mixture was then filtered and concentrated. The crude residue was pre-purified by preparative TLC (3% MeOH in DCM) to give the impure product (40 mg, yellow solid), which was further purified by reverse-phase HPLC to give (R)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (25 mg, 0.054 mmol, 29% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6)d ppm:8.88(s, 1H), 7.71(d, J=7.8Hz, 1H), 7.53(d, J=7.8Hz, 1H), 7.38(d, J=7.8Hz, 1H), 7.30(d, J=6.4Hz, 1H), 6.86(s, 1H) , 5.16(m, 2H), 4.19-4.03(m, 2H), 3.55(s, 2H), 3.24(s, 3H), 2.54(s, 3H), 2.10(m, 2H), 1.82(m, 2H), 1.48(d, J=6.8Hz, 3H). MS measurement value (ESI + ):463.4[(M+H) + ].

[0409] Example 5: (R)-2-Methyl-6-(tetrahydro-2H-pyran-4-yl)-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione [ka] A solution of (2-methyl-1,7-dioxo-6-tetrahydropyran-4-yl-pyrido[3,4-d]pyridazin-4-yl) 2,4,6-triisopropylbenzenesulfonate (150 mg, 0.28 mmol, 1.0 equiv.), CsCO (269.83 mg, 0.83 mmol, 3.0 equiv.), Xantphos Pd G (26.17 mg, 0.03 mmol, 0.1 equiv.), and (1R)-1-[3-(trifluoromethyl)phenyl]ethanamine (78.29 mg, 0.41 mmol, 1.5 equiv.) in 1,4-dioxane (5 mL) was stirred at 100 °C for 16 h. The mixture was cooled to room temperature, filtered through a pad of Celite, and purified by preparative HPLC to give (R)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (34 mg, 0.07 mmol, 28% yield). 1 H NMR (400MHz, CDCl3)δ 8.01(s, 1H), 7.66(s, 1H), 7.59(d, J=7.4Hz, 1H), 7.52(d, J=7.6Hz, 1H), 7.45(t, J=7.6Hz, 1H), 7.37(s, 1 H), 5.34(m, 1H), 5.03(m, 1H), 4.13(m, 2H), 3.62(m, 2H), 3.46(s, 3H), 1.96(s, 3H), 1.61(d, J=6.6Hz, 5H). MS measurement value (ESI + ):449.5[(M+H) + ].

[0410] Example 6: (R)-6-Cyclopropyl-8-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione [ka] Step A: 8-Bromo-6-cyclopropyl-2-methyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4,7(6H)-trione 6-Cyclopro...

Claims

1. Formula (I): 【Chemical 1】 〔wherein, X is phenyl, naphthyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, each of which may be optionally substituted by 1 to 3 R Ａ which may be optionally substituted; R １ is C １ -C ６ alkyl, -(C １ -C ６ alkyl)-NR Ｂ R Ｃ , C １ -C ６ hydroxyalkyl or 5- to 6-membered heteroaryl; R ２ is hydrogen, halogen, cyano, hydroxyl, -NR Ｄ R Ｅ , C １ -C ６ alkyl, 3- to 10-membered cycloalkyl or heterocyclyl which may optionally be substituted with C １ -C ６ alkoxy, C(O)C １ -C ６ alkyl, C １ -C ６ hydroxycycloalkyl, C １ -C ６ hydroxyheterocyclyl or 3- to 10-membered heterocyclyl which may optionally be substituted with amino; R ３ is (A) Hydroxyl, cyano, C １ -C ６ alkyl or C optionally substituted with 1 to 3 fluorines ３ -C ８ cycloalkyl, C ３ -C ６ cycloalkyl, 5- to 10-membered heteroaryl optionally substituted with 1 to 3 fluorines, 3- to 10-membered -CH ２ -heterocyclyl substituted with 1 to 3 fluorines, C １ -C ６ haloalkyl, C １ -C ６ hydroxyalkyl, -C(O)NR Ｆ R Ｇ or C １ -C ６ alkyl, or (B) independently one or more halogens, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, -C(O)C １ -C ６ -alkyl, halogen, C １ -C ６ -alkyl or C １ -C ６ -alkoxy optionally substituted -C(O)C １ -C ６ -cycloalkyl or -C(O)NR Ｆ R Ｇ -substituted 3- to 10-membered heterocyclyl which may be optionally substituted is; Each R Ａ is independently one or more halogens, cyano, nitro, -(C １ -C ６ -alkyl) ｐ -NR Ｈ R Ｉ ; C １ -C ６ -alkyl, C １ -C ６ -alkoxy, C １ -C ６ -haloalkoxy, C optionally substituted with 1 to 3 fluorines １ -C ６ -hydroxyalkyl, 1 or more of 1 to 3 fluorines or C １ -C ６ -alkyl optionally substituted with; C １ -C ６ -alkoxyalkyl, 3- to 10-membered heterocyclyl optionally substituted with; C １ -C ６ -haloalkyl, -CH optionally substituted with 1 to 3 fluorines ２ C(O)NR Ｆ R Ｇ ; 5- to 6-membered -CH substituted with 1 to 3 fluorines ２ -heteroaryl and -(C １ -C ６ -alkyl) ｐ -NR Ｊ R Ｋ and is optionally selected from 3- to 10-membered cycloalkyl optionally substituted with; Each R Ｂ 、R Ｃ 、R Ｄ 、R Ｅ 、R Ｆ 、R Ｇ 、R Ｈ 、R Ｉ 、R Ｊ 、R Ｋ is independently selected from hydrogen and C １ -C ６ alkyl, or R Ｂ and R Ｃ together with the atom to which they are attached may form a 5- to 10-membered heterocyclyl optionally substituted with one or more of halogen, C １ -C ６ alkyl and C １ -C ６ alkoxy; p is 0 or 1〕 a compound of or a pharmaceutically acceptable salt thereof.

2. R １ is C １ -C ６ is alkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

4. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

5. R ２ is C １ -C ６ is alkoxy, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. R ２ The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R is methoxy.

7. R ３ is hydroxyl, cyano, 5- to 10-membered heteroaryl, C １ -C ６ -haloalkyl, -C(O)NR Ｆ R Ｇ or C １ -C ６ optionally substituted with alkyl C ３ -C ６ -cycloalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. R ３ is hydroxyl, cyano, 5- to 10-membered heteroaryl, C １ -C ６ -haloalkyl, -C(O)NR Ｆ R Ｇ or C １ -C ６ cyclopropyl which may optionally be substituted with alkyl, the compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. R ３ is halogen, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -C(O)C １ -C ６ alkyl or -C(O)NR Ｆ R Ｇ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a 3- to 10-membered heterocyclyl optionally substituted by

10. R ３ is halogen, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -C(O)C １ -C ６ alkyl or -C(O)NR Ｆ R Ｇ and is optionally substituted tetrahydropyran, the compound according to claim 9 or a pharmaceutically acceptable salt thereof.

11. X is phenyl, naphthyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, each of which is optionally substituted with 1 to 3 R's independently selected Ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be optionally substituted with Ａ .

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is 【Chemical Formula 2】 selected from.

13. Each R Ａ is selected independently from cyano, halogen, C １ -C ３ -alkyl and C optionally substituted with 3- to 10-membered heterocyclyl １ -C ３ -haloalkyl, and the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. Each R Ａ is independently selected from cyano, methyl, fluoro, methoxy, difluoromethyl, trifluoromethyl, trifluoromethoxy and hydroxyethyl, the compound according to claim 13 or a pharmaceutically acceptable salt thereof.

15. At least one R Ａ The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein at least one R is fluoro.

16. At least one R Ａ The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein R is difluoromethyl.

17. A compound selected from the compounds consisting of the following or a pharmaceutically acceptable salt thereof: (R)-6-Cyclopropyl-2-methyl-4-((1-(naphthalen-1-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethylamino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-8-Bromo-6-cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-2-Methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-2-Methyl-6-(tetrahydro-2H-pyran-4-yl)-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-8-methoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-2,8-dimethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-2-ethyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-6-(1-Acetylpiperidin-4-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazine-8-carbonitrile, (R)-8-Chloro-6-cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-8-Amino-6-cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-((1r,3r)-3-Hydroxycyclobutyl)-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-((1s,3s)-3-Hydroxycyclobutyl)-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-2-Methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylcyclopropyl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-(Bicyclo[1.1.1]pentan-1-yl)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-8-ethoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 8-((R)-3-Aminopyrrolidin-1-yl)-6-cyclopropyl-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 8-((S)-3-Aminopyrrolidin-1-yl)-6-cyclopropyl-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-2-Methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(piperidin-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-2-Methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylpiperidin-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-2-(2-Aminoethyl)-6-cyclopropyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-(1-((6-Cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-1-methyl-1H-indazole-3-carbonitrile, (S)-6-(1-((6-Cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-1-methyl-1H-indazole-3-carbonitrile, (R)-6-(1-((6-Cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-1,4-dimethyl-1H-indazole-3-carbonitrile, (S)-6-(1-((6-Cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-1,4-dimethyl-1H-indazole-3-carbonitrile, 6-((1r,3R)-3-(1H-Imidazol-1-yl)cyclobutyl)-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-Cyclopropyl-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-((S)-pyrrolidin-2-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-Cyclopropyl-2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-8-((R)-pyrrolidin-2-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((S)-tetrahydro-2H-pyran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((R)-tetrahydro-2H-pyran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-6-Cyclopropyl-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((S)-1-(3-(Difluoro((S)-tetrahydrofuran-2-yl)methyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(Difluoro((S)-tetrahydrofuran-2-yl)methyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-Fluorobenzofuran-7-yl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3,3-Difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-8-Acetyl-6-cyclopropyl-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclohexyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(3-morpholinobicyclo[1.1.1]pentan-1-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(2-oxaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((S)-3-methyltetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((R)-3-methyltetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 2-methyl-4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-((S)-3-methyltetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-((R)-3-methyltetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-4-((1-(4-bromothiophen-2-yl)ethyl)amino)-6-cyclopropyl-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-6-cyclopropyl-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((3R,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-8-methoxy-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-8-methoxy-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-8-methoxy-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4 - ((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-8-methoxy-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-4-((1-(benzo[b]thiophen-4-yl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (S)-4-((1-(benzo[b]thiophen-4-yl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-4-((1-(benzo[b]thiophen-4-yl)ethyl)amino)-6-cyclopropyl-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (S)-4-((1-(benzo[b]thiophen-4-yl)ethyl)amino)-6-cyclopropyl-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-1,7-dioxo-1,7-dihydropyrido[3,4-d]pyridazin-6(2H)-yl)cyclopropane-1-carbonitrile (R)-4-((1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazine-1,7(2H,6H)-dione (S)-4-((1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyridazine-1,7(2H,6H)-dione (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-1,7-dioxo-1,7-dihydropyrido[3,4-d]pyridazin-6(2H)-yl)-N,N-dimethylbicyclo[1.1.1]pentane-1-carboxamide (R)-4-((1-(3-(1,1-Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-(trifluoromethyl)cyclopropyl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-8-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-8-methoxy-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2,8-dimethyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (1S,3S)-3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-1,7-dioxo-1,7-dihydropyrido[3,4-d]pyridazin-6(2H)-yl)cyclobutane-1-carbonitrile, (1R,3S)-3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-1,7-dioxo-1,7-dihydropyrido[3,4-d]pyridazin-6(2H)-yl)cyclobutane-1-carbonitrile, (R)-6-Cyclopropyl-2-(2-hydroxyethyl)-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-2-(2-(3-methoxy-3-methylazetidin-1-yl)ethyl)-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-2-(2-(3-fluoro-3-methylazetidin-1-yl)ethyl)-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-8-(dimethylamino)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-8-isopropoxy-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-8-(cyclopropylmethoxy)-2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-8-(2-(dimethylamino)ethoxy)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-8-(3,3-Difluorocyclobutoxy)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-8-(oxetan-3-yloxy)pyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, 4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-8-((1r,3R)-3-fluorocyclobutoxy)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-8-(oxetan-3-ylmethoxy)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-[(1S,2R)-2-(5-Fluoro-3-pyridyl)cyclopropyl]-2-methyl-4-[[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4-d]pyridazine-1,7-dione, 6-[(1R,2S)-2-(5-Fluoro-3-pyridyl)cyclopropyl]-2-methyl-4-[[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4-d]pyridazine-1,7-dione, 4-[[(1R)-1-[3-(Difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-[(1S,2R)-2-(5-fluoro-3-pyridyl)cyclopropyl]-2-methyl-pyrido[3,4-d]pyridazine-1,7-dione, 4-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino-6-[(1R,2S)-2-(5-fluoropyridin-3-yl)cyclopropyl]-2-methyl-pyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((R)-3-(trifluoromethyl)pyrrolidin-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((S)-3-(trifluoromethyl)pyrrolidin-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((S)-1-methyl-3-(trifluoromethyl)pyrrolidin-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((R)-1-methyl-3-(trifluoromethyl)pyrrolidin-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 6-((S)-1-acetyl-3-(trifluoromethyl)pyrrolidin-3-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 6-((R)-1-acetyl-3-(trifluoromethyl)pyrrolidin-3-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-6-cyclopropyl-2-methyl-4-((1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (S)-6-Cyclopropyl-2-methyl-4-((1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (S)-6-Cyclopropyl-4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-Cyclopropyl-4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (S)-2-(3-(1-((6-Cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoro-N,N-dimethylacetamide, (R)-2-(3-(1-((6-Cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoro-N,N-dimethylacetamide, (R)-2-(3-(1-((6-Cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoro-N-methylacetamide, (S)-2-(3-(1-((6-Cyclopropyl-2-methyl-1,7-dioxo-1,2,6,7-tetrahydropyrido[3,4-d]pyridazin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoro-N-methylacetamide, (R)-6-Cyclopropyl-4-((1-(3-(1,1-difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(1,1-Difluoro-2-methoxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (S)-6-Cyclopropyl-4-((2,2-difluoro-1-(3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-6-Cyclopropyl-4-((2,2-difluoro-1-(3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (S)-6-(1-(Difluoromethyl)cyclopropyl)-4-((1-(indolizin-5-yl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-(1-(Difluoromethyl)cyclopropyl)-4-((1-(indolizin-5-yl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (S)-6-(1-(Difluoromethyl)cyclopropyl)-2-methyl-4-((1-(pyrazolo[1,5-a]pyridin-7-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-(1-(Difluoromethyl)cyclopropyl)-2-methyl-4-((1-(pyrazolo[1,5-a]pyridin-7-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-Cyclopropyl-2-methyl-4-[[(1S)-1-[3-methyl-5-(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4-d]pyridazine-1,7-dione, 6-Cyclopropyl-2-methyl-4-[[(1R)-1-[3-methyl-5-(trifluoromethyl)phenyl]ethyl]amino]pyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((S)-3-(difluoromethyl)tetrahydrofuran-3-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4 - ((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((R)-3-(difluoromethyl)tetrahydrofuran-3-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6 - ((S)-3,3-difluorocyclopentyl)-4 - ((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, 6 - ((R)-3,3-difluorocyclopentyl)-4 - ((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-4 - ((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(hydroxymethyl)cyclopropyl)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-4 - ((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-4 - ((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)cyclopropyl)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-6-(1-(1,1-difluoroethyl)cyclopropyl)-4 - ((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-2-methyl-4 - ((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4 - ((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((R)-spiro[2.2]pentan-1-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((S)-spiro[2.2]pentan-1-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((S)-6,6-difluorospiro[2.5]octan-1-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((R)-6,6-difluorospiro[2.5]octan-1-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((R)-2,2-dimethylcyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((S)-2,2-dimethylcyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione (R)-6-(3,3-difluoro-1-methylcyclobutyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 6-((1R,2S)-[1,1'-bi(cyclopropane)]-2-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 6-((1S,2R)-[1,1'-bi(cyclopropane)]-2-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-((1S,5R)-3-acetyl-3-azabicyclo[3.1.0]hexan-1-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-((1R,5S)-3-acetyl-3-azabicyclo[3.1.0]hexan-1-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-((1S,5R)-3-(cyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-((1R,5S)-3-(cyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexan-1-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-((R)-1-acetyl-3-methylpyrrolidin-3-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-((S)-1-acetyl-3-methylpyrrolidin-3-yl)-4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-(2-Azabicyclo[2.1.1]hexan-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-(2-Acetyl-2-azabicyclo[2.1.1]hexan-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclobutyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-[[(1R)-1-[3-(Difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2-methyl-6-[(1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl]pyrido[3,4-d]pyridazine-1,7-dione, (R)-6-(1-Acetyl-3-methylazetidin-3-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-6-(1-(Cyclopropanecarbonyl)-3-methylazetidin-3-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(1-methoxycyclopropane-1-carbonyl)-3-methylazetidin-3-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(3-methylazetidin-3-yl)pyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(1-fluorocyclopropane-1-carbonyl)-3-methylazetidin-3-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-6-(1-acetyl-3-(difluoromethyl)azetidin-3-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(3-(trifluoromethyl)oxetan-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2-methyl-6-((S)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methoxy-2-methyl-6-((R)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6-cyclopropyl-4-((1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyridazine-1,7(2H,6H)-dione, (R)-4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-[[(1R)-1-[3-(1,1-difluoro-2-methoxy-ethyl)-2-fluoro-phenyl]ethyl]amino]-6-[1-(difluoromethyl)cyclopropyl]-2-methyl-pyrido[3,4-d]pyridazine-1,7-dione, 4-[[(1S)-1-[3-(1,1-difluoro-2-methoxy-ethyl)-2-fluoro-phenyl]ethyl]amino]-6-[1-(difluoromethyl)cyclopropyl]-2-methyl-pyrido[3,4-d]pyridazine-1,7-dione, (R)-6-(1-(difluoromethyl)cyclopropyl)-4-((1-(3-fluorobenzofuran-7-yl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((S)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-((R)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-fluorobenzofuran-7-yl)ethyl)amino)-2-methyl-6-((S)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3-fluorobenzofuran-7-yl)ethyl)amino)-2-methyl-6-((R)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4-(((R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methyl-6-((S)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 4 - ((((R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methyl-6-((R)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6 - ((S)-1-acetyl-3-(trifluoromethyl)pyrrolidin-3-yl)-4 - ((((R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6 - ((R)-1-acetyl-3-(trifluoromethyl)pyrrolidin-3-yl)-4 - ((((R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6 - ((S)-1-acetyl-3-(trifluoromethyl)pyrrolidin-3-yl)-4 - ((((R)-1-(3-fluorobenzofuran-7-yl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, 6 - ((R)-1-acetyl-3-(trifluoromethyl)pyrrolidin-3-yl)-4 - ((((R)-1-(3-fluorobenzofuran-7-yl)ethyl)amino)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4 - ((1-(3-(difluoro(pyridin-4-yl)methyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (S)-4 - ((1-(3-(difluoro(pyridin-4-yl)methyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4 - ((1-(3-(difluoro(5-methylpyrazin-2-yl)methyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (S)-4-((1-(3-(Difluoro(5-methylpyrazin-2-yl)methyl)-2-fluorophenyl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (R)-4-((1-(4,4-Difluorochroman-8-yl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, (S)-4-((1-(4,4-Difluorochroman-8-yl)ethyl)amino)-6-(1-(difluoromethyl)cyclopropyl)-2-methyl-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione, and (R)-6-Cyclopropyl-2-methyl-4-((1-(naphthalen-2-yl)ethyl)amino)-2,6-dihydropyrido[3,4-d]pyridazine-1,7-dione.

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

19. A medicament for treating cancer in a subject, comprising an effective amount of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

20. The medicament according to claim 19, wherein the cancer is a Ras pathway-related cancer.

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