Phenylamide Compounds and Methods of Use

Abstract

This application relates to compounds of formula (I) as defined herein, and pharmaceutically acceptable salts thereof. This application also describes pharmaceutical compositions comprising a compound of formula (I), and pharmaceutically acceptable salts thereof, as well as methods of using the compounds and compositions for inhibiting certain protein-protein interactions and for treating cancer. Also provided herein is a method of treating cancer in a subject in need of treatment for SOS1-related cancer, the method 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.

Description

Technical Field

[0001] This application relates to phenylamide compounds useful for treating proliferative disorders such as cancer.

Background Art

[0002] Cancer is characterized by abnormal cell growth and proliferation. The Ras protein is an important component of the signaling network that controls cell growth, 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 the active GTP-bound state and the inactive GDP-bound state. GTP-bound Ras can activate several downstream signaling pathways involved in cell cycle progression, survival, and apoptosis. Guanine nucleotide exchange factors (GEFs) such as SOS1 are required to activate Ras by promoting the exchange of GDP (inactive Ras) for GTP (active Ras). SOS1 itself is activated by Ras via allosteric interactions, which strongly activates the GEF function of SOS1, thus creating 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). Mutations in Ras occur in many human cancers, but currently, no drugs targeting the Ras protein have been approved. See Hillig, et al., Proc. Nat. Acad. Sci., Vol. 117, No. 7, pp. 2551-2560 (2019). Therefore, there remains a need for new therapies that disrupt Ras signaling.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0004] Here, it has been found that a certain phenylamide compound is an inhibitor of SOS1 activity and is useful for treating various diseases and disorders such as cancer.

[0005] Therefore, provided herein is a compound of formula (I):

Chemical Formula

[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 of inhibiting the proliferation of mammalian cells in vitro or in vivo, the method 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 of cancer treatment, the method 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 of treating cancer in a subject in need of treatment of SOS1-related cancer, the method 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-related disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having a Ras pathway-related 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-related cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a Ras pathway-related 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 of 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) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0013] Also provided herein is a method of treating Ras-related cancer in a subject, comprising administering to a subject identified or diagnosed as having Ras-related 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 of treating SOS1-related cancer in a subject, comprising administering to a subject identified or diagnosed as having SOS1-related 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] Also provided herein is a method for treating cancer in a subject in need of cancer treatment, (a) determining that the cancer is associated with deregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them; (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.

[0016] Also provided herein is a method for treating cancer in a subject in need of cancer treatment, comprising administering to a subject determined to have a cancer associated with deregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of 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] Also provided herein is a method for treating cancer in a subject in need of cancer treatment, (a) determining that the cancer is associated with deregulation of a Ras gene, a Ras protein, or the expression or activity or level of any of them; (b) administering to a subject in need thereof an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is also provided.

[0018] Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to a subject determined to have cancer associated with deregulation of the expression, 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 for treating cancer in a subject in need thereof, the method comprising administering to a subject determined to have cancer associated with deregulation of the expression, activity, or level of a SOS1 gene, a 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] Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising: (a) determining that the cancer is associated with deregulation of the expression, activity, or level of a SOS1 gene, a 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.

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

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

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

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

[0026] Also provided herein is a method for inhibiting metastasis in a subject having a specific cancer in need of treatment for inhibition of metastasis, which comprises 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] Also provided herein is 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 use in the treatment of a Ras pathway-related disease or disorder.

[0029] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of Ras pathway-related cancers.

[0030] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of cancer and / or inhibition of metastasis associated with certain cancers.

[0031] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in inhibiting SOS1-Ras protein-protein interactions in mammalian cells.

[0032] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for inhibiting SOS1-Ras protein-protein interactions in mammalian cells.

[0033] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for the treatment of Ras pathway-related diseases or disorders.

[0034] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for the treatment of Ras pathway-related cancers.

[0035] Also provided herein is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

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

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

Best Mode for Carrying Out the Invention

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention, and other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0039] Definitions As used herein, the term "compound" means including all stereoisomers, geometric isomers, tautomers, and isotope-enriched variants of the structures shown. In this specification, a compound identified by a name or structure as a particular tautomeric form is intended to include other tautomeric forms unless otherwise specified.

[0040] As used herein, the term "tautomer" refers to compounds that have significantly different structures in the arrangement of atoms but exist in easy and rapid equilibrium. The compounds provided herein may be shown as different tautomers, and if a compound has tautomeric forms, it is intended that all tautomeric forms are within the scope of the present invention, and it should be understood that the naming of the compound does not exclude any tautomer. Examples of tautomeric forms include the following:

Chemical formula

[0041] Certain compounds provided herein may contain one or more centers of asymmetry and, accordingly, it will be understood that they can be prepared and isolated in a mixture of isomers, such as a racemic mixture, or in enantiomerically pure form. Examples of enantiomeric forms include the following: [Chemical formula] .

[0042] The term "halo" refers to a halogen, one of Group 17 of the Periodic Table. Specifically, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0043] The term "C 1~3 alkyl" refers to a straight or branched chain saturated hydrocarbon chain containing 1, 2, or 3 carbon atoms, such as methyl, ethyl, n-propyl.

[0044] The term "C 1~6 alkyl" refers to a straight or branched chain saturated hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0045] The term "C 1~6 alkylene" refers to a straight or branched chain divalent hydrocarbon (alkyl) chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, consisting only of carbon and hydrogen, that links the remainder of the molecule to a radical group. Alkylene can have 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is bonded to the remainder of the molecule through a single bond or a double bond. The point of attachment of the alkylene chain to the remainder of the molecule can be through one carbon or any two carbons within the chain.

[0046] The term "C 1~12The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon chain containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.

[0047] As used herein, the term "alkoxy" refers to an alkyl ether radical, either alone or in combination, and the term alkyl is as defined above. An alkoxy group can have the general formula: alkyl-O-. For an alkyl group, an alkoxy group can have any suitable number of carbon atoms, such as C1-C3. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. An alkoxy group can be further optionally substituted as defined herein.

[0048] "C 1~6 The term "haloalkyl" refers to a C 1~6 alkyl group as defined herein substituted with at least one halogen atom, for example, fluorine, chlorine, bromine, and iodine, independently selected at each occurrence. The halogen atom(s) can be present at any position on the alkyl group. For example, C 1~6 haloalkyl can refer to chloromethyl, fluoromethyl, difluoromethyl, 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, difluoroethyl, for example 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, for example, 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. Similarly, "C1~3 "Haloalkyl" refers to a C alkyl group as defined herein, substituted at each occurrence, independently at any position on the alkyl group, with at least one halogen atom (e.g., fluorine, chlorine, bromine, and iodine). 1~3 refers to an alkyl group.

[0049] As used herein, the term "amine" refers to an -NR'R'' group when the amine is a terminal group and is used herein to describe an -NR' group when the amine is a linking group, as defined below.

[0050] The phrase "terminal group" describes a group (substituent) that is attached to another part of the compound through one of its atoms.

[0051] The phrase "linking group" describes a group (substituent) that is attached to another part of the compound through two or more of its atoms.

[0052] Thus, an amine group can be a primary amine when both R' and R'' are hydrogen, a secondary amine when R' is hydrogen and R'' is C 1~6 alkyl, or a tertiary amine when each of R' and R'' is independently C 1~6 alkyl.

[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 are replaced by heteroatoms independently selected from N, O, and S. Non-limiting examples of heteroaryl groups include furanyl, furazanyl, thiophenyl, benzothiophenyl, phthalazinyl, pyrrolyl, oxazolyl, benzoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, indolyl, indazole, pyrazolyl, benzopyrazolyl, isoxazolyl, benzisoxazole, isothiazolyl, triazolyl, benzotriazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, pteridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, triazinyl, 2,3-dihydrobenzofuranyl, and 5,6,7,8-tetrahydroimidazo[1,5]pyridinyl. In some embodiments, heteroaryl has 1 to 3 heteroatoms independently selected from N, O, and S.

[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, such as a cycloalkyl group and a C3-C6 cycloalkyl group. Bicyclic cycloalkyl groups include fused, spiro, and bridged ring systems. Non-limiting examples of cycloalkyl groups include phenyl, 2,3-dihydro-1H-indene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and spiro[2.5]octyl. 10

[0055] ​The term "heterocyclyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or bicyclic ring system having from 3 to 10 ring atoms, not aromatic, having at least one heteroatom within the ring selected from N, O, and S. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. The heterocyclyl group may be represented, for example, as a "5- to 10-membered heterocyclyl group", which is a ring system containing 5, 6, 7, 8, 9, or 10 atoms, with at least one atom being a heteroatom. Similarly, "5- to 8-membered heterocyclyl" is a ring system containing 5, 6, 7, or 8 atoms, with at least one atom being a heteroatom. The heterocyclyl group can have, for example, 1, 2, 3, or more heteroatoms. In some embodiments, the heterocyclyl group has 1 or 2 independently selected heteroatoms. The heterocycle may further contain one or more carbonyl or thiocarbonyl functional groups and includes oxo- and thio-based systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates, as defined. The heterocyclyl group can be attached to the remainder of the molecule through any carbon atom or through a heteroatom such as nitrogen.Exemplary heterocyclic groups include, but are not limited to, azepanyl, 1,3-dioxolane, 1,4-dioxolanil, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, quinuclidinyl, 4H-pyranyl, azetidinyl, oxetanyl, octahydrocyclopenta[c]pyrrol, 2-azaspiro[3.3]heptanyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 4-azaspiro[2.5]octanyl, 6-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.1]octanyl, hexahydro-1H-cyclopenta[c]pyrrolyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, and hexahydro-1H-pyrrolidinyl.

[0056] The term "oxo", as used herein, means oxygen double-bonded to a carbon atom. When a substituent is oxo, one of ordinary skill in the art will recognize that the oxo is attached through a double bond in accordance with the standard rules of chemical valence.

[0057] The term "cyano", as used herein, refers to -CN, alone or in combination.

[0058] As used herein, when a ring is described as "partially unsaturated", it means that the ring has one or more additional degrees of unsaturation (e.g., one or more double or triple bonds between constituent ring atoms, in addition to the degree of unsaturation due to the ring itself), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0059] The term "optionally substituted" means that the preceding group or groups may or may not be substituted.

[0060] The compounds of formula (I) include their pharmaceutically acceptable salts. In addition, the compounds of formula (I) may include other salts of such compounds that are not necessarily pharmaceutically acceptable salts but are 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).

[0061] Furthermore, the compounds of formula (I) or their salts may be isolated in the form of solvates, and thus, it will be understood that any such solvates are included within the scope of the present invention. For example, the compounds of formula (I) and their salts may exist in non-solvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0062] In some embodiments, the compounds of formula (I) include the compounds of Examples 1 to 81 and their stereoisomers, pharmaceutically acceptable salts, and solvates. In some embodiments, the compounds of Examples 1 to 81 are in the free base form. In some embodiments, the compounds of Examples 1 to 81 are in the form of pharmaceutically acceptable salts.

[0063] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not eliminate the biological activity and properties of the compound. In some embodiments, the pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids 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, the pharmaceutically acceptable salts can be obtained by reacting a compound having an acidic group described herein with a base to form a salt (e.g., ammonium salt), an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt), a salt of an organic base (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts containing amino acids (e.g., arginine and lysine), etc.), or by other methods determined previously. Pharmaceutically acceptable salts are not specifically limited as long as they can be used in medicine. Examples of salts of the compounds described herein having a base include: their salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; their salts with organic bases such as methylamine, ethylamine, and ethanolamine; their salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts can be acid addition salts, such as addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, iodic 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.

[0064] The compounds provided herein may also contain non-natural proportions of atomic isotopes in one or more of the atoms that make up such compounds. That is, the atoms, specifically when referred to in connection with the compounds of formula (I), are either naturally occurring or synthetically produced, and are in either their natural abundance or in an isotopically enriched form, including all isotopes and mixtures of isotopes of that atom. For example, unless otherwise specified, when hydrogen is referred to, the atom is 1 H, 2 H, 3 H, or mixtures thereof, and when carbon is referred to, the atom is 11 C, 12 C, 13 C, 14 C, or mixtures thereof, and when nitrogen is referred to, the atom is 13 N, 14 N, 15 N, or mixtures thereof, and when oxygen is referred to, the atom is 14 O, 15 O, 16 O, 17 O, 18 O, or mixtures thereof, and when fluorine is referred to, the atom is 18 F, 19 F, or mixtures thereof. For example, in deuterated alkyl and deuterated alkoxy groups, one or more hydrogen atoms are specifically replaced by deuterium ( 2 H). Since some of the aforementioned isotopes are radioactive, accordingly, the compounds provided herein also include compounds having one or more isotopes of one or more of the atoms, including radioactive compounds, and mixtures thereof, wherein one or more non-radioactive atoms are replaced by one of its radioisotopically enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, such as cancer therapeutic agents, research reagents, such as assay reagents, and diagnostic agents, such as in vivo imaging agents. All isotopic variants of the compounds provided herein are intended to be encompassed within the scope of the invention, whether radioactive or not.

[0065] The ability of a test compound to act as an inhibitor of SOS1-Ras (e.g., KRas (e.g., KRas G12C)) interaction can be demonstrated by the biological assays described herein. The IC 50 values are shown in Table A.

[0066] 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 within 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, for the treatment of a subject having cancer (e.g., Ras pathway-related cancer (e.g., SOS1-related cancer, Ras-related cancer (e.g., KRas-related cancer, HRas-related cancer, and / or NRas-related cancer), EGFR-related cancer, ErbB2-related cancer, ErbB3-related cancer, ErbB4-related cancer, NF1-related cancer, PDGFR-A-related cancer, PDGFR-B-related cancer, FGFR1-related cancer, FGFR2-related cancer, FGFR3-related cancer, IGF1 R-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 (e.g., BRAF-related cancer), PI3K-related cancer, AKT-related cancer, mTOR-related cancer, MEK-related cancer, ERK-related cancer, or combinations thereof) e.g., Ras pathway-related brain cancer or CNS cancer), administration of the compound to the subject (e.g., oral administration) can be mentioned. In some such embodiments, the compounds provided herein are useful for treating primary or metastatic brain tumors. For example, Ras pathway-related primary or metastatic brain tumors.

[0067] The compound of formula (I) or a pharmaceutically acceptable salt thereof is useful for the treatment of diseases or disorders that can be treated with an SOS1 inhibitor, such as blood cancers, solid tumors, neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Leopard syndrome, capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-skin syndrome (CFC), Legius syndrome, and hereditary gingival fibromatosis, 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), 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 disorders, FGFR1-related diseases or disorders, FGFR2-related diseases or disorders, FGFR3-related diseases or disorders, IGF1 R-related diseases or disorders, INSR-related diseases or disorders, ALK-related diseases or disorders, ROS-related diseases or disorders, TrkA-related diseases or disorders, TrkB-related diseases or disorders, TrkC-related diseases or disorders, RET-related diseases or disorders, c-MET-related diseases or disorders, VEGFR1-related diseases or disorders, VEGFR2-related diseases or disorders, VEGFR3-related diseases or disorders, AXL-related diseases or disorders, SHP2-related diseases or disorders, RAF-related diseases or disorders (e.g., a BRAF-related disease or disorder), PI3K-related diseases or disorders, AKT-related diseases or disorders, mTOR-related diseases or disorders, MEK-related diseases or disorders, ERK-related diseases or disorders, or combinations thereof).

[0068] 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 including blood cancers and solid tumors.

[0069] As used herein, the terms "treating" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of all or part of the symptoms associated with a disease, disorder or condition, whether detectable or not, diminishment of the extent of the disease, stabilization (i.e., not worsening) of the disease state, delay or slowing of the progression of the disease, improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0070] 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 a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of a disease or disorder to be treated and / or prevented.

[0071] In some embodiments, the subject is identified or diagnosed as having a cancer associated with dysregulation 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 combinations 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 combinations thereof), or the expression or activity or level of any of them (Ras pathway-related cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., an assay or kit approved by the FDA). In some embodiments, the subject has a tumor (e.g., as determined using an assay or kit approved by a regulatory agency) that is positive for dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them. The subject can be a subject having a tumor (s) that is positive for dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, e.g., an assay or kit approved by the FDA). The subject can be a subject in which the tumor has dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level thereof (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, e.g., an assay or kit approved by the FDA).In some embodiments, the subject is suspected of having a Ras pathway-related cancer. In some embodiments, the subject has a clinical record (and optionally, the clinical record indicates that the subject should be treated by any of the compositions provided herein) indicating that the subject has a tumor having dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is identified or diagnosed as having a cancer (Ras pathway-related cancer) determined to be associated with dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them based on histological examination.

[0072] In some embodiments, the subject is identified or diagnosed as having a cancer (Ras-related cancer) associated with dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA). In some embodiments, the subject has a tumor that is positive for dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency). The subject can be a subject having a tumor (s) that is positive for dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA). The subject can be a subject in which the tumor has dysregulation of the Ras gene, Ras protein, or the expression or activity or level thereof (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an assay or kit approved by the FDA). In some embodiments, the subject is suspected of having a Ras-related cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor having dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them (and optionally, the clinical record indicates 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 is identified or diagnosed as having a cancer (Ras-related cancer) determined to be associated with dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them based on histological examination.

[0073] In some embodiments, the subject is identified or diagnosed as having a cancer (KRas-related cancer) associated with dysregulation of the KRas gene, KRas protein, or the expression, activity, or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA). In some embodiments, the subject has a tumor that is positive for dysregulation of the KRas gene, KRas protein, or the expression, activity, or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency). The subject can be a subject having a tumor (s) that is positive for dysregulation of the KRas gene, KRas protein, or the expression, activity, or level of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA). The subject can be a subject in which the tumor has dysregulation of the KRas gene, KRas protein, or the expression, activity, or level of them (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an assay or kit approved by the FDA). In some embodiments, the subject is suspected of having a KRas-related cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor having dysregulation of the KRas gene, KRas protein, or the expression, activity, or level of any of them (and optionally, the clinical record indicates 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 is identified or diagnosed as having a cancer (KRas-related cancer) determined to be associated with dysregulation of the KRas gene, KRas protein, or the expression, activity, or level of any of them based on histological examination.

[0074] In some embodiments, the subject is identified or diagnosed as having a cancer (HRas-related cancer) associated with dysregulation of the HRas gene, the HRas protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA). In some embodiments, the subject has a tumor that is positive for dysregulation of the HRas gene, the HRas protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency). The subject can be a subject having a tumor (s) that is positive for dysregulation of the HRas gene, the HRas protein, or the expression or activity or level of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA). The subject can be a subject in which the tumor has dysregulation of the HRas gene, the HRas protein, or the expression or activity or level of them (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an assay or kit approved by the FDA). In some embodiments, the subject is suspected of having an HRas-related cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor having dysregulation of the HRas gene, the HRas protein, or the expression or activity or level of any of them (and optionally, the clinical record indicates 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 is identified or diagnosed as having a cancer (HRas-related cancer) determined to be associated with dysregulation of the HRas gene, the HRas protein, or the expression or activity or level of any of them based on histological examination.

[0075] In some embodiments, the subject is identified or diagnosed as having a cancer (NRas-related cancer) associated with dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA). In some embodiments, the subject has a tumor that is positive for dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency). The subject can be a subject having a tumor (s) that is positive for dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA). The subject can be a subject in which the tumor has dysregulation of the NRas gene, NRas protein, or the expression or activity or level thereof (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an assay or kit approved by the FDA). In some embodiments, the subject is suspected of having an NRas-related cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor having dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them (and optionally, the clinical record indicates 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 is identified or diagnosed as having a cancer (NRas-related cancer) determined to be associated with dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them based on histological examination.

[0076] In some embodiments, the subject is identified or diagnosed as having a cancer (SOS1-related cancer) associated with dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). In some embodiments, the subject has a tumor (e.g., as determined using an assay or kit approved by a regulatory agency) that is positive for dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them. The subject can be a subject having a tumor (s) (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit) that is positive for dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them. The subject can be a subject in which the tumor has dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of them (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an FDA-approved kit or assay). In some embodiments, the subject is suspected of having an SOS1-related cancer. In some embodiments, the subject has a clinical record (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein) indicating that the subject has a tumor having dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is identified or diagnosed as having a cancer (SOS1-related cancer) determined to be associated with dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them based on histological examination.

[0077] As used herein, the term "pediatric subject" refers to a subject less than 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations including neonates (from birth to 1 month of age), infants (from 1 month to 2 years of age), children (from 2 years to 12 years of age), and adolescents (from 12 years to 21 years of age (including up to but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. 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 28 days of age, from 29 days to less than 2 years of age, from 2 years to less than 12 years of age, or from 12 years to 21 years of age (including up to but not including the 22nd birthday).

[0078] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is useful for preventing diseases and disorders as defined herein (e.g., autoimmune diseases, inflammatory diseases, and cancer). As used herein, the term "preventing" means preventing the onset, recurrence, or spread of all or a portion of a disease or condition described herein, or its symptoms.

[0079] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is useful for preventing diseases and disorders as defined herein (e.g., Ras pathway-related diseases or disorders, autoimmune diseases, inflammatory diseases, and cancer as described herein). As used herein, the term "preventing" means preventing the onset, recurrence, or spread of all or a portion of a disease or condition described herein, or its symptoms.

[0080] Abnormal cell growth and proliferation are characteristics of cancer. One such pathway through which such abnormal cell growth can occur is via Ras family protein signaling. Human Ras proteins (e.g., KRas (V-Ki-Ras2 Kirsten rat sarcoma 2 virus oncogene homolog), HRas (V-Ha-Ras Harvey rat sarcoma virus oncogene homolog), and / or NRas (neuroblastoma RAS virus (V-Ras) oncogene homolog), also 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 that are involved in many cancer gene signaling cascades. Each of these proteins is approximately 21 kD in size. KRas has two common isoforms known as KRas4A and KRas4B.

[0081] Mature Ras proteins typically associate with the cell membrane through 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 is methionine, serine, leucine, or glutamine). In the inactive state, the Ras protein binds to GDP. See, e.g., Adjei, J. Nat’l. Cancer Inst. 93.14 (2001): 1062-1074.

[0082] Activation of Ras proteins can be initiated through a plurality of 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 leads, directly or indirectly, to the activation of one or more guanine nucleotide exchange factors (GEFs) that promote the Ras protein to release GDP, enabling GTP to bind. Non-limiting examples of GEFs include the SOS (Son of Sevenless homolog) protein and RASGRF1 (Ras protein-specific guanine nucleotide releasing factor 1, also sometimes called Cdc25). For example, upon activation, dimerization, and autophosphorylation of EGFR, the receptor can bind to the SH2 domain of the adapter protein growth factor receptor-bound protein 2 (GRB2), and subsequently, the adapter protein growth factor receptor-bound protein 2 (GRB2) can bind to the SOS protein (e.g., SOS1 or SOS2 respectively, sometimes also called SOS-1 and SOS-2), thereby co-localizing the SOS protein with Ras family proteins in the cell membrane.For example, see Xuehua et al., Proc. Nat. Acad. Sci. Nov. 2017, 114(47) E10092 - E10101; Vetter and Wittinghofer, Science 294.5545(2001): 1299 - 1304; Downward, Nat. Rev. Cancer 3.1(2003): 11 - 22; Pierre and Coumoul, Biochem. Pharmacol. 82.9(2011): 1049 - 1056. Kortum, et al. Proc. Nat. Acad. Sci. 108.30(2011): 12407 - 12412; U.S. Patent Application Publication Nos. 2019 / 0358230 and 2019 / 0194192, and PCT Publication Nos. WO2018 / 172250 and WO2019 / 201848.

[0083] When activated by GTP binding, the Ras protein can bind to and activate a number of 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 is involved in many cancers, including, but not limited to, pancreatic cancer, thyroid cancer (e.g., papillary thyroid cancer), colon cancer, lung cancer (e.g., non-small cell lung cancer), melanoma, biliary cancer, small intestine cancer, endometrial cancer, ovarian cancer, cervical cancer, prostate cancer, soft tissue cancer, peritoneal cancer, liver cancer, urinary tract cancer, breast cancer, and combinations thereof. See, for example, 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, signal transduction via the Ras-PI3K / AKT / mammalian target of rapamycin (mTOR) pathway of rapamycin has been shown to play 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, stomach cancer, and combinations thereof.See, 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, Luo, et al. Cancer Cell 4.4 (2003): 257 - 262.

[0084] The Ras protein has intrinsic GTPase activity but is typically not physiologically relevant. Instead, hydrolysis of the bound GTP is enhanced (e.g., by up to about 5 orders of magnitude) by the binding of a GTPase - activating protein (GAP) such as neurofibromatosis type 1 (NF1) or p120. See, for example, 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. GAP Activating mutations (particularly at residues G12, G13, and / or Q61) in Ras family proteins are estimated to be present in up to about 30% of all human cancers. In general, activating mutations in Ras family proteins render the Ras protein insensitive to GAP activity. See, for example, Santarpia, et al. Expert Opinion on Therapeutic Targets 16.1 (2012): 103 - 119. Exemplary non - limiting examples of Ras mutations are presented in Tables 1 (KRas mutations), 2 (HRas mutations), and 3 (NRas mutations).

[0085]

[0086] As used herein, the term "Ras pathway-related disease or disorder" refers to a disease or disorder associated with, or having a dysregulation of, a gene within the Ras pathway, a protein within the Ras pathway, or the expression or activity or level of any (e.g., one or more) of them (e.g., any of the types of dysregulation of the expression or activity or level of a gene within the Ras pathway, a protein within the Ras pathway, or any of them described herein). Non-limiting examples of Ras pathway-related diseases or disorders include, for example, neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Leopard syndrome, capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-skin syndrome (CFC), Legius syndrome, hereditary gingival fibromatosis, and cancer.

[0087] In some embodiments, the Ras pathway-related disease or disorder is a Ras pathway-related cancer. As used herein, the term "Ras pathway-related cancer" refers to a cancer that is associated with or has dysregulation of the expression, activity, or level of a gene within the Ras pathway, a protein within the Ras pathway, or any one (e.g., one or more) of them (e.g., any one of the types of dysregulation of the expression, activity, or level of a gene within the Ras pathway, a protein within the Ras pathway, or any one of them described herein). Non-limiting examples of Ras pathway-related cancers are described herein. In some embodiments, the Ras pathway-related cancer can be a KRas-related cancer, an HRas-related cancer, an NRas-related cancer, a 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 IGF1 R-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.

[0088] As used herein, the term "Ras-related cancer" refers to a cancer that is associated with or has dysregulation of the expression, activity, or level of the Ras gene, the Ras protein, or any one (e.g., one or more) of them (e.g., any one of the types of dysregulation of the expression, activity, or level of the Ras gene, the Ras protein, or any one of them described herein). Non-limiting examples of Ras-related cancers are described herein. In some embodiments, the Ras-related cancer can be a KRas-related cancer, an HRas-related cancer, an NRas-related cancer, or a combination thereof.

[0089] The phrase "dysregulation of a Ras gene, a Ras protein, or the expression or activity or level of any of them" refers to genetic mutations (e.g., a Ras (KRas, NRas, or HRas) gene translocation that results in the expression of a fusion protein, a mutation in a Ras gene that results in the expression of a Ras protein that contains 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 that has 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 that has at least one inserted amino acid compared to the wild-type Ras protein, a gene duplication that results in an increase in the level of the Ras protein in the cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increase in the level of the Ras protein in the cell), an alternative splice version of Ras mRNA that results in a Ras protein that has at least one amino acid deletion in the Ras protein compared to the wild-type Ras protein or that has at least one amino acid insertion in the Ras protein compared to the wild-type Ras protein, or an increase (e.g., an increase in level) in the expression of the wild-type Ras protein in mammalian cells due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of a Ras gene, a Ras protein, or the expression or activity or level of any of them can be a mutation in a Ras gene that encodes a Ras protein that is constitutively active or has increased activity compared to the protein encoded by a non-mutated Ras gene. In some embodiments of any of the methods described herein, dysregulation of a Ras gene, a Ras protein, or the expression or activity or level of any of them can be selected from the group consisting of G12 mutations, G13 mutations, Q61 mutations, and combinations thereof.

[0090] Table 1 lists several non-limiting, exemplary KRas mutations. Table 1A lists non-limiting, exemplary KRas fusions. In some embodiments of any of the methods described herein, dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them may be selected from the group consisting of G12 mutations (e.g., G12I, G12A, G12C, G12D, G12E, G12F, G12L, G12N, G12R, G12S, G12T, G12V, G12W, or G12Y), G13 mutations (e.g., G13A, G13C, G13D, G13E, G13F, G13I, G13M, G13N, G13P, G13R, G13S, G13V, or G13Y), Q61 mutations (e.g., Q61D, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R), and combinations thereof.

[0091] Table 2 lists several non-limiting, exemplary HRas mutations. In some embodiments of any of the methods described herein, dysregulation of the HRas gene, the HRas protein, or the expression or activity or level of any of them may be selected from the group consisting of G12 mutations (e.g., G12A, G12C, G12D, G12R, G12S, G12V), G13 mutations (e.g., G13A, G13C, G13D, G13R, G13S, G13V), Q61 mutations (e.g., Q61H, Q61K, Q61L, Q61P, Q61R, Q61*), and combinations thereof.

[0092] Table 3 lists some non-limiting exemplary HRas mutations. In some embodiments of any of the methods described herein, dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them may be 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 1A

Table 2

Table 3

[0093] However, Ras proteins are often considered "undruggable," and direct Ras inhibitors have not been approved by the US Food and Drug Administration. Therefore, other targets in the Ras signaling pathway have been targeted to suppress abnormal signaling through these pathways, including both upstream and downstream targets of Ras family proteins. See, 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.

[0094] Guanine nucleotide exchange factors that facilitate the exchange of GDP for GTP bound by Ras family proteins can be suitable targets for reducing signaling through the Ras pathway. Inhibition of GEFs promotes the inactive (GDP-bound) state of Ras family proteins and can thus reduce signaling through the pathway. See, 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. Chem. Bio. 7.9 (2011): 585~587: Maurer, et al. Proc. Nat. Acad. Sci. 109.14 (2012): 5299-5304, Winter, et al. J. Med. Chem. 58.5 (2015): 2265-2274. One such GEF is SOS1.

[0095] SOS1 has a central "catalytic" core of approximately 500 residues (SOScat ) and is sufficient for Ras activation activity. SOS1 binds to the nucleotide binding site of the Ras protein, thereby promoting the release of the bound nucleotide (e.g., GDP) and enabling another nucleotide (e.g., GTP). It has a primary (sometimes also referred to as the "catalytic") Ras binding site (e.g., including the Cdc25 homology domain). SOS1 can bind to two Ras molecules in a ternary complex, and the binding of the Ras·GTP complex to the second (sometimes also referred to as the "allosteric") site on SOS1 further activates the catalytic activity of SOS1 in a positive feedback-type mechanism. See, for example, Margarit, et al. Cell 112.5 (2003): 685-695; Freedman, et al. Proc. Nat. Acad. Sci. 103.45 (2006): 16692-16697. Further, it has been shown that small molecule binders of SOS1 can 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 respect to the Ras protein, and such molecules may also be referred to herein as "SOS1 inhibitors" and may be said to "inhibit SOS1 activity". Some SOS1 inhibitors have been shown to bind proximal to the primary Ras binding site, for example, causing a shift in the side chain of Tyr884 and reducing the favorable stacking interaction with Arg73 of KRas. Further, the antiproliferative activity of some such SOS1 inhibitors has been demonstrated. See, for example, 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. WO2018 / 172250 and WO2019 / 201848.

[0096] As used herein, the term "SOS1-related cancer" refers to a cancer that is associated with, or has deregulation (e.g., any of the types of deregulation of the expression, activity, or level of the SOS1 gene, SOS1-GEF (also referred to herein as the SOS1 protein), or any one (e.g., one or more) of them), such as any of the types of deregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any one of them described herein. Non-limiting examples of SOS1-related cancers are described herein.

[0097] The phrase "dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them" refers to gene mutations (e.g., SOS1 gene translocations that result in the expression of a fusion protein, mutations in the SOS1 gene that result in the expression of an SOS1 protein containing at least one amino acid deletion compared to the wild-type SOS1 protein, mutations in the SOS1 gene that result in the expression of an SOS1 protein with one or more point mutations compared to the wild-type SOS1 protein, mutations in the SOS1 gene that result in the expression of an SOS1 protein with at least one inserted amino acid compared to the wild-type SOS1 protein, gene duplications that result in an increase in the level of SOS1 protein in the cell, or mutations in regulatory sequences (e.g., promoters and / or enhancers) that result in an increase in the level of SOS1 protein in the cell), alternative splice versions of SOS1 mRNA that result in an SOS1 protein having (e.g., compared to the wild-type SOS1 protein) at least one amino acid deletion in the SOS1 protein or at least one amino acid insertion in the SOS1 protein, or an increase (e.g., an increase in level) in the expression of wild-type SOS1 protein in mammalian cells due to abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them can be a mutation in the SOS1 gene that encodes an SOS1 protein that is constitutively active or has increased activity compared to the protein encoded by the SOS1 gene without the mutation. Non-limiting examples of SOS1 protein point mutations / insertions / deletions are listed in Table 4. Table 4A enumerates non-limiting exemplary SOS1 fusions.

Table 4-1

Table 4-2

Table 4A

[0098] The term "wild type" refers to a nucleic acid or protein (e.g., SOS1-related disease or disorder) that is found in a subject that does not have a disease or disorder associated therewith (and optionally also 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 in a cell or tissue from a subject that does not have a disease or disorder associated with the nucleic acid or protein (e.g., cancer associated with the nucleic acid or protein) (and optionally also 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).

[0099] The term "regulatory agency" refers to the national agency by which a country approves the medical use of a pharmaceutical agent. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0100] Compound As used herein, a compound of formula (I):

Chemical formula

[0101] In one embodiment, R 1 is a 3- to 10-membered heterocyclyl. In another embodiment, R 1 is a 6-membered heterocyclyl optionally substituted with C 1~3 alkyl.

[0102] In one embodiment, R 1 is azepanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, quinuclidinyl, 4H-pyran, azetidinyl, oxetanyl, octahydrocyclopenta[c]pyrrol, 2-azaspiro[3.3]heptanyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 4-azaspiro[2.5]octanyl, 6-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.1]octanyl, hexahydro-1H-cyclopenta[c]pyrrolyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, or hexahydro-1H-pyrrolidinyl optionally substituted with one or more C 1~3 alkyl.

[0103] In one embodiment, R 1 is tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl. In another embodiment, R 1 is tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl optionally substituted with one or more C 1~3 alkyls.

[0104] In one embodiment, R 1 is

Chemical formula

[0105] In one embodiment, R 1 is C 1~12 alkyl. In one embodiment, C 1~12 alkyl is substituted with 1 to 3 substituents each individually selected from halo, OH, amine, cyano, C 1~3 alkyl, C 1~3 alkoxy, and C 1~3 haloalkyl, oxo, and -C(O)R 10 , and R 10 is hydrogen, OH, C 1~3 alkyl, or C 1~3 alkoxy. In one embodiment, R 1 is unsubstituted C 1~12 alkyl.

[0106] In one embodiment, R 1 is C 1~6 alkyl. In one embodiment, C 1~6 alkyl is substituted with 1 to 3 substituents each individually selected from halo, OH, amine, cyano, C 1~3 alkyl, C 1~3 alkoxy, and C 1~3 haloalkyl, oxo, and -C(O)R 10 , and R 10 is hydrogen, OH, C 1~3 alkyl, or C 1~3is an alkoxy group.

[0107] In one embodiment, R 1 is a C 1~4 alkyl substituted with cyano or amine. In some embodiments, the amine substituent is an alkylamine (e.g., dimethylamine).

[0108] In one embodiment, R 1 is a C 3~6 cycloalkyl. In one embodiment, the C 3~6 cycloalkyl is substituted with 1 to 3 substituents each individually selected from halo, OH, amine, cyano, C 1~3 alkyl, C 1~3 alkoxy, and C 1~3 haloalkyl, oxo, and -C(O)R 10 wherein R 10 is hydrogen, OH, C 1~3 alkyl, or C 1~3 alkoxy. In one embodiment, R 1 is a C 3~6 cycloalkyl.

[0109] In one embodiment, R 1 is a C 3~6 cycloalkyl substituted with amine. In embodiments, the amine substituent is an alkylamine (e.g., dimethylamine).

[0110] In one embodiment, R 2 is hydrogen, halo, cyano, or C 1~3 haloalkyl.

[0111] In one embodiment, R 2 is halo.

[0112] In one embodiment, R 3 is a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl.

[0113] In one embodiment, R 3is a 4- to 6-membered heterocyclyl. In some embodiments, R 3 is a 4- to 6-membered heterocyclyl optionally substituted with one or more halo, OH, or C 1~3 alkyl.

[0114] In one embodiment, R 3 is a 4- to 6-membered heterocyclyl optionally substituted with one or more halo, OH, or C 1~3 alkyl, and is azepanyl, 1,3-dioxolan, 1,4-dioxolanil, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, quinuclidinyl, 4H-pyranyl, azetidinyl, oxetanyl, octahydrocyclopenta[c]pyrrol, 2-azaspiro[3.3]heptanyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 4-azaspiro[2.5]octanyl, 6-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.1]octanyl, hexahydro-1H-cyclopenta[c]pyrrolyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, hexahydro-1H-pyrrolidinyl, 2-oxa-7-azaspiro[4.4]nonanyl, and 6-oxa-1-azaspiro[3.4]octanyl.

[0115] In one embodiment, R 3is one or more halo, OH, or C 1~3 tetrahydropyranyl, azepanyl, azetidinyl, morpholinyl, pyrrolidinyl, piperidinyl, 4-azaspiro[2.5]octanyl, 7-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, or hexahydro-1H-cyclopenta[c]pyrrolyl, optionally substituted with one or more halo, OH, or C

[0116] In one embodiment, R 3 is morpholinyl optionally substituted with one or more halo, OH, or C 1~3 alkyl.

[0117] In one embodiment, R 3 is piperidinyl optionally substituted with one or more halo, OH, or C 1~3 alkyl.

[0118] In one embodiment, R 3 is morpholinyl.

[0119] In one embodiment, R 3 is 5- to 10-membered heteroaryl.

[0120] In one embodiment, R 3 is oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyridone.

[0121] In one embodiment, R 3 is pyridyl optionally substituted with one or more halo, oxo, or C 1~3 alkyl.

[0122] In one embodiment, R 3 is C 3~6 cycloalkyl.

[0123] In one embodiment, R 3is -C(O)R 7 or -C(O)NR 8 R 9 wherein R 7 , R 8 and R 9 are as described herein, including those in the embodiments.

[0124] In one embodiment, R 7 is C 1~3 alkoxy.

[0125] In one embodiment, R 8 is H or C 1~3 alkyl, and R 9 is C 1~3 alkyl.

[0126] In one embodiment, R 8 and R 9 together form a 5- to 8-membered heterocyclyl. In some embodiments, the 5- to 8-membered heterocyclyl is morpholino or piperidinyl.

[0127] In one embodiment, R 4 is C 1~3 alkyl. In another embodiment, R 4 is methyl.

[0128] In one embodiment, R 5 is halo, C 1~3 alkyl, or C 1~3 haloalkyl. In another embodiment, R 5 is -CH3. In another embodiment, R 5 is CN. In another embodiment, R 5 is halogen.

[0129] In one embodiment, the compound is a compound selected from Examples 1 to 81.

[0130] Treatment method Disclosed herein is a method for treating cancer (e.g., Ras pathway-related cancer) in a subject in need thereof, the method comprising administering to the 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-related cancer. In some embodiments, the cancer is a Ras-related cancer. In some embodiments, the cancer is a KRas-related cancer. In some embodiments, the cancer is an HRas-related cancer. In some embodiments, the cancer is an NRas-related cancer. In some embodiments, the cancer is an SOS1-related cancer.

[0131] For example, disclosed herein is a method for treating 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 IGF1 R-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), the method comprising: a) detecting in a sample from the subject a dysregulation of the expression, activity, or level of a Ras pathway gene, a Ras pathway protein, or any combination thereof; 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 Ras pathway gene, the Ras pathway protein, or the expression, activity, or level of any combination thereof comprises one or more fusion proteins.

[0132] For example, provided herein is a method for treating a Ras-related cancer in a subject in need thereof, the method comprising: a) detecting a dysregulation in the expression, activity, or level of a Ras gene, a Ras protein, or any combination thereof 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 in the expression, activity, or level of a Ras gene, a Ras protein, or any combination thereof comprises one or more fusion proteins.

[0133] For example, provided herein is a method for treating a KRas-related cancer in a subject in need thereof, the method comprising: a) detecting a dysregulation in the expression, activity, or level of a KRas gene, a KRas protein, or any combination thereof 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 in the expression, activity, or level of a KRas gene, a KRas protein, or any combination thereof comprises one or more fusion proteins.

[0134] For example, provided herein is a method for treating a HRas-related cancer in a subject in need thereof, the method comprising: a) detecting a dysregulation in the expression, activity, or level of a HRas gene, a HRas protein, or any combination thereof 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 in the expression, activity, or level of a HRas gene, a HRas protein, or any combination thereof comprises one or more fusion proteins.

[0135] For example, provided herein is a method for treating an NRas-related cancer in a subject in need thereof, the method comprising: a) detecting a deregulation in the expression, activity, or level of the NRas gene, NRas protein, or any combination thereof 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 deregulation in the expression, activity, or level of the NRas gene, NRas protein, or any combination thereof comprises one or more fusion proteins.

[0136] For example, provided herein is a method for treating a SOS1-related cancer in a subject in need thereof, the method comprising: a) detecting a deregulation in the expression, activity, or level of the SOS1 gene, SOS1 protein, or any combination thereof 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 deregulation in the expression, activity, or level of the SOS1 gene, SOS1 protein, or any combination thereof comprises one or more fusion proteins.

[0137] A method for treating cancer in a subject in need thereof, comprising: (a) detecting Ras pathway-related 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 been previously treated with another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have Ras pathway-related cancer by using a regulatory agency-approved, e.g., FDA-approved, test or assay for identifying dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them in a biopsy sample from or in the subject, 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.

[0138] A method for treating cancer in a subject in need thereof, comprising: (a) detecting Ras-related 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 been previously treated with another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have Ras-related cancer by using a regulatory agency-approved, e.g., FDA-approved, test or assay for identifying dysregulation of a Ras gene, a Ras protein, or the expression, activity, or level of any of them in a biopsy sample from or in the subject, 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.

[0139] A method for treating cancer in a subject in need thereof, comprising: (a) detecting KRas-related 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 been previously treated by another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have KRas-related cancer by use of a test or assay approved by a regulatory agency, such as the FDA, for identifying dysregulation of the KRas gene, KRas protein, or the expression or activity or level of any of them in a biopsy sample from or in the subject, 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.

[0140] A method for treating cancer in a subject in need thereof, comprising: (a) detecting HRas-related 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 been previously treated with another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have HRas-related cancer by using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the HRas gene, HRas protein, or the expression, activity, or level of any of them in a biopsy sample from or in the subject, 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.

[0141] A method for treating cancer in a subject in need thereof, comprising: (a) detecting KRas-related 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 been previously treated with another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have NRas-related cancer by using a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the NRas gene, NRas protein, or the expression, activity, or level of any of them in a biopsy sample from or in the subject, 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.

[0142] A method for treating cancer in a subject in need of cancer treatment, comprising: (a) detecting SOS1-related 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 been previously treated by another anti-cancer treatment, such as at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have SOS1-related cancer by use of a regulatory-approved, e.g., FDA-approved, test or assay for identifying dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them in a biopsy sample from or in the subject, 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.

[0143] A method for treating cancer in a subject in need of cancer treatment, the method comprising administering to a subject determined to have cancer associated with dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them, 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 been previously treated by another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have a Ras pathway-related cancer by use of a test or assay approved by a regulatory agency, such as the FDA, for identifying dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them in a biopsy sample from or in the subject, 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.

[0144] A method for treating cancer in a subject in need thereof, comprising administering to a subject determined to have cancer associated with dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them, 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 been previously treated by another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have Ras-related cancer by use of a test or assay approved by a regulatory agency, such as the FDA, for identifying dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them in a biopsy sample from or in the subject, 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.

[0145] A method for treating cancer in a subject in need thereof, comprising administering to a subject determined to have cancer associated with dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them, 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 been previously treated by another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have KRas-related cancer by use of a test or assay approved by a regulatory agency, e.g., approved by the FDA, for identifying dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them in a biopsy sample from or in the subject, 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.

[0146] A method for treating cancer in a subject in need thereof, comprising administering to a subject determined to have cancer associated with deregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them, 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 been previously treated by another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have HRas-related cancer by use of a test or assay approved by a regulatory agency, such as the FDA, for identifying deregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them in a biopsy sample from or in the subject, 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.

[0147] A method for treating cancer in a subject in need of cancer treatment, comprising administering to a subject determined to have cancer associated with deregulation of the expression, activity, or level 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, 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 been previously treated by another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have NRas-related cancer by use of a regulatory-approved, e.g., FDA-approved, test or assay for identifying deregulation of the expression, activity, or level of the NRas gene, NRas protein, or any of them in a biopsy sample from or in the subject, 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.

[0148] A method for treating cancer in a subject in need thereof, comprising administering to a subject determined to have cancer associated with deregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them, 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 been previously treated by another anti-cancer treatment, such as at least partial resection of the tumor, or radiation therapy. In some embodiments, the subject is determined to have SOS1-related cancer by use of a regulatory-approved, e.g., FDA-approved, test or assay for identifying deregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them in a biopsy sample from or in the subject, 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.

[0149] Performing an assay on a sample obtained from a subject to determine whether the subject has a Ras pathway gene, a Ras pathway protein, or a dysregulation of the expression or activity or level of any of them, and administering to the subject determined to have a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., administering specifically or selectively), also provided is a method of treating a subject. Some embodiments of these methods further include administering to the subject another anti-cancer agent (e.g., small molecule or immunotherapy). In some embodiments of these methods, the subject has been previously treated by another anti-cancer treatment, such as at least partial resection of a tumor, or radiotherapy. In some embodiments, the subject is a subject suspected of having a Ras pathway-related cancer, a subject presenting one or more symptoms of a Ras pathway-related cancer, or a subject at high risk of developing a Ras pathway-related cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or fluorescence in situ hybridization (FISH) analysis. In some embodiments, the assay is an assay approved by a regulatory agency, such as a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0150] Performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them, and administering to the subject determined to have the Ras gene, Ras protein, or the expression or activity or level of any of them an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., administering specifically or selectively), also provides a method of treating a subject. Some embodiments of these methods further include administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has been previously treated by another anti-cancer treatment, such as at least partial resection of a tumor, or radiotherapy. In some embodiments, the subject is a subject suspected of having a Ras-related cancer, a subject presenting one or more symptoms of a Ras-related cancer, or a subject at high risk of developing a Ras-related cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is an assay approved by a regulatory agency, e.g., a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0151] Performing an assay on a sample obtained from a subject to determine whether the subject has a KRas gene, a KRas protein, or a dysregulation of the expression or activity or level of any of them, and administering to the subject determined to have a KRas gene, a KRas protein, or the expression or activity or level of any of them an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., administering specifically or selectively), also provides a method of treating a subject. Some embodiments of these methods further include administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has been previously treated by another anti-cancer treatment, such as at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is a subject suspected of having a KRas-related cancer, a subject presenting one or more symptoms of a KRas-related cancer, or a subject at high risk of developing a KRas-related cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is an assay approved by a regulatory agency, such as a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0152] Performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them, and administering to the subject determined to have the expression or activity or level of the HRas gene, HRas protein, or any of them an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., administering specifically or selectively), also provided is a method of treating a subject. 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 been previously treated by another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is a subject suspected of having an HRas-related cancer, a subject presenting one or more symptoms of an HRas-related cancer, or a subject at high risk of developing an HRas-related cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is an assay approved by a regulatory agency, e.g., a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0153] Performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them, and administering to the subject determined to have the expression or activity or level 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, or a pharmaceutical composition thereof (e.g., administering specifically or selectively), also provided is a method of treating a subject. Some embodiments of these methods further include administering to the subject another anti-cancer agent (e.g., small molecule or immunotherapy). In some embodiments of these methods, the subject has been previously treated by another anti-cancer treatment, such as at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is a subject suspected of having an NRas-related cancer, a subject presenting one or more symptoms of an NRas-related cancer, or a subject at high risk of developing an NRas-related cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is an assay approved by a regulatory agency, such as a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0154] Performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them, and administering to the subject determined to have the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., administering specifically or selectively), also provided is a method of treating a subject. 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 been previously treated by another anti-cancer treatment, such as at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is a subject suspected of having an SOS1-related cancer, a subject presenting one or more symptoms of an SOS1-related cancer, or a subject at high risk of developing an SOS1-related cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or fluorescence in situ hybridization (FISH) analysis. In some embodiments, the assay is an assay approved by a regulatory agency, such as a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0155] Performing an assay (e.g., an in vitro assay) on a sample obtained from a subject, and determining whether the subject has dysregulation of the expression, activity, or level of a Ras pathway protein, a Ras pathway protein, or any of them, through which a subject is identified or diagnosed as having a Ras pathway-related cancer, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of a Ras pathway-related cancer in a subject identified or diagnosed as having a Ras pathway-related cancer, wherein the presence of dysregulation of the expression or level of a Ras pathway gene, a Ras pathway protein, or any of them identifies that the subject has a Ras pathway-related cancer, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is also provided. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a Ras pathway-related cancer in a subject identified or diagnosed as having a Ras pathway-related cancer, through performing an assay on a sample obtained from the subject and determining whether the subject has dysregulation of the expression, activity, or level of a Ras pathway gene, a Ras pathway protein, or any of them, wherein the presence of dysregulation of the expression or level of a Ras pathway gene, a Ras pathway protein, or any of them identifies that the subject has a Ras pathway-related cancer, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is also provided. 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 it has been determined through performing the assay that the subject has dysregulation of the expression, activity, or level of a Ras pathway gene, a Ras pathway protein, or any of them, and that a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof should be administered. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or fluorescence in situ hybridization (FISH) analysis. In some embodiments, the assay is an assay approved by a regulatory agency, e.g., a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy.

[0156] Performing an assay (e.g., an in vitro assay) on a sample obtained from a subject and determining whether the subject has dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of Ras-related cancer in a subject identified or diagnosed as having Ras-related cancer, wherein the presence of dysregulation of the Ras gene, Ras protein, or the expression or level of any of them identifies that the subject has Ras-related cancer, is also provided. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of Ras-related cancer in a subject identified or diagnosed as having Ras-related cancer by performing an assay on a sample obtained from the subject and determining whether the subject has dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them, wherein the presence of dysregulation of the Ras gene, Ras protein, or the expression or level of any of them identifies that the subject has Ras-related cancer, is also provided. Some embodiments of any of the methods or uses described herein further comprise recording in the subject's clinical record (e.g., a computer-readable medium) that it has been determined through performance of the assay that the subject has dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them, and that a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof should be administered. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is an assay approved by a regulatory agency, e.g., a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy.

[0157] Performing an assay (e.g., an in vitro assay) on a sample obtained from a subject to determine whether the subject has dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of KRas-related cancer in a subject identified or diagnosed as having KRas-related cancer, wherein the presence of dysregulation of the KRas gene, the KRas protein, or the expression or level of any of them identifies that the subject has KRas-related cancer, is also provided. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of KRas-related cancer in a subject identified or diagnosed as having KRas-related cancer by performing an assay on a sample obtained from the subject to determine whether the subject has dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them, wherein the presence of dysregulation of the KRas gene, the KRas protein, or the expression or level of any of them identifies that the subject has KRas-related cancer, is also provided. 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 it has been determined through performance of the assay that the subject has dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them, and that a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof should be administered. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is an assay approved by a regulatory agency, e.g., a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy.

[0158] Performing an assay (e.g., an in vitro assay) on a sample obtained from a subject, and determining whether the subject has dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them, through which a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of HRas-related cancer in a subject identified or diagnosed as having HRas-related cancer is provided, wherein the presence of dysregulation of the HRas gene, HRas protein, or the expression or level of any of them identifies that the subject has HRas-related cancer. Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of HRas-related cancer in a subject identified or diagnosed as having HRas-related cancer by performing an assay on a sample obtained from the subject and determining whether the subject has dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them, wherein the presence of dysregulation of the HRas gene, HRas protein, or the expression or level of any of them identifies that the subject has HRas-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 it has been determined through performing the assay that the subject has dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them, and that a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof should be administered. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is an assay approved by a regulatory agency, e.g., a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy.

[0159] Performing an assay (e.g., an in vitro assay) on a sample obtained from a subject, and determining whether the subject has dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them, through which a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of NRas-related cancer in a subject identified or diagnosed as having NRas-related cancer is provided, wherein the presence of dysregulation of the NRas gene, NRas protein, or the expression or level of any of them identifies that the subject has NRas-related cancer. Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of NRas-related cancer in a subject identified or diagnosed as having NRas-related cancer, through performing an assay on a sample obtained from the subject and determining whether the subject has dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them, wherein the presence of dysregulation of the NRas gene, NRas protein, or the expression or level of any of them identifies that the subject has NRas-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 it has been determined through performance of the assay that the subject has dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them, and that a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof should be administered. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or fluorescence in situ hybridization (FISH) analysis. In some embodiments, the assay is an assay approved by a regulatory agency, e.g., a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy.

[0160] Performing an assay (e.g., an in vitro assay) on a sample obtained from a subject, and determining whether the subject has a dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them, through which a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of SOS1-related cancer in a subject identified or diagnosed as having SOS1-related cancer is provided, wherein the presence of dysregulation of the SOS1 gene, SOS1 protein, or the expression or level of any of them identifies that the subject has SOS1-related cancer. Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of SOS1-related cancer in a subject identified or diagnosed as having SOS1-related cancer, by performing an assay on a sample obtained from the subject and determining whether the subject has a dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them, wherein the presence of dysregulation of the SOS1 gene, SOS1 protein, or the expression or level of any of them identifies that the subject has SOS1-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 it has been determined through performance of the assay that the subject has a dysregulation of the SOS1 gene, SOS1 protein, or the expression or activity or level of any of them, and that a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof should be administered. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or fluorescence in situ hybridization (FISH) analysis. In some embodiments, the assay is an assay approved by a regulatory agency, e.g., a kit approved by the FDA. In some embodiments, the assay is a liquid biopsy.

[0161] In some embodiments of any of the methods or uses described herein, the subject is identified or diagnosed as having a cancer associated with dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject having a tumor (s) that is positive for dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject in which the tumor has dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a Ras pathway-related cancer. In some embodiments, provided herein is a method for treating a Ras pathway-related cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of 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 a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them comprises one or more Ras pathway protein point mutations / insertions / deletions.

[0162] In some embodiments of any of the methods or uses described herein, the subject is identified or diagnosed as having a cancer associated with deregulation of the Ras gene, Ras protein, or the expression, activity, or level of any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for deregulation of the Ras gene, Ras protein, or the expression, activity, or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject having a tumor (s) that is positive for deregulation of the Ras gene, Ras protein, or the expression, activity, or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject in which the tumor has deregulation of the Ras gene, Ras protein, or the expression, activity, or level of any of them. In some embodiments of any 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 thereof, the method comprising: a) detecting deregulation of the Ras gene, Ras protein, or the expression, activity, or level of 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 deregulation of the Ras gene, Ras protein, or the expression, activity, or level of any of them comprises one or more Ras protein point mutations / insertions / deletions.

[0163] In some embodiments of any of the methods or uses described herein, the subject is identified or diagnosed as having a cancer associated with dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject having a tumor (s) that is positive for dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject in which the tumor has dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a KRas-related cancer. In some embodiments, provided herein is a method for treating a KRas-related cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of 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 KRas gene, the KRas protein, or the expression or activity or level of any of them comprises one or more KRas protein point mutations / insertions / deletions. Non-limiting examples of KRas protein point mutations / insertions / deletions are described in Table 1.

[0164] In some embodiments of any of the methods or uses described herein, the subject is identified or diagnosed as having a cancer associated with dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject having a tumor (s) that is positive for dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject in which the tumor has dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject is suspected of having an HRas-related cancer. In some embodiments, provided herein is a method for treating an HRas-related cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the HRas gene, HRas protein, or the expression or activity or level of 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 HRas gene, HRas protein, or the expression or activity or level of any of them comprises one or more HRas protein point mutations / insertions / deletions. Non-limiting examples of HRas protein point mutations / insertions / deletions are described in Table 2.

[0165] In some embodiments of any of the methods or uses described herein, the subject is identified or diagnosed as having a cancer associated with dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject having a tumor (s) that is positive for dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject in which the tumor has dysregulation of the NRas gene, NRas protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject is suspected of having an NRas-related cancer. In some embodiments, provided herein is a method for treating an NRas-related cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the NRas gene, NRas protein, or the expression or activity or level of 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 NRas gene, NRas protein, or the expression or activity or level of any of them comprises one or more NRas protein point mutations / insertions / deletions. Non-limiting examples of NRas protein point mutations / insertions / deletions are described in Table 3.

[0166] In some embodiments of any of the methods or uses described herein, the subject is identified or diagnosed as having cancer associated with dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject having a tumor (s) that is positive for dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject can be a subject in which the tumor has dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them. In some embodiments of any of the methods or uses described herein, the subject is suspected of having SOS1-related cancer. In some embodiments, provided herein is a method for treating SOS1-related cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of 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 SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them comprises one or more SOS1 protein point mutations / insertions / deletions. Non-limiting examples of SOS1 protein point mutations / insertions / deletions are described in Table 4.

[0167] In some embodiments, cancers associated with deregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or level of any of them are determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA. In some embodiments, tumors associated with deregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or level of any of them are determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA.

[0168] In some embodiments, cancers associated with deregulation of Ras genes, Ras proteins, or the expression or activity or level of any of them are determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA. In some embodiments, tumors associated with deregulation of Ras genes, Ras proteins, or the expression or activity or level of any of them are determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA.

[0169] In some embodiments, cancers associated with deregulation of KRas genes, KRas proteins, or the expression or activity or level of any of them are determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA. In some embodiments, tumors associated with deregulation of KRas genes, KRas proteins, or the expression or activity or level of any of them are determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA.

[0170] In some embodiments, cancers associated with dysregulation of the HRas gene, HRas protein, or their expression or activity or levels are determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit. In some embodiments, tumors associated with dysregulation of the HRas gene, HRas protein, or their expression or activity or levels are determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit.

[0171] In some embodiments, cancers associated with dysregulation of the NRas gene, NRas protein, or their expression or activity or levels are determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit. In some embodiments, tumors associated with dysregulation of the NRas gene, NRas protein, or their expression or activity or levels are determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit.

[0172] In some embodiments, cancers associated with dysregulation of the SOS1 gene, SOS1 protein, or their expression or activity or levels are determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit. In some embodiments, tumors associated with dysregulation of the SOS1 gene, SOS1 protein, or their expression or activity or levels are determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit.

[0173] In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor having dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them. Also provided is a method of treating a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject has a clinical record indicating that the subject has dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them.

[0174] In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor having dysregulation of a Ras gene, a Ras protein, or the expression or activity or level of any of them. Also provided is a method of treating a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject has a clinical record indicating that the subject has dysregulation of a Ras gene, a Ras protein, or the expression or activity or level of any of them.

[0175] In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor having dysregulation of a KRas gene, a KRas protein, or the expression or activity or level of any of them. Also provided is a method of treating a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject has a clinical record indicating that the subject has dysregulation of a KRas gene, a KRas protein, or the expression or activity or level of any of them.

[0176] In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor having dysregulation of the HRas gene, the HRas protein, or the expression or activity or level of any of them. Also provided is a method of treating a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject has a clinical record indicating that the subject has dysregulation of the HRas gene, the HRas protein, or the expression or activity or level of any of them.

[0177] In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor having dysregulation of the NRas gene, the NRas protein, or the expression or activity or level of any of them. Also provided is a method of treating a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject has a clinical record indicating that the subject has dysregulation of the NRas gene, the NRas protein, or the expression or activity or level of any of them.

[0178] In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor having dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them. Also provided is a method of treating a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject has a clinical record indicating that the subject has dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them.

[0179] In some embodiments, the methods provided herein include performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or level of any of them. In some such embodiments, the method also includes administering to a subject determined to have a dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining, via an assay performed on a sample obtained from the subject, whether the subject has a dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or level of any of them. In such embodiments, the method also includes administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the methods provided herein include performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of a Ras gene, a Ras protein, or the expression or level of any of them. In some such embodiments, the method also includes administering to a subject determined to have a dysregulation of a Ras gene, a Ras protein, or the expression or activity or level of any of them, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining, via an assay performed on a sample obtained from the subject, whether the subject has a dysregulation of a Ras gene, a Ras protein, or the expression or level of any of them. In such embodiments, the method also includes administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the methods provided herein include performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the KRas gene, the KRas protein, or the expression or level of either of them. In some such embodiments, the method also includes administering to a subject determined to have a dysregulation of the KRas gene, the KRas protein, or the expression, activity, or level of either of them, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining, via an assay performed on a sample obtained from the subject, that the subject has a dysregulation of the KRas gene, the KRas protein, or the expression or level of either of them. In such embodiments, the method also includes administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, the methods provided herein include performing an assay on a sample obtained from a subject to determine whether the subject has a dysregulation of the HRas gene, the HRas protein, or the expression or level of either of them. In some such embodiments, the method also includes administering to a subject determined to have a dysregulation of the HRas gene, the HRas protein, or the expression, activity, or level of either of them, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining, via an assay performed on a sample obtained from the subject, that the subject has a dysregulation of the HRas gene, the HRas protein, or the expression or level of either of them. In such embodiments, the method also includes administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the methods provided herein include performing an assay on a sample obtained from a subject to determine whether the subject has dysregulation of the NRas gene, NRas protein, or the expression or level of any of them. In some such embodiments, the method also includes administering to the subject determined to have dysregulation of the NRas gene, NRas protein, or the expression, activity, or level of any of them, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining, via an assay performed on a sample obtained from the subject, that the subject has dysregulation of the NRas gene, NRas protein, or the expression or level of any of them. In such embodiments, the method also includes administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the methods provided herein include performing an assay on a sample obtained from a subject to determine whether the subject has dysregulation of the SOS1 gene, SOS1 protein, or the expression or level of any of them. In some such embodiments, the method also includes administering to the subject determined to have dysregulation of the SOS1 gene, SOS1 protein, or the expression, activity, or level of any of them, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining, via an assay performed on a sample obtained from the subject, that the subject has dysregulation of the SOS1 gene, SOS1 protein, or the expression or level of any of them. In such embodiments, the method also includes administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments of any of the methods or uses described herein, the cancer is a blood cancer. Examples of blood cancers (e.g., blood cancers that are Ras pathway-related cancers) include, for example, leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, juvenile myelomonocytic leukemia (JMML), and hairy cell leukemia) and lymphoma (e.g., non-Hodgkin lymphoma, Hodgkin disease cutaneous T-cell lymphoma, and Burkitt lymphoma).

[0186] In some embodiments of any of the methods or uses described herein, the cancer is a solid tumor. Examples of solid tumors (e.g., solid tumors that are Ras pathway-related cancers) include, for example, thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, bronchial adenoma, and pleuropulmonary blastoma), pancreatic cancer, pancreatic ductal cancer, biliary tract cancer, breast cancer (e.g., invasive ductal cancer, invasive lobular cancer, intraductal carcinoma, and lobular carcinoma in situ), gastric cancer, small intestine cancer, colon cancer, colorectal cancer, peritoneal cancer, ovarian cancer, uterine cancer, liver cancer, uterine cancer, endometrial cancer, prostate cancer (including benign prostatic hyperplasia), testicular cancer, bladder cancer, ureteral cancer, uterine cancer, head and neck cancer, brain cancer (e.g., glioblastoma, brainstem and lower brainstem glioma, cerebral and cerebral astrocytoma, medulloblastoma, and ependymoma), squamous cell carcinoma, and malignant tumor.

[0187] In some embodiments, the subject is human.

[0188] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful for treating Ras pathway-related cancers.

[0189] Accordingly, provided herein is a method for treating a subject diagnosed or identified as having a Ras pathway-related cancer, such as any of the exemplary Ras pathway-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0190] Accordingly, provided herein is a method for treating a subject diagnosed or identified as having a Ras pathway-related cancer, such as any of the exemplary Ras pathway-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0191] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful for treating Ras-related cancers.

[0192] Accordingly, provided herein is a method for treating a subject diagnosed or identified as having a Ras-related cancer, such as any of the exemplary Ras-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0193] Accordingly, provided herein is also a method for treating a subject diagnosed or identified as having a Ras-related cancer, such as any of the exemplary Ras-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0194] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful for treating KRas-related cancers.

[0195] Accordingly, provided herein is also a method for treating a subject diagnosed or identified as having a KRas-related cancer, such as any of the exemplary KRas-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0196] Accordingly, provided herein is also a method for treating a subject diagnosed or identified as having a KRas-related cancer, such as any of the exemplary KRas-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0197] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful for treating HRas-related cancers.

[0198] Accordingly, provided herein is also a method for treating a subject diagnosed or identified as having an HRas-related cancer, such as any of the exemplary HRas-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0199] Accordingly, provided herein is also a method for treating a subject diagnosed or identified as having an HRas-related cancer, such as any of the exemplary HRas-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0200] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful for treating NRas-related cancers.

[0201] Accordingly, provided herein is also a method for treating a subject diagnosed or identified as having an NRas-related cancer, such as any of the exemplary NRas-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0202] Accordingly, provided herein is also a method for treating a subject diagnosed or identified as having an NRas-related cancer, such as any of the exemplary NRas-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0203] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful for treating SOS1-related cancers.

[0204] Accordingly, provided herein is also a method for treating a subject diagnosed or identified as having an SOS1-related cancer, such as any of the exemplary SOS1-related cancers disclosed herein, the method 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 Examples 1-81, or a pharmaceutically acceptable salt thereof.

[0205] Dysregulation of the expression, activity, or level of a Ras pathway protein, a Ras pathway gene, or any (e.g., one or more) thereof can contribute to tumorigenesis. For example, a fusion protein can have increased activity (e.g., in the case of SOS1, increased Ras activity and / or increased GEF activity due to more favorable binding) compared to a wild-type Ras pathway protein, and increased expression (e.g., increased levels) of a wild-type Ras pathway protein in mammalian cells can result in abnormal cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells), and Ras pathway mRNA splice variants can also result in dysregulation of the Ras pathway.

[0206] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) penetration. Such compounds are capable of crossing the blood-brain barrier and inhibiting 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, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or combinations thereof) activity within the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in an effective amount. For example, the treatment of a subject having cancer (e.g., Ras pathway-related cancer such as Ras pathway-related brain or CNS cancer) can include administration (e.g., oral administration) of the compound to the subject. In some such embodiments, the compounds provided herein are useful for treating primary or metastatic brain tumors. For example, the compound can be used in the treatment of one or more gliomas (e.g., see the tumors listed in Louis, D.N. et al. Acta Neuropathol 131(6), 803-820 (June 2016)), such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendroglioma, ependymoma, and mixed glioma, meningioma, medulloblastoma, ganglioglioma, schwannoma (neurilemmoma), and craniopharyngioma. In some embodiments, the brain tumor is a primary brain tumor.In some embodiments, the subject has been previously treated with another anti-cancer agent, such as another Ras pathway inhibitor (e.g., a compound other than a compound of general formula (I), or an inhibitor of 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 combinations thereof), or combinations thereof). In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the subject has been previously treated with another anti-cancer agent, such as another Ras pathway inhibitor (e.g., a compound other than a compound of formula (I), or an inhibitor of another Ras pathway gene or protein).

[0207] 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 aggregate-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 microscopy (e.g., confocal microscopy). In some such embodiments, the ability of the compound to penetrate the surface barrier of the model can be represented by the 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 live cells, where it is hydrolyzed by intracellular esterases to produce a fluorescent compound that is retained within the cell and can be quantified by a spectrophotometer. 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), far-red IRDye® 650 (LICOR #929-70020), fluorescein sodium (Na-F), lucifer yellow (LY), 5’ carboxyfluorescein, and calcein-acetoxymethyl ester (calcein-AM). In some embodiments, the BBB model (e.g., tissue or cell aggregate) can be sectioned, and the compounds 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 a transcellular transport system 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, assays to determine whether a compound can be effluxed by P-glycoprotein (Pgp) include monolayer efflux assays in which the movement of a compound through Pgp is quantified 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). An alternative in vivo assay for identifying compounds that cross the blood-brain barrier includes phage-based systems (see, for example, 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 are not bound to brain tissue can be detected using LC-MS / MS (Cyprotex: Brain Tissue Binding Assay www.cyprotex.com / admepk / protein_binding / brain-tissue-binding / ).

[0208] In some embodiments, the subject is identified or diagnosed as having a cancer (Ras pathway-related cancer) associated with a regulatory defect in a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). In some embodiments, the subject has a tumor (e.g., as determined using an assay or kit approved by a regulatory agency) that is positive for a regulatory defect in a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them. The subject can be a subject having a tumor (s) (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit) that is positive for a regulatory defect in a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them. The subject can be a subject in which the tumor has a regulatory defect in a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of them (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an 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 a clinical record (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein) indicating that the subject has a tumor having a regulatory defect in a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them.

[0209] In some embodiments, the subject is identified or diagnosed as having a cancer (Ras-related cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit) associated with dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them. In some embodiments, the subject has a tumor (e.g., as determined using an assay or kit approved by a regulatory agency) that is positive for dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them. The subject can be a subject having a tumor (s) (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit) that is positive for dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them. The subject can be a subject in which the tumor has dysregulation of the Ras gene, Ras protein, or the expression or activity or level thereof (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an FDA-approved kit or assay). In some embodiments, the subject is suspected of having a Ras-related cancer. In some embodiments, the subject has a clinical record (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein) indicating that the subject has a tumor having dysregulation of the Ras gene, Ras protein, or the expression or activity or level of any of them.

[0210] In some embodiments, the subject is identified or diagnosed as having a cancer (KRas-related cancer) associated with dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency). For example, the subject has a tumor that is positive for a mutation as set forth in Table 1. The subject can be a subject having a tumor (s) that is positive for dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). The subject can be a subject in which the tumor has dysregulation of the KRas gene, the KRas protein, or the expression or activity or level thereof (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an FDA-approved kit or assay). In some embodiments, the subject is suspected of having a KRas-related cancer. In some embodiments, the subject has a clinical record (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein) indicating that the subject has a tumor having dysregulation of the KRas gene, the KRas protein, or the expression or activity or level of any of them.

[0211] In some embodiments, the subject is identified or diagnosed as having a cancer (HRas-related cancer) associated with dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them (e.g., as determined using an assay or kit approved by a regulatory agency). For example, the subject has a tumor that is positive for a mutation as set forth in Table 2. The subject can be a subject having a tumor (s) that is positive for dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). The subject can be a subject in which the tumor has dysregulation of the HRas gene, HRas protein, or the expression or activity or level of them (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an FDA-approved kit or assay). In some embodiments, the subject is suspected of having an HRas-related cancer. In some embodiments, the subject has a clinical record (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein) indicating that the subject has a tumor having dysregulation of the HRas gene, HRas protein, or the expression or activity or level of any of them.

[0212] In some embodiments, the subject is identified or diagnosed as having a cancer associated with NRas (NRas-related cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., an assay or kit approved by the FDA) that involves dysregulation of the NRas gene, the NRas protein, or the expression or activity or level of any of them. In some embodiments, the subject has a tumor (e.g., as determined using an assay or kit approved by a regulatory agency) that is positive for dysregulation of the NRas gene, the NRas protein, or the expression or activity or level of any of them. For example, the subject has a tumor that is positive for the mutations as set forth in Table 3. The subject can be a subject having a tumor (s) (e.g., identified as positive using an assay or kit approved by a regulatory agency, e.g., an assay or kit approved by the FDA) that is positive for dysregulation of the NRas gene, the NRas protein, or the expression or activity or level of any of them. The subject can be a subject in which the tumor has dysregulation of the NRas gene, the NRas protein, or the expression or activity or level of them (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, e.g., an assay or kit approved by the FDA). In some embodiments, the subject is suspected of having an NRas-related cancer. In some embodiments, the subject has a clinical record (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein) indicating that the subject has a tumor having dysregulation of the NRas gene, the NRas protein, or the expression or activity or level of any of them.

[0213] In some embodiments, the subject is identified or diagnosed as having a cancer associated with SOS1 (SOS1-related cancer) (e.g., as determined using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA) that involves dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them. In some embodiments, the subject has a tumor (e.g., as determined using an assay or kit approved by a regulatory agency) that is positive for dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them. For example, the subject has a tumor that is positive for a mutation as set forth in Table 4. The subject can be a subject having a tumor (s) (e.g., identified as positive using an assay or kit approved by a regulatory agency, such as an assay or kit approved by the FDA) that is positive for dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them. The subject can be a subject in which the tumor has dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of them (e.g., the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an assay or kit approved by the FDA). In some embodiments, the subject is suspected of having an SOS1-related cancer. In some embodiments, the subject has a clinical record (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein) indicating that the subject has a tumor having dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or level of any of them.

[0214] In some embodiments of any of the methods or uses described herein, an assay used to determine whether a subject has a dysregulation of a Ras pathway gene, or a Ras pathway protein, or the expression or activity or level of any of them using a sample from the subject can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, fluorescence in situ hybridization (FISH) analysis, Southern blotting, Western blotting, fluorescence-activated cell sorting (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, an assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay can utilize other detection methods known in the art to detect dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression or activity or level of any of them. In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a Ras pathway-related cancer, a subject having one or more symptoms of a Ras pathway-related cancer, or a subject with an increased risk of developing a Ras pathway-related cancer.

[0215] In some embodiments, dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of any of them can be identified using liquid biopsy (also variously referred to as fluid biopsy or liquid-phase biopsy). See, for example, Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of any of them. Liquid biopsy can be performed on biological samples relatively easily obtained from a subject (e.g., via simple blood draw), and is generally less invasive than conventional methods used to detect total tumor burden and / or dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of any of them. In some embodiments, liquid biopsy can be used to detect the presence of dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of 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 fluid, bile, lymph fluid, cyst fluid, feces, 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 (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 identify dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of any of them.

[0216] 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. (For example, but not limited to, using sensitive detection techniques such as next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) Analysis of ctDNA can be used to identify dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of any of them.

[0217] In some embodiments, ctDNA derived from a single gene can be detected using a liquid biopsy. In some embodiments, ctDNA derived from multiple genes (e.g., 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 between these numbers of genes) can be detected using a liquid biopsy. In some embodiments, ctDNA derived from multiple genes can be detected using any of a variety of commercially available test panels (e.g., a commercially available test panel designed to detect dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of any of them). A liquid biopsy can be used to detect dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of 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, a liquid biopsy can be used to detect germline mutations. In some embodiments, a liquid biopsy can be used to detect somatic mutations. In some embodiments, a liquid biopsy can be used to detect primary gene mutations (e.g., primary mutations or primary fusions associated with the initial onset of a disease, e.g., cancer). In some embodiments, the dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of any of them identified using a liquid biopsy is also present in cancer cells present in a subject (e.g., in a tumor). In some embodiments, any of the types of dysregulation of Ras pathway genes, Ras pathway proteins, or the expression or activity or levels of any of them described herein can be detected using a liquid biopsy. In some embodiments, gene mutations identified via a liquid biopsy can be used to identify a subject as a candidate for a particular treatment.For example, detection of dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them in a subject can indicate that the subject would respond to treatment involving administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0218] Some embodiments of these methods can further include administering to the subject at least one dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof between a first time point and a second time point. For example, a reduction in the allele frequency (AF) of dysregulation of a Ras pathway gene in cfDNA obtained from the subject at a second time point compared to the AF of dysregulation of the Ras pathway gene in cfDNA obtained from the subject at a first time point (e.g., a 1% to about 99% reduction, a 1% reduction to about 50% reduction, a about 1% reduction to about 10% reduction, a about 50% to about 99% reduction, or a about 75% to about 95% reduction) indicates that the compound of formula (I) or a pharmaceutically acceptable salt thereof was effective in the subject. In some embodiments, the AF is reduced such that the level is below the detection limit of the instrument. Alternatively, an increase in the AF of dysregulation of a Ras pathway gene in cfDNA obtained from the subject at a second time point compared to the AF of dysregulation of the Ras pathway gene in cfDNA obtained from the subject at a first time point indicates that the compound of formula (I) or a pharmaceutically acceptable salt thereof was not effective in the subject. Some embodiments of these methods can further include administering an additional dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject determined to be responsive to the compound of formula (I) or a pharmaceutically acceptable salt thereof. Some embodiments of these methods can further include administering a different treatment (e.g., a treatment not including administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as monotherapy) to a subject determined to be non-responsive to the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0219] In some examples of these methods, the time difference between the first time point and the second time point can be from about 1 day to about 1 year, from about 1 day to about 1 month, from about 1 day to about 5 days, from about 1 month to about 3 months, from about 3 months to about 6 months, or from about 7 months to about 9 months. In some embodiments of these methods, the subject can be previously identified as having a cancer having 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 been previously diagnosed as having any of the cancer types described herein. In some embodiments of these methods, the subject can have one or more metastases (e.g., one or more brain metastases).

[0220] In some of the above embodiments, the cfDNA includes ctDNA such as Ras pathway-related (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or combinations thereof) related) ctDNA. For example, the cfDNA is ctDNA such as Ras pathway-related ctDNA. In some embodiments, at least some portions of the cfDNA are determined to be Ras pathway-related ctDNA, e.g., the sequencing and / or quantified amount of the total cfDNA is determined to have a Ras pathway fusion and / or overexpression of the Ras pathway.

[0221] Combination In the field of medical oncology, it is common practice to use combinations of different forms of treatment to treat each subject having cancer. In medical oncology, in addition to the compositions provided herein, such conjoint treatment or other component(s) of the therapy can be, for example, surgery, radiation therapy, and chemotherapeutic agents such as other Ras pathway inhibitors, kinase inhibitors, signal transduction inhibitors, and / or monoclonal antibodies. For example, the surgery can be open surgery or minimally invasive surgery. Thus, the compounds of formula (I) or pharmaceutically acceptable salts thereof can also be useful as adjuvants to cancer treatment, i.e., they can be used in combination with one or more additional therapies or therapeutic agents, for example, chemotherapeutic agents that function by the same or different mechanisms of action. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof can be used prior to the administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof over a period of time and then can undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the size (e.g., tumor mass) of the tumor prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof over a period of time under one or more rounds of radiation therapy. In some embodiments, treatment with one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the size (e.g., tumor mass) of the tumor prior to one or more rounds of radiation therapy.

[0222] As used herein, a "Ras pathway-targeted therapeutic agent" includes any compound that exhibits an inactivating activity (e.g., active site (e.g., competitive) inhibition, allosteric inhibition, dimerization inhibition, expression inhibition, protein-protein interaction inhibition, and induction of degradation) of any protein in the Ras pathway. Non-limiting examples of proteins in the Ras pathway include any 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 combinations thereof. In some embodiments, the Ras pathway-targeted therapeutic agent can be selective for a protein in the Ras pathway. For example, the Ras pathway-targeted therapeutic agent can be selective for a Ras protein (e.g., KRas, HRas, and / or NRas, or a variant thereof). Such an agent can also be referred to as a "Ras modulator". In some embodiments, the Ras modulator is a covalent inhibitor. In some embodiments, the Ras pathway-targeted therapeutic agent can be selective for a specific Ras protein (e.g., KRas, HRas, or NRas), or a variant thereof (e.g., G12 variant, G13 variant, or Q61 variant). Non-limiting examples of KRas-targeted therapeutic agents (e.g., KRas inhibitors (such as 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.

[0223] 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, such as chemotherapeutic agents that function by the same or different mechanisms of action. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used prior to the administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof 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 then can undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof reduces the size (e.g., tumor mass) of the tumor prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof 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 rounds 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 the size (e.g., tumor mass) of the tumor prior to one or more rounds of radiation therapy.

[0224] In some embodiments, one or more additional therapies or therapeutic agents independently include an EGFR inhibitor (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, and ormutinib), 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 MEK inhibitor (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib), a RAS (KRas, HRas, and / or NRas) inhibitor (e.g., MRTX849, LY3499446, JNJ-74699157, AMG510, and AZD4785), a Bcr-Abl inhibitor (e.g., imatinib, dasatinib, nilotinib), an FGFR1, 2, or 3 inhibitor (e.g., nintedanib), a MET inhibitor (e.g., capmatinib), an AXL inhibitor (e.g., citravatinib), a RET inhibitor (e.g., sunitinib and selpercatinib), an ERK inhibitor (e.g., ulixertinib), a Shp2 inhibitor (e.g., RLY-1971, RMC-4630, TNO155, and JAB-3068), a Bcl-2 inhibitor (e.g., ABT-263, obatoclax, ABT-737, and navitoclax), an mTOR inhibitor (e.g., everolimus and tacrolimus), a Trk inhibitor (e.g., larotrectinib and entrectinib), a checkpoint inhibitor (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and pidilizumab) or other immunotherapy (e.g., monoclonal antibody), a PARP inhibitor (e.g., olaparib), a PI3K inhibitor (e.g., buparlisib), a BET inhibitor (e.g., GSK1210151A), a Raf inhibitor (e.g., encorafenib), an MCL-1 inhibitor (e.g., AZD5991), an AKT inhibitor (e.g., miltefosine), a PDK1 inhibitor (e.g., GSK2334470), and other chemotherapeutic agents such as taxanes (e.g., paclitaxel and docetaxel), platinum-based agents (e.g., cisplatin and carboplatin),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 (registered trademark) and gemcitabine hydrochloride (Gemzar (registered trademark))), alkylating agents (e.g., temozolomide (registered trademark) and temodal (registered trademark)), dactinomycin (also known as actinomycin-D, cosmege (registered trademark)), carmustine (BiCNU (registered trademark)), bendamustine (registered trademark), and lomustine (CeeNU (registered trademark))), and cytotoxic agents (e.g., vincristine, cytarabine, and pemetrexed).

[0225] Osimertinib (AZD9291, Meleitinib, 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), Nakotinib (ASP8273), Nazartinib (EGF816, NVS-816), PF-06747775, Icotinib (BPI-2009H), Afatinib (BIBW 2992, 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 mAb 806, ABT-806), Depatuxizumab mafodotin (ABT-414), ABT-806, mAb806, canertinib (CI-1033), sikonin, sikonin derivatives (e.g., deoxysikonin, isobutyrylsikonin, acetylsikonin, β,β-dimethylacrylsikonin, and acetylalkanin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG (registered trademark)), pelitinib (EKB-569), tarloroxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, valentinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG595, BDTX-189, avacitinib, Disruptin, CL-387785, EGFRBi arm-type autologous T cells, and epidermal growth factor receptor (EGFR) inhibitors such as 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.

[0226] Inhibitors of human epidermal growth factor receptor 2 (HER2 receptor) (also known as Neu, ErbB-2, CD340, or p185), such as trastuzumab (e.g., TRAZIMERA™, 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™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S-222611, and AEE-788.

[0227] In some embodiments, the FGFR inhibitor is selected from infliximab, AZD4547, erdafitinib (JNJ-42756493), nintedanib dovitinib, ponatinib, and TAS120.

[0228] In some embodiments, the ALK inhibitor is selected from alectinib, crizotinib (XALKORI®), ceritinib, AP26113, ASP3026, TSR-011, PF-06463922, X-396, and CEP-37440.

[0229] In some embodiments, the ROS1 inhibitor is selected from crizotinib (XALKORI®), ceritinib, lorlatinib, brigatinib, cabozantinib, and repotrectinib.

[0230] In some embodiments, the mTOR inhibitor is selected from everolimus, tacrolimus rapamycin, perifosine, and temsirolimus.

[0231] In some embodiments, the Trk inhibitor is selected from larotrectinib, lestaurtinib, and entrectinib.

[0232] In some embodiments, the RET inhibitor is selected from sunitinib (Sutent®), selpercatinib (RETEVMO®), vandetanib (Caprelsa®), motesanib (AMG706), sorafenib, regorafenib, and danusertib.

[0233] In some embodiments, the MET inhibitor is selected from capmatinib, tepotinib, savolitinib, crizotinib, cabozantinib, tivantinib, bozitinib, merestinib, glesatinib, citravatinib, olaratumab, and emibetuzumab.

[0234] In some embodiments, the AXL inhibitor is selected from citravatinib, bemcentinib, duberatinib, DS-1205, SLC-391, INCB081776, ONO-7475, and BA3011.

[0235] In some embodiments, the Shp2 inhibitor is selected from TNO155, BBP-398, JAB-3068, RMC-4360, and RLY-1971.

[0236] In some embodiments, the RAF inhibitor is a BRAF inhibitor, for example, 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.

[0237] In some embodiments, the PI3K inhibitor is selected from 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), serabelisib (TAK-117, MLN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), bractolisib (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.

[0238] In some embodiments, the AKT inhibitor is selected from 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, edelfosine, miltefosine, perifosine, erucylphosphocholine, elfornithine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine, API-1, ARQ092, BAY1125976, 3-oxo-thylcalicinic acid, lactoquinomycin, GSK2141795, ONC201, triciribine, A674563, and AT7867.

[0239] 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 hypeuticin.

[0240] In some embodiments, the ERK inhibitor is selected from FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcitriol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-oxozeaneol, 5-iodoberbisine, GDC0994, and ONC201.

[0241] In some embodiments, the PARP inhibitor includes 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.

[0242] In some embodiments, the RAS inhibitor is MRX849, LY3499446, JNJ-74699157, AMG510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRX-849.

[0243] In some embodiments, the PDK-1 inhibitor is selected from GSK2334470, JX06, SNS-510, and AR-12.

[0244] 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.

[0245] In some embodiments, the MCL-1 inhibitor is AZD5991.

[0246] In some embodiments, the Bcl-2 protein family inhibitor is selected from ABT-263, tetrocalcin A, antimycin, gossypol ((−)BL-193), obatoclax, HA14-1, oblimersen (Genasense®), (−)-gossypol acetic acid (AT-101), ABT-737, and navitoclax.

[0247] In some embodiments, the Bcr / Abl kinase inhibitor is selected from imatinib (Gleevec®), nilotinib, nilotinib (Tasigna®), dasatinib (BMS-345825), bosutinib (SKI-606), ponatinib (AP24534), bafetinib (INNO406), danusertib (PHA-739358), AT9283, saracatinib (AZD0530), and PF-03814735.

[0248] 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, enoblituzumab, JNJ-61610588, and indoximod. See, for example, Marin-Acevedo, et.al., J Hematol Oncol. 11:39 (2018).

[0249] In some embodiments, the immunotherapy is an antibody therapy (e.g., monoclonal antibody). In some embodiments, the antibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), rituximab (MabThera™, Rituxan®), edrecolomab (Panorex), daratumumab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, dinutuximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), necitumumab (Portrazza™), siltuximab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, urelumab, pidilizumab, and amatuximab.

[0250] In some embodiments, the other chemotherapeutic agents are selected from anthracyclines, alkylating agents, taxanes, platinum-based agents, eribulin (HALAVEN™), farnesyltransferase inhibitors, topoisomerase inhibitors, DNA synthesis inhibitors, and cytotoxic agents.

[0251] In some embodiments, the taxanes are selected from paclitaxel, docetaxel, cabazitaxel, abraxane, and taxotere.

[0252] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0253] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.

[0254] In some embodiments, the farnesyltransferase inhibitor is selected from lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0255] 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 tufoploside).

[0256] In some embodiments, the DNA synthesis inhibitor is selected from capecitabine (Xeloda®), gemcitabine hydrochloride (Gemzar®), nelarabine (Arranon® and Atriance®), and sapacitabine.

[0257] In some embodiments, the alkylating agent is selected from 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®), chlorambucil (Leukeran®), cyclophosphamide (Cytoxan® and Neosar®), dacarbazine (DTIC-Dome®), altretamine (Hexalen®), ifosfamide (Ifex®), prednimustine, procarbazine (Matulane®), mechlorethamine (Mustargen®), streptozocin (Zanosar®), and thiotepa (Thioplex®).

[0258] In some embodiments, the cytotoxic agent is selected from bleomycin, cytarabine, dacarbazine, methotrexate, mitomycin C, pemetrexed, and vincristine.

[0259] As used herein, 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 in the treatment of cancer, wherein the amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are both effective for the treatment of cancer; a pharmaceutical composition comprising such a combination; the use of such a combination for the preparation of a medicament for the treatment of cancer; and a commercial package or product comprising such a combination as a combined formulation for parallel, separate or sequential use, and a method for treating cancer in a subject in need thereof are also provided. In some embodiments, the cancer is a Ras pathway-related cancer.

[0260] The term "pharmaceutical combination" as used herein refers to a pharmaceutical therapy resulting from the mixing or combination of two or more active ingredients, including both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are both administered to the subject simultaneously in a single composition or dosage form. The term "non-fixed combination" means that the compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent) are formulated as separate compositions or dosages such that they can be administered to a subject in need thereof simultaneously, concurrently or sequentially with a variable intermediate time interval, and such administration provides effective levels of two or more compounds in the subject's body. These also apply to cocktail therapies, e.g., the administration of three or more active ingredients.

[0261] Accordingly, there is also provided herein a method of treating cancer comprising administering to a subject in need of cancer treatment a pharmaceutical combination for the treatment of cancer comprising (a) 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 the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent together are effective for the treatment of 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 dosages. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially as separate dosages in any order, in a jointly effective amount, for example, daily or intermittently. 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 dosage. In some embodiments, the cancer is a Ras pathway-related cancer.

[0262] Accordingly, provided herein is a method for doing so in a subject in need of inhibiting, preventing, assisting in preventing, or reducing the symptoms of cancer metastasis, the method comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Such methods can be used for the treatment of one or more of the cancers described herein. See, for example, US Publication No. 2013 / 0029925, International Publication No. 2014 / 083567, and US Patent No. 8,568,998. See, for example, 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-related cancer. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent described herein.

[0263] The term "metastasis" is a term known in the art and means the formation of additional tumors (e.g., solid tumors) at sites remote from the primary tumor in a subject, where the additional tumors contain cancer cells that are the same or similar to those of the primary tumor.

[0264] A method of reducing the risk of developing metastases or additional metastases in a subject having a Ras pathway-related cancer, the method comprising selecting, identifying, or diagnosing a subject as having a Ras pathway-related cancer, and administering to the subject so selected, identified, or diagnosed as having a Ras pathway-related cancer, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method of reducing the risk of developing metastases or additional metastases in a subject having a Ras pathway-related cancer, the method comprising administering to a subject having a Ras pathway-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in the risk of developing metastases or additional metastases in a subject having a Ras pathway-related cancer is compared to the risk of developing metastases or additional metastases in the subject prior to treatment, or to a subject or population of subjects having a similar or the same Ras pathway-related cancer who have not been treated or who have 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 the compound of formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0265] A method of reducing the risk of developing metastases or additional metastases in a subject having a Ras-related cancer, the method comprising selecting, identifying, or diagnosing a subject as having a Ras-related cancer and administering to the subject so selected, identified, or diagnosed as having a Ras-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method of reducing the risk of developing metastases or additional metastases in a subject having a Ras-related cancer, the method comprising administering to the subject having a Ras-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in the risk of developing metastases or additional metastases in a subject having a Ras-related cancer is compared to the risk of developing metastases or additional metastases in the subject prior to treatment or to a subject or population of subjects having a similar or the same Ras-related cancer that has not been treated 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 the compound of formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0266] A method of reducing the risk of developing metastases or additional metastases in a subject having a KRas-related cancer, the method comprising selecting, identifying, or diagnosing a subject as having a KRas-related cancer, and administering to the subject so selected, identified, or diagnosed as having a KRas-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method of reducing the risk of developing metastases or additional metastases in a subject having a KRas-related cancer, the method comprising administering to the subject having a KRas-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in the risk of developing metastases or additional metastases in a subject having a KRas-related cancer is compared to the risk of developing metastases or additional metastases in the subject prior to treatment, or to a subject or population of subjects having a similar or the same KRas-related cancer who have not been treated or have 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 the compound of formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0267] A method of reducing the risk of developing metastases or additional metastases in a subject having an HRas-related cancer, the method comprising selecting, identifying, or diagnosing a subject as having an HRas-related cancer, and administering to the subject so selected, identified, or diagnosed as having an HRas-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method of reducing the risk of developing metastases or additional metastases in a subject having an HRas-related cancer, the method comprising administering to the subject having an HRas-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in the risk of developing metastases or additional metastases in a subject having an HRas-related cancer is compared to the risk of developing metastases or additional metastases in the subject prior to treatment, or to a subject or population of subjects having a similar or the same HRas-related cancer who have not been treated or have 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.

[0268] A method of reducing the risk of developing metastases or additional metastases in a subject having NRas-related cancer, the method comprising selecting, identifying, or diagnosing a subject as having NRas-related cancer and administering to the subject so selected, identified, or diagnosed as having NRas-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method of reducing the risk of developing metastases or additional metastases in a subject having NRas-related cancer, the method comprising administering to the subject having NRas-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in the risk of developing metastases or additional metastases in a subject having NRas-related cancer is compared to the risk of developing metastases or additional metastases in the subject prior to treatment or to a subject or population of subjects having a similar or the same NRas-related cancer who have not been treated or who have 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 the compound of formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0269] A method of reducing the risk of developing metastasis or additional metastases in a subject having SOS1-related cancer, the method comprising selecting, identifying, or diagnosing a subject as having SOS1-related cancer, and administering to the subject so selected, identified, or diagnosed as having SOS1-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Also provided is a method of reducing the risk of developing metastasis or additional metastases in a subject having SOS1-related cancer, the method comprising administering to a subject having SOS1-related cancer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The reduction in the risk of developing metastasis or additional metastases in a subject having SOS1-related cancer may be compared to the risk of developing metastasis or additional metastases in the subject prior to treatment, or to a subject or population of subjects having a similar or the same SOS1-related cancer that has not been treated 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.

[0270] The phrase "risk of developing metastasis" means the risk that a subject having a primary tumor will develop additional tumors (e.g., solid tumors) at sites remote from the primary tumor in the subject over a period of time, the additional tumors comprising cancer cells that are the same or similar to the primary tumor. Methods for reducing the risk of developing metastasis in a subject having cancer are described herein.

[0271] The phrase "risk of developing additional metastases" means the risk that a subject having a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors contain cancer cells that are the same as or similar to the primary tumor) will develop one or more further tumors distant from the primary tumor, and the further tumors contain cancer cells that are the same as or similar to the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0272] Treatment of a subject having cancer with a multi-kinase 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 result in dysregulation of Ras pathway genes, Ras pathway proteins, or their expression or activity or levels in cancer. 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.

[0273] Treatment of a subject having cancer with an SOS1 inhibitor in combination with a multi-kinase 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) can enhance the therapeutic effect as compared to treatment of the same or similar subjects with an SOS1 inhibitor as a monotherapy or with a multi-kinase inhibitor or a target-specific kinase inhibitor as a monotherapy. See, e.g., 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., Clin. Cancer Res. 23:1988-1997, 2017.

[0274] Disclosed herein is a method of treating a subject having cancer (e.g., any of the cancers described herein) who has previously been administered a multi-kinase 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 a 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 a 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.

[0275] A method for inhibiting SOS1 activity in mammalian cells, comprising contacting the mammalian cells with a compound of formula (I) is also provided. In some embodiments, contacting is in vitro. In some embodiments, contacting is in vivo. In some embodiments, contacting is in vivo and 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 cancer described herein. In some embodiments, the mammalian cancer cells are Ras pathway-related cancer cells.

[0276] A method for inhibiting Ras activity in mammalian cells, comprising contacting the mammalian cells with a compound of formula (I) is also provided. In some embodiments, contacting is in vitro. In some embodiments, contacting is in vivo. In some embodiments, contacting is in vivo and 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 cancer described herein. In some embodiments, the mammalian cancer cells are Ras pathway-related cancer cells.

[0277] A method for inhibiting SOS1-Ra (e.g., KRas, HRas, and / or NRas) protein-protein interactions in mammalian cells, the method comprising contacting a mammalian cell with a compound of formula (I) is also provided. In some embodiments, contacting is in vitro. In some embodiments, contacting is in vivo. In some embodiments, contacting is in vivo and 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-Ra (e.g., KRas, HRas, and / or NRas) protein-protein interactions. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any cancer described herein. In some embodiments, the mammalian cancer cells are Ras pathway-related cancer cells.

[0278] A method for inhibiting Ras pathway activity in mammalian cells, the method comprising contacting a mammalian cell with a compound of formula (I) is also provided. In some embodiments, contacting is in vitro. In some embodiments, contacting is in vivo. In some embodiments, contacting is in vivo and 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 cancer described herein. In some embodiments, the mammalian cancer cells are Ras pathway-related cancer cells.

[0279] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro or in vivo system. For example, "contacting" an SOS1 protein with a compound provided herein includes administering the compound provided herein to a subject such as a human having the SOS1 protein, and introducing the compound provided herein into a sample containing mammalian cells or a purified preparation containing, for example, the SOS1 protein.

[0280] Also provided herein is a method of inhibiting the growth of mammalian cells in vitro or in vivo, the method comprising contacting the mammalian 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.

[0281] The phrase "effective amount" means that when administered to a subject in need of such treatment, it is sufficient to (i) treat a Ras pathway-related disease or disorder (such as a Ras pathway-related cancer), (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof that would correspond to such amount, will vary depending on factors such as the particular compound, disease state and its severity, the identity of the subject in need of treatment (e.g., body weight), etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0282] Pharmaceutical composition When used as a medicament, the compounds of formula (I), including their pharmaceutically acceptable salts, can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be local (including transdermal, epidermal, ocular, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., intratracheal or intranasal by inhalation or insufflation of a powder or aerosol including by nebulizer), 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 continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oily bases, thickening agents, etc. may be required or desirable.

[0283] Also provided herein are pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients as the active ingredient. 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. When preparing the compositions provided herein, the active ingredient is typically admixed with the excipient, diluted by the excipient, or enclosed within such a carrier in the form of, for example, capsules, sachets, papers, or other containers. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions can be, for example, tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or a capsule.

[0284] Further provided herein are pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as the 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 wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0285] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, issued by the American Pharmaceutical Association and the British Pharmacopoeia Commission.

[0286] Methods of 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 and published by Marcel Dekker, Inc.

[0287] When preparing the composition in an oral dosage form, any of the conventional pharmaceutical media may be used. Accordingly, 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., and for solid oral preparations such as powders, capsules, and tablets, suitable carriers and additives include starch, sugar, diluents, granulating agents, lubricants, binders, disintegrants, etc. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, 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 may also be coated with a substance such as sugar or enteric-coated so as to regulate the major absorption site. For parenteral administration, the carrier is usually composed of sterile water, and other components may be added to increase solubility or preservability. Injectable suspensions or solutions may also be prepared using an aqueous carrier with appropriate additives. The pharmaceutical compositions herein will contain the amount of active ingredient necessary to deliver the effective dosage described herein per dosage unit, e.g., per tablet, capsule, powder, injection, tablespoonful, etc.

[0288] Compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated in unit dosage forms, and each dosage contains from about 5 to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit being calculated to contain a predetermined quantity of the active material (i.e., a compound of formula (I) or a pharmaceutically acceptable salt thereof) so as to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0289] In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient.

[0290] In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient.

[0291] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient.

[0292] 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 or more per day per adult, or any range 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 the active ingredient for symptomatic adjustment of the dosage to the subject being treated. The effective amount of the drug is usually supplied at a dosage level of about 0.1 mg / kg to about 1000 mg / kg of body weight per day, or any range therein. Preferably, the range is from about 0.5 to about 500 mg / kg of body weight per day, or any range therein. In one example, the range can be from about 0.1 to about 50.0 mg / kg of body weight per day, or any amount or range therein. In another example, the range can be from about 0.1 to about 15.0 mg / kg of body weight per day, or any range therein. In yet another example, the range can be from about 0.5 to about 7.5 mg / kg of body weight per day, or any amount or range therein. The pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered in a regimen of 1 to 4 times per day, or as a single daily dose.

[0293] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. The optimal dosage to be administered can be readily determined by one of ordinary skill in the art. Thus, it will be understood that the amount of the compound actually administered will usually be determined by a physician and will vary according to the relevant circumstances, including the method of administration, the actual compound being administered, the strength of the preparation, the condition being treated, and the progression of the disease state. In addition, factors related to the particular subject being treated, including the subject's response, age, weight, diet, time of administration, and severity of the subject's symptoms, will result in the need to adjust the dosage.

[0294] In some embodiments, the compounds provided herein can be administered in an amount in the range of about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein can be administered in an amount of 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. In some embodiments, such administration can be once daily or twice daily (BID) dosing.

[0295] One of ordinary skill in the art will recognize that both in vivo and in vitro tests using suitable, known, and generally accepted cell and / or animal models can predict the ability of a test compound to treat or prevent a given disorder.

[0296] One of ordinary skill in the art will further recognize that human clinical trials, including initial human dose range and efficacy studies in healthy subjects and / or subjects suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0297] As used herein, for example, there is provided a pharmaceutical kit useful for the treatment of Ras pathway-related diseases or disorders such as cancer, comprising one or more containers containing a pharmaceutical composition comprising an effective amount of a compound provided herein. Such kits can further comprise one or more of various conventional pharmaceutical kit components, such as containers with one or more pharmaceutically acceptable carriers, additional containers, etc., if desired, for example, to be readily apparent to those skilled in the art. Instructions indicating the amount of the administered component, guidelines for administration, and / or guidelines for mixing the components can also be included in the kit, either as an insert or a label.

Examples

[0298] Materials and Methods The compounds provided herein, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0299] The reactions for preparing the compounds provided herein can be carried out in a suitable solvent that 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, for example, a temperature within the range from the freezing temperature to the boiling temperature 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, the solvent suitable for the particular reaction step can be selected by one skilled in the art.

[0300] The preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, for example, in Protecting Group Chemistry, 1 st Ed., Oxford University Press, 2000, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 thIt can be found in Ed., Wiley-Interscience Publication, 2001, and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297(1997).

[0301] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectrometry, etc., 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 various methods including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” K.F. Blom, et al., J. Combi. Chem. 6(6), 874(2004)), normal phase silica chromatography, and supercritical fluid chromatography (SFC).

[0302] All solvents and reagents were obtained from commercial sources and used without further purification, unless otherwise indicated. Anhydrous solvents were purchased and used as supplied. Reactions were monitored by thin layer chromatography (TLC) visualized using a UV lamp (254 nm) and KMnO4 staining. 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 acquired on an Agilent 1260-6125B single quadrupole mass spectrometer using 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 and 210 nm and 280 nm). Chiral HPLC was performed on a Waters acquity UPC2 system under basic conditions on 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 performed by DAD (254 nm). Preparative HPLC was performed on a GILSON Trilution LC system using a Welch XB-C18 column (5um, 21.2 * 150 mm). Flash chromatography was performed on a Biotage Isolera Prime system using a Welch WelFlash flash column (40 - 63 μm). Compounds synthesized have a purity of 95% or greater, unless otherwise specified.

[0303] Abbreviations °C = Celsius temperature 1 H NMR = Proton nuclear magnetic resonance spectrum ACN = Acetonitrile AcOH = Acetic acid Boc = tert-butoxycarbonyl con. = concentration d = doublet DAST = diethylaminosulfur trifluoride DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DMF = N,N-dimethylformamide DMF-DMA = dimethylformamide dimethylacetal DMSO = dimethyl sulfoxide EtOAc and EA = ethyl acetate EtOH = ethanol ESI = electrospray ionization g = gram(s) hr = hour(s) HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC = high performance liquid chromatography IPA = 2-propanol LCMS = liquid chromatography-mass spectrum M = mass m / z = mass-to-charge ratio MeCN = acetonitrile MeOH = methanol MeONa = sodium methoxide mg = milligram(s) mL = milliliter mmol = millimole(s) mol = mole(s) MS = mass spectrum NaBH3CN = sodium cyanoborohydride NBS = N-bromosuccinimide Ni(dtbbpy)Br2 = (2,2’-bipyridine)nickel(II) dibromide obsd. = observed Pd(OAc)2 = Palladium(II) acetate Pd(dppf)Cl2 = (1,1’-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0) PE = Petroleum ether ppm = Parts per million rt = Room temperature RuPhos = 2-Dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl s = Singlet S-Phos = Dicyclohexyl(2’,6’-dimethoxy[1,1’-biphenyl]-2-yl)phosphane Tf = Trifluoromethanesulfonate T3P = Propylphosphonic anhydride t = Triplet TBAF = Tetrabutylammonium fluoride TEA = Triethylamine 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 XPhos = Dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane XPhos-Pd-G3 = (2-Dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate

[0304] Examples Example 1: (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide

Chemical formula

[0305] Step B: Methyl 2-amino-4-fluoro-5-morpholinobenzoate To a solution of methyl 4-fluoro-5-morpholino-2-nitrobenzoate (600 mg, 2.11 mmol) in MeOH (15 mL) was added Pd / C (200 mg, 1.65 mmol, 10 wt%). The reaction mixture was stirred under H2 atmosphere (1 atm) for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 0% - 50% EtOAc in PE) to give the title compound (530 mg, 87% yield). MS obsd.(ESI + ): 255.2 [(M + H) + .

[0306] Step C: Methyl 2-bromo-4-fluoro-5-morpholinobenzoate A solution of methyl 2-amino-4-fluoro-5-morpholinobenzoate (200 mg, 0.79 mmol) in acetonitrile (15 mL) was added with CuBr (169 mg, 1.18 mmol) and isopentyl nitrite (138 mg, 1.18 mmol). The reaction mixture was stirred at 60 °C for 1 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 0% - 50% EtOAc in PE) to afford the title compound (150 mg, 60% yield). MS obsd. (ESI + ): 79 Br / 81 Br 318.2, 320.2 [(M + H) + .

[0307] Step D: Methyl 4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzoate A solution of methyl 2-bromo-4-fluoro-5-morpholinobenzoate (100 mg, 0.31 mmol) in dioxane (0.5 mL) was added with 1-methylpiperidin-4-amine (72 mg, 0.63 mmol), Xantphos-Pd-G3 (60 mg, 0.06 mmol) and cesium carbonate (307 mg, 0.94 mmol). The mixture was stirred at 100 °C for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 0% - 5% MeOH in DCM) to afford the title compound (101 mg, 77% yield). MS obsd. (ESI + ): 352.3 [(M + H) + .

[0308] Step E: Lithium 4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzoate A solution of methyl 4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzoate (101 mg, 0.29 mmol.) in THF (4 mL) and H2O (1 mL) was added lithium hydroxide (14 mg). The reaction mixture was stirred at 45 °C for 16 h. The solvent was removed in vacuo to afford the title compound (100 mg, crude) as a white solid. The crude product was used for the next step without further purification. MS obsd.(ESI + ): 338.3 [(M+H) + .

[0309] Step F: (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide (Example 1) To a solution of lithium 4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzoate (100 mg, crude) in DMF (5 mL) was added HATU (133 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 10 min. Then, (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine, hydrochloride (85 mg, 0.38 mmol), and DIPEA (113 mg, 0.87 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with (3 × 20 mL), and the combined organic layers were dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (eluting with 0% - 50% MeOH in DCM), followed by preparative HPLC (ACN / H2O / 0.1% NH4HCO3) to afford the title compound (55.5 mg, yield 36%). MS obsd.(ESI + ): 509.3 [(M+H) + . 11H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (1H), 7.69 (1H), 7.63 (1H), 7.52 (1H), 7.41 (1H), 7.38 - 7.33 (1H), 7.22 (1H), 6.54 (1H), 5.36 (1H), 3.78 - 3.69 (4H), 3.27 - 3.21 (1H), 2.97 - 2.90 (4H), 2.58 - 2.52 (2H), 2.12 (3H), 2.10 - 2.00 (2H), 1.85 - 1.79 (2H), 1.49 (3H), 1.37 - 1.23 (2H).

[0310] Example 2: 5 - ((1R,4R)-2 - oxa - 5 - azabicyclo[2.2.1]heptan - 5 - yl)-N - ((R)-1-(3 - (difluoromethyl)-2 - fluorophenyl)ethyl)-4 - fluoro - 2 - ((1 - methylpiperidin - 4 - yl)amino)benzamide

Chemical Structure

[0311] Example 3: (R)-4 - fluoro - N-(1-(2 - methyl - 3 - (trifluoromethyl)phenyl)ethyl)-2 - ((1 - methylpiperidin - 4 - yl)amino)-5 - morpholinobenzamide

Chemical Structure

[0312] Step B: (R)-4-Fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide (Example 3) To a solution of 4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzoic acid (80 mg, 0.24 mmol) in DMF (2 mL) were added HATU (90.1 mg, 0.24 mmol), DIPEA (76 mg, 0.59 mmol), and (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethanamine (48.2 mg, 0.24 mmol), and the mixture was stirred at 20 °C for 2 h. The crude mixture was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50%B - 70%B in 7 min, 70%B) to give the title compound (21.1 mg, 17% yield). 19 F NMR (400 MHz, DMSO-d6) δ -58.713, -117.110. MS obsd.(ESI - ): 521.15 [M-H] - .

[0313] Example 4: (R)-4-Cyano-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide

Chemical Structure

[0314] Step B: 2-Amino-4-cyano-5-morpholinobenzoic acid To a mixture of methyl 4-bromo-5-morpholino-2-nitrobenzoate (1.2 g, 3.48 mmol) in DMF (12 mL) were added zinc cyanide (816 mg, 6.95 mmol), zinc powder (227 mg, 3.48 mmol), triethylamine (1.06 g, 10.43 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (564 mg, 0.69 mmol). The mixture was stirred at 120 °C for 16 hours under a N2 atmosphere. The mixture was diluted with MeOH (50 mL) and filtered through a Celite pad washed with MeOH (20 mL×3). The filtrate was concentrated and the residue was partitioned between EtOAc and H2O. The aqueous layer was concentrated to give the title compound (630 mg, crude). This material was used without further purification. MS obsd. (ESI+ ): 248.0 [(M+H) + .

[0315] Step C: (R)-2-Amino-4-cyano-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-morpholinobenzamide To a mixture of 2-amino-4-cyano-5-morpholino-benzoic acid (310 mg, crude) in DMF (15 mL) were added HATU (715 mg, 1.88 mmol), DIPEA (486 mg, 3.76 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (339 mg, 1.50 mmol). The mixture was stirred at room temperature for 3 h. The mixture was diluted with EtOAc (60 mL) and washed with H2O (45 mL×3) and brine (45 mL×3). The organic layer was dried (Na2SO4), concentrated and purified by silica gel chromatography column (PE:EtOAc = 1:1) to afford the title compound (101 mg). MS obsd.(ESI + ): 419.0 [(M+H) + .

[0316] Step D: (R)-4-Cyano-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide (Example 4) To a solution of (R)-2-amino-4-cyano-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-morpholinobenzamide (91 mg, 0.22 mmol) in acetic acid (6 mL) were added 1-methylpiperidin-4-one (123 mg, 1.09 mmol), and sodium triacetoxyborohydride (230 mg, 1.09 mmol). The mixture was stirred at 25 °C for 3 h. The mixture was concentrated and the residue was diluted with DCM (20 mL). The mixture was washed with saturated NaHCO3, followed by H2O and brine. The organic layer was dried (Na2SO4), concentrated and purified by preparative HPLC (ACN / water / 0.1N NH4HCO3) to afford the title compound (28.3 mg, yield 25%). MS obsd.(ESI+ ): 516.4 [(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (1H), 7.64 (1H), 7.53 (1H), 7.45 (s, 1H), 7.39 - 7.07 (4H), 5.38 (1H), 3.78 (m, 4H), 3.42 - 3.33 (1H), 3.06 - 2.97 (4H), 2.55 (2H), 2.13 (3H), 2.07 (2H), 1.83 (2H), 1.50 (3H), 1.36 - 1.21 (2H).

[0317] Example 5: (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(4-methylpiperazin-1-yl)-2-((1-methylpiperidin-4-yl)amino)benzamide

Chemical formula

[0318] Step B: Methyl 2-amino-4-fluoro-5-(4-methylpiperazin-1-yl)benzoate A solution of methyl 4-fluoro-5-(4-methylpiperazin-1-yl)-2-nitrobenzoate (605 mg, 2.04 mmol) in MeOH (12 mL) was added Pd / C (10 wt%, 200 mg), and the mixture was stirred at 40 °C for 1 h under H2 (1 atm). The mixture was filtered through a layer of celite. The filtrate was concentrated in vacuo. The residue was then purified by silica gel chromatography (eluting with 5% MeOH in DCM) to afford the title compound. MS obsd.(ESI + ): 268.1 [(M+H)] + .

[0319] Step C: 2-Amino-4-fluoro-5-(4-methylpiperazin-1-yl)benzoic acid To a solution of methyl 2-amino-4-fluoro-5-(4-methylpiperazin-1-yl)benzoate (285 mg, 1.07 mmol) in THF (12 mL) and MeOH (3 mL) was added LiOH (1 M in water, 7 mL). The reaction was stirred at 60 °C for 2 h. The solvent was removed in vacuo and then acidified to pH = 3 with 2 M HCl (3.5 mL). The mixture was concentrated in vacuo to afford the title compound (725 mg, crude), which was used without further purification. MS obsd.(ESI + ): 254.1 [(M+H)] + .

[0320] Step D: (R)-2-Amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(4-methylpiperazin-1-yl)benzamide To a solution of methyl 2-amino-4-fluoro-5-(4-methylpiperazin-1-yl)benzoate (725 mg, crude) in DMF (6 mL) were added HATU (610 mg, 1.61 mmol), (1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethanamine (202 mg, 1.07 mmol) and DIPEA (415 mg, 3.21 mmol). The reaction was stirred at room temperature for 2 h. The mixture was poured into water (40 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with 3% MeOH in DCM) to give the title compound (447 mg). MS obsd.(ESI + ): 425.2 [(M+H)] + .

[0321] Step E: (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(4-methylpiperazin-1-yl)-2-((1-methylpiperidin-4-yl)amino)benzamide (Example 5) To a solution of (R)-2-amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(4-methylpiperazin-1-yl)benzamide (70 mg, 0.16 mmol) in AcOH (5 mL) were added 1-methylpiperidin-4-one (187 mg, 1.65 mmol) and NaBH3CN (41 mg, 0.66 mmol). The reaction was stirred at 40 °C for 4 h. The mixture was concentrated in vacuo, then the residue was neutralized with aqueous NaHCO3 and extracted with DCM (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with 3% MeOH in DCM), followed by reverse phase chromatography (C18, eluting with 30% MeCN in 0.1% NH4HCO3-H2O) to give the title compound (31 mg, 59.43 μmol, 36% yield). MS obsd.(ESI + ): 522.3 [(M+H)] + . 11H NMR (400 MHz, DMSO-d6) δ: 8.68 (1H), 7.63 (2H), 7.51 (1H), 7.44 - 7.33 (2H), 7.21 (1H), 6.52 (1H), 5.36 (1H), 3.23 (1H), 2.95 (4H), 2.57 (2H), 2.47 (4H), 2.23 (3H), 2.13 (3H), 2.06 (2H), 1.82 (2H), 1.48 (3H), 1.35 - 1.23 (2H).

[0322] Example 6: 5-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide

Chemical Structure

[0323] Example 7: (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide

Chemical Structure

[0324] Step B: Methyl 2-amino-5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluorobenzoate To a solution of methyl 5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluoro-2-nitrobenzoate (162 mg, 505.81 μmol) in acetic acid (4 mL) was added Fe (283 mg, 5.06 mmol). The reaction mixture was stirred at 50 °C for 1 h. The mixture was filtered and the solvent was removed under vacuum. The residue was dissolved in water and basified with NaHCO3 (aqueous solution). The mixture was extracted with EtOAc (2 × 15 mL). The organic layer was washed with brine (2 × 20 mL), dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (eluting with 0% - 5% MeOH in DCM) to give the title compound (154 mg, crude). This material was used without further purification. MS obsd.(ESI + ): 291.3, [M+H] + .

[0325] Step C: Lithium 2-amino-5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluorobenzoate A solution of methyl 2-amino-5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluorobenzoate (154 mg, crude) in MeOH (1.5 mL) and H2O (0.3 mL) was treated with lithium hydroxide (89 mg, 2.12 mmol), and the mixture was stirred at 45 °C for 16 h. The reaction was concentrated in vacuo to afford the title compound (170 mg, crude), which was used without further purification. MS obsd.(ESI + ): 277.2 [M+H] for the free acid + .

[0326] Step D: (R)-2-Amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluorobenzamide To a solution of lithium 2-amino-5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluorobenzoate (170 mg, crude) in DMF (6 mL) were added DIPEA (233 mg, 1.81 mmol) and HATU (274 mg, 0.72 mmol), and the mixture was stirred at room temperature for 20 min. To the reaction was added 1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-aminium chloride (135 mg, 0.6 mmol). The reaction was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (eluting with 0% - 5% MeOH in DCM) to afford the impure title compound (334 mg, crude), which was used without further purification. MS obsd.(ESI+): 448.4 [M+H] + .

[0327] Step E: (R)-2-Amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluorobenzamide (Example 7): A solution of (R)-2-amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluorobenzamide (334 mg, crude) in acetic acid (6 mL) was treated with 1-methylpiperidin-4-one (845 mg, 7.47 mmol) at 45 °C. After 10 minutes, sodium cyanoborohydride (462 mg, 7.47 mmol) was added. The reaction was stirred at 45 °C for 4 hours. The mixture was adjusted to pH 8 using aqueous NaHCO3. The reaction was diluted with water and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (eluting with 50% - 60% EtOAc in PE), followed by preparative HPLC (CH3CN / H2O / 0.1% NH4HCO3) to afford the title compound (7.31 mg). MS obsd.(ESI+):545.5,[M+H] + .

[0328] Example 8: (R)-5-(2,2-dioxide-2-thia-6-azaspiro[3.3]heptan-6-yl)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide

Chemical Structure

[0329] Example 9: N-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(((R)-tetrahydrofuran-3-yl)oxy)benzamide [Chemical Structure] Step A: Methyl (R)-4-fluoro-2-nitro-5-((tetrahydrofuran-3-yl)oxy)benzoate Potassium carbonate (255 mg, 1.84 mmol) was added to a solution of methyl 4,5-difluoro-2-nitro-benzoate (200 mg, 0.92 mmol) and (3R)-tetrahydrofuran-3-ol (122 mg, 1.38 mmol) in DMSO (6 mL). The reaction mixture was stirred at 30 °C for 16 h. The mixture was diluted with water and extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluting with 0% - 50% EtOAc in PE) to give the title compound (197 mg, 74% yield). MS obsd. (ESI + ): 286.2 [(M + H) + .

[0330] Steps B - E: N-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(((R)-tetrahydrofuran-3-yl)oxy)benzamide (Example 9) Steps B - E were carried out according to a procedure similar to that of Example 7. MS obsd. (ESI + ): 510.5 [(M + H) + . 11H NMR (400 MHz, DMSO-d6) δ: 8.67 (1H), 7.76 (1H), 7.63 (1H), 7.58 (1H), 7.52 (1H), 7.38 - 7.32 (1H), 7.21 (1H), 6.60 (1H), 5.35 (1H), 4.93 (1H), 3.91 - 3.85 (2H), 3.83 - 3.74 (2H), 3.24 (1H), 2.61 - 2.53 (2H), 2.13 (3H), 2.11 - 1.97 (4H), 1.88 - 1.77 (2H), 1.48 (3H), 1.36 - 1.26 (2H).

[0331] Example 10: N-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(((S)-tetrahydrofuran-3-yl)oxy)benzamide

Chem.

[0332] Example 11: (R)-4-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide

Chem.

[0333] Step B: Lithium 2-amino-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzoate To a 0 °C solution of methyl 2-amino-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzoate (121 mg, 0.49 mmol) in MeOH (4 mL) was added a solution of lithium hydroxide (2.25 mg, 0.97 mmol) in H2O (1 mL). The mixture was stirred at 30 °C for 16 h. The mixture was concentrated to afford the crude title compound (117 mg, crude), which was used without further purification. MS obsd.(ESI + ): For the free acid, 236.1 [(M+H) + .

[0334] Step C: (R)-2-Amino-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)benzamide To a mixture of 2-amino-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzoate (117 mg, crude) in DMF (3 mL) were added HATU (277 mg, 0.73 mmol), DIPEA (188 mg, 1.46 mmol), and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (118 mg, 0.58 mmol). The mixture was stirred at room temperature for 3 h. The mixture was diluted with EtOAc (20 mL) and washed with H2O (15 mL×3) and brine (15 mL×3). The organic layer was dried (Na2SO4) and purified by preparative HPLC (ACN / H2O / 0.1% NH4HCO3) to afford the title compound (160 mg, 78% yield). MS obsd.(ESI + ): 421.0 [(M+H) + .

[0335] Step D: (R)-4-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide (Example 11) To a mixture of (R)-2-amino-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)benzamide (150 mg, 0.36 mmol) in AcOH (6 mL) were added 1-methylpiperidin-4-one (202 mg, 1.78 mmol) and sodium triacetoxyborohydride (378 mg, 1.78 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated and the residue was diluted with DCM (20 mL) and washed with saturated aqueous NaHCO3 (10 mL×3), H2O (10 mL×3), and brine (10 mL×3). The organic layer was dried (Na2SO4), filtered, and concentrated. Purification by preparative HPLC (ACN / H2O / 0.1% NH4HCO3) gave the title compound (62 mg, 33% yield). MS obsd.(ESI + ): 518.5 [(M+H) + . 11H NMR (400 MHz, DMSO-d6) δ: 8.78 (1H), 8.00 - 7.81 (4H), 7.76 (1H), 7.57 (1H), 7.41 (1H), 6.57 (1H), 5.39 (1H), 3.89 (3H), 3.31 - 3.26 (1H), 2.58 (2H), 2.14 (3H), 2.09 (2H), 1.87 (2H), 1.46 (3H), 1.35 (2H).

[0336] Example 12: (R)-4-Fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-(oxazol-5-yl)benzamide

Chemical Structure

[0337] Example 13: (R)-4-Chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide

Chemical Structure

[0338] Step B: Methyl 2-amino-4-chloro-5-morpholinobenzoate A solution of methyl 4-chloro-5-morpholino-2-nitrobenzoate (100 mg, 0.33 mmol) in AcOH (6.0 mL) was added with Fe powder (186 mg, 3.33 mmol) at 50 °C. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated until dry, the residue was diluted with aqueous NaHCO3 solution (15 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were washed with water (15 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (70 mg, 77% yield). MS obsd.(ESI + ): 35 Cl / 37 Cl 271.0 / 272.0,[M+H] + .

[0339] Step C: Lithium 2-amino-4-chloro-5-morpholinobenzoate A solution of methyl 2-amino-4-chloro-5-morpholinobenzoate (60 mg, 0.22 mmol) in water (1.0 mL) and THF (4.0 mL) was added with LiOH (16 mg, 0.66 mmol) at room temperature. The reaction mixture was stirred at 45 °C for 16 h. The reaction mixture was concentrated directly to give the crude title compound (60 mg, crude). The crude product was used directly in the next step. MS obsd.(ESI + ): For the free acid 35 Cl / 37 Cl 257.1 / 259.2[M+H] + .

[0340] Step D: (R)-2-Amino-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-5-morpholinobenzamide To a solution of lithium 2-amino-4-chloro-5-morpholinobenzoate (60 mg, crude) in DMF (30 mL) were added HATU (105 mg, 0.28 mmol, 1.2 equiv), N-ethyl-N-isopropyl-propan-2-amine (89 mg, 0.69 mmol) and (1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethanamine (56 mg, 0.28 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (5.0 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0 - 20% EA in PE) to give the title compound (60 mg, 61% yield). MS obsd.(ESI + ): 35 Cl / 37 Cl 442.4 / 444.4[M+H] +

[0341] Step E: (R)-4-Chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide (Example 13) A solution of (R)-2-amino-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-5-morpholinobenzamide (50 mg, 0.11 mmol) in AcOH (4.0 mL) was added with 1-methylpiperidin-4-one (128 mg, 1.13 mmol) and sodium triacetoxyborohydride (240 mg, 1.13 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was diluted with aqueous NaHCO3 (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (22.5 mg, 36% yield). MS obsd.(ESI + ): 35 Cl / 37 Cl 539.5 / 541.6[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 8.77 (1H), 7.73 (1H), 7.58 (1H), 7.53 (1H), 7.48 (1H), 7.42 (1H), 6.75 (1H), 5.38 (1H), 3.80 - 3.69 (4H), 3.26 (1H), 2.95 - 2.89 (4H), 2.61 - 2.51 (2H), 2.48 (3H), 2.12 (3H), 2.10 - 1.99 (2H), 1.87 - 1.76 (2H), 1.46 (3H), 1.35 - 1.24 (2H).

[0342] Example 14: (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(piperidin-4-ylamino)benzamide

Chem.

[0343] Step B: Methyl 2-amino-4-fluoro-5-morpholinobenzoate Iron powder (10.8 g, 193.50 mmol) was added to a solution of methyl 4-fluoro-5-morpholino-2-nitrobenzoate (5.5 g, 19.35 mmol) in acetic acid (50 mL). The mixture was stirred at 50 °C for 1 h. The mixture was concentrated directly, and the residue was diluted with aqueous NaHCO3 (100 mL) and DCM (100 mL). The mixture was stirred at room temperature for 15 min and then filtered. The filtrate was extracted with DCM (150 mL×3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude title compound (4.8 g, yield 97%), which was used for the next step without further purification. MS obsd.(ESI + ):255.2[M+H] + .

[0344] Step C: Lithium 2-amino-4-fluoro-5-morpholinobenzoate To a solution of methyl 2-amino-4-fluoro-5-morpholinobenzoate (4.8 g, 18.88 mmol) in THF (50 mL) were added lithium hydroxide (2.26 g, 94.39 mmol) and water (10 mL). The mixture was stirred at 40 °C for 16 h, and then the mixture was concentrated directly to give the crude title compound (4.5 g, crude product). This material was used without further purification. MS obsd.(ESI +): For the free acid, 241.2 [M+H] + .

[0345] Step D: (R)-2-Amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholinobenzamide To a solution of lithium 2-amino-4-fluoro-5-morpholinobenzoate (4.5 g, crude) in DMF (50 mL) were added HATU (9.3 g, 24.35 mmol), triethylamine (5.7 g, 56.20 mmol), and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (5.32 g, 28.10 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was poured into water (150 mL) and extracted with DCM (150 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (AcOEt / PE, 0~50%) to give the target compound (6.1 g, 78% yield over 2 steps). MS obsd.(ESI + ): 412.3 [M+H] +

[0346] Step E: Tert-butyl (R)-4-((2-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-5-fluoro-4-morpholinophenyl)amino)piperidine-1-carboxylate To a solution of (R)-2-amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholinobenzamide (200 mg, 0.49 mmol) in acetic acid (10 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (969 mg, 4.86 mmol). The mixture was stirred at room temperature for 15 minutes, then sodium triacetoxyborohydride (1.0 g, 4.86 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM (120 mL), and the organic layer was washed with water (120 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (AcOEt / DCM, 10 - 60%) to give the target compound (243 mg, 0.41 mmol, 84% yield). MS obsd.(ESI + ): 595.5 [M+H] +

[0347] Step F: (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(piperidin-4-ylamino)benzamide (Example 14) To a solution of tert-butyl (R)-4-((2-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-5-fluoro-4-morpholinophenyl)amino)piperidine-1-carboxylate (243 mg, 0.49 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour, then the mixture was concentrated under vacuum. The residue was neutralized with NH3 in methanol (2 mL, 7M), concentrated again, and the residue was purified by preparative HPLC (ACN / water / 0.1% HCOOH) to give the target compound (60.8 mg, 39% yield, 0.7 eq HCOOH salt). MS obsd.(ESI + ): 495.4 [M+H] +

[0348] Examples 15 and 16: N-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(((R)-quinucidin-3-yl)amino)benzamide (Example 15) and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(((S)-quinucidin-3-yl)amino)benzamide (Example 16) [Chemical formula] A mixture of (R)-2-amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholinobenzamide (206 mg, 0.50 mmol), quinucidin-3-one hydrochloride (809 mg, 5.01 mmol) and NaBH3CN (158 mg, 2.50 mmol) in AcOH (10 mL) was stirred at 60 °C for 24 hours. The reaction solution was concentrated under vacuum. The residue was purified by chromatography column (0 - 10% MeOH in DCM) to give N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(quinucidin-3-ylamino)benzamide as a diastereomeric mixture (90 mg, 0.17 mmol, yield 34.5%). LCMS: m / z, 521.3, [M+H] + .

[0349] The mixture was purified by SFC (Regis (R,R) Whelk-O1 (25*250, 10um), CO2 / EtOH [0.5% of NH3 (7M in MeOH)] = 65 / 35) to obtain the following: Example 15: (19.1 mg) MS obsd. (ESI + ): 521.3 [M+H] + Analytical chiral HPLC: (Column: (R,R)-Whelk-O1, 4.6*100 mm 3um, flow rate: 3.0 mL / min, co-solvent: EtOH (1% of 7M NH3 in MeOH), temperature 40 °C) retention time = 2.2 minutes Example 16: (18.6 mg) MS obsd. (ESI + ): 521.3 [M+H]+ Analytical chiral HPLC: (Column: (R,R)-Whelk-O1, 4.6 * 100 mm 3um, flow rate: 3.0 mL / min, co-solvent: EtOH (1% of 7M NH3 in MeOH), temperature 40 °C) Retention time = 1.6 minutes

[0350] Examples 17 and 18: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-5-morpholinobenzamide, and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-5-morpholinobenzamide

Chemical Structure

[0351] Step B: 2-((3-azabicyclo[3.1.1]heptan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholinobenzamide Tert-butyl 6-((2-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-5-fluoro-4-morpholinophenyl)amino)-3-azabicyclo[3.1.1]heptane-3-carboxylate (180 mg, 0.29 mmol) was dissolved in HCl (4 M solution in 1,4-dioxane, 4 mL). The mixture was stirred at room temperature for 2 hours. Then, the reaction solution was concentrated. The residue was diluted with water (50 mL) and adjusted to pH ~10 using aqueous NaHCO3. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the title compound (200 mg, crude) as a mixture of diastereomers. This material was used without further purification. MS obsd. (ESI + ): 507.4 [M+H] +

[0352] Step C: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-5-morpholinobenzamide, and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-5-morpholinobenzamide A solution of the crude 2-((3-azabicyclo[3.1.1]heptan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholinobenzamide (180 mg) in EtOH (3 mL) was treated with paraformaldehyde (95 mg, 1.07 mmol) and NaBH3CN (110 mg, 1.78 mmol). The mixture was stirred at room temperature for 16 h. The reaction solution was poured into water (100 mL). The mixture was extracted with EtOAc (70 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0 - 10% MeOH in DCM) to give the title compound (40 mg) as a mixture of diastereomers. MS obsd.(ESI + ):521.3[M+H] +

[0353] The above material (40 mg, 0.076 mmol) was further separated by SFC (Regis (R,R) Whelk-O1 (25*250,10um), CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 65 / 35) to give the following: Example 17 (10.6 mg). MS obsd.(ESI + ):521.4[M+H] + . Analytical chiral HPLC: (Column: (R,R)-Whelk-O1, 4.6*100 mm 3um, flow rate: 3.0 mL / min, co-solvent: EtOH (1% 7M NH3 in MeOH), temperature 40 °C) retention time = 1.26 min Example 18 MS obsd.(ESI + ):521.4[M+H] + . Analytical chiral HPLC: (Column: (R,R)-Whelk-O1, 4.6*100 mm 3um, flow rate: 3.0 mL / min, co-solvent: EtOH (1% 7M NH3 in MeOH), temperature 40 °C) retention time = 1.59 min

[0354] Example 19: 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide [Chemical Structure] Step A: Methyl 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-fluoro-2-nitrobenzoate To a solution of methyl 4,5-difluoro-2-nitrobenzoate (500 mg, 2.30 mmol) in THF (4.0 mL) were added triethylamine (466 mg, 4.60 mmol) and ((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl chloride (375 mg, 2.76 mmol) at 0 °C. The mixture was stirred at 0 °C for 16 h. The reaction mixture was quenched with NH4Cl (5.0 mL aqueous solution) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0 - 30% EtOAc in PE) to give the title compound (600 mg, 87% yield). MS obsd. (ESI + ): 297.0 [M+H] + .

[0355] Step B: Methyl 2-amino-5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-fluorobenzoate To a solution of methyl 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-fluoro-2-nitrobenzoate (600 mg, 2.03 mmol) in MeOH (10 mL) was added Pd / C (200 mg, 10 wt%) at room temperature. The reaction mixture was stirred at room temperature for 16 h under H2 (1 atm). The reaction mixture was filtered and concentrated to give the title compound (500 mg, crude), which was used directly in the next step. MS obsd. (ESI+ ): 267.2 [M+H] + .

[0356] Step C: Methyl 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzoate To a solution of methyl 2-amino-5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-fluorobenzoate (100 mg, crude, assumed to be 0.38 mmol) in AcOH (8 mL) were added 1-methylpiperidin-4-one (425 mg, 3.80 mmol) and sodium triacetoxyborohydride (398 mg, 1.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated until dry. Saturated aqueous NaHCO3 (15 mL) was added to the residue, and the mixture was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0 - 30% EtOAc in PE) to give the title compound (90 mg, 65% yield). MS obsd. (ESI + ): 364.2 [M+H] + .

[0357] Step D: Lithium 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzoate To a solution of methyl 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzoate (80 mg, 0.22 mmol) in water (0.4 mL) and THF (2.0 mL) at 30 °C was added anhydrous LiOH (16 mg, 0.66 mmol). The reaction mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated directly to give the crude title compound (80 mg, crude). The crude product was used directly in the next step. MS obsd. (ESI +): For the free acid, 350.2 [M+H] + .

[0358] Step E: 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide (Example 19) To a solution of lithium 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzoate (80 mg, crude) in DMF (5.0 mL) were added HATU (103 mg, 0.27 mmol), N-ethyl-N-isopropyl-propan-2-amine (89 mg, 0.69 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (51 mg, 0.27 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0 - 20% MeOH in DCM), followed by preparative HPLC (ACN / water / 0.1% NH4HCO3) to afford the title compound (51.5 mg). MS obsd.(ESI + ): 350.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (1H), 7.61 (1H), 7.52 (1H), 7.38 - 7.05 (4H), 6.54 (1H), 5.38 - 5.30 (1H), 4.55 (1H), 4.43 (1H), 3.82 (1H), 3.73 (1H), 3.45 (1H), 3.20 (1H), 3.10 (1H), 2.56 (2H), 2.13 (3H), 2.10 - 2.01 (2H), 1.93 - 1.75 (4H), 1.48 (3H), 1.34 - 1.23 (2H).

[0359] Example 20: (R)-5-(6-Acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide

Chemical formula

[0360] Step B: Tert-butyl 6-(4-amino-2-fluoro-5-(methoxycarbonyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate To a mixture of tert-butyl 6-(2-fluoro-5-(methoxycarbonyl)-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (300 mg, 0.76 mmol) in acetic acid (10 mL) was added iron powder (424 mg, 7.59 mmol). The mixture was stirred at 50 °C for 2 h. The mixture was filtered, concentrated, and the residue was diluted with DCM (30 mL). The organic mixture was washed with saturated aqueous NaHCO3 (15 mL × 3), H2O (15 mL × 3), and brine (15 mL × 3). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc = 2:1) to afford the title compound (150 mg, 54% yield). MS obsd.(ESI + ): 366.3 [(M+H) + .

[0361] Step C: Lithium 2-amino-5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluorobenzoate To a mixture of tert-butyl 6-(4-amino-2-fluoro-5-(methoxycarbonyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.27 mmol) in MeOH (3 mL) at 0 °C was added a solution of lithium hydroxide (13 mg, 0.55 mmol) in H2O (1 mL). The mixture was stirred at 30 °C for 16 h. The mixture was concentrated to afford the crude title compound (97 mg, crude). This material was used without further purification. MS obsd.(ESI + ): 352.2 [(M+H) + for the free acid.

[0362] Step D: tert-butyl (R)-6-(4-amino-2-fluoro-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate To a mixture of lithium 2-amino-5-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluorobenzoate (97 mg, crude) in DMF (3 mL), HATU (155 mg, 0.41 mmol), DIPEA (105 mg, 0.81 mmol) were added, followed by (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (61 mg, 0.3 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (20 mL), washed with H2O (15 mL×3), brine (15 mL×3), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column (PE:EtOAc = 1:1) to afford the title compound (130 mg, 89% yield). MS obsd.(ESI + ):537.2[(M+H) + .

[0363] Step E: (R)-2-Amino-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)benzamide 2,2,2-trifluoroacetate To a mixture of tert-butyl (R)-6-(4-amino-2-fluoro-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (115 mg, 0.21 mmol) in DCM (5 mL), TFA (2.5 mL) was added. The mixture was stirred at room temperature for 2 h. The mixture was concentrated to afford the crude product (117 mg, crude). This material was used without further purification. MS obsd.(ESI + ): for free acid 437.4[(M+H) + .

[0364] Step F: (R)-5-(6-Acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-amino-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)benzamide To a mixture of acetic acid (13 mg, 0.21 mmol) in DMF (3 mL) was added HATU (121 mg, 0.32 mmol), DIPEA (82 mg, 0.64 mmol) and (R)-2-amino-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-5-(2,6-diazaspiro[3.3]heptan-2-yl)benzamide 2,2,2-trifluoroacetate (117 mg, crude). The mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (20 mL). The organic mixture was washed with H2O (15 mL × 3) and brine (15 mL × 3), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column (DCM:MeOH = 1:1) to afford the crude title compound (85 mg, purity ca. 50%, contaminated with some bis-acetylated product) which was used without further purification. This material was used without further purification. MS obsd.(ESI + ):479.2[(M+H) + .

[0365] Step G: (R)-5-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide (Example 20): A mixture of (R)-5-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-amino-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)benzamide (75 mg, crude) in acetic acid (3 mL) was added 1-methylpiperidin-4-one (89 mg, 0.78 mmol) and sodium triacetoxyborohydride (166 mg, 0.78 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated and then the residue was diluted with DCM (20 mL). The mixture was washed with saturated aqueous NaHCO3 (10 mL × 3), H2O (10 mL × 3), and brine (10 mL × 3). The organic layer was dried (Na2SO4), concentrated, and purified by preparative HPLC (ACN / H2O / 0.1% HCOOH) to afford the title compound (13.1 mg, 0.65 eq FA salt). MS obsd.(ESI + ):576.5[(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ:8.68(1H),7.72(1H),7.57(1H),7.40(1H),7.34(1H),6.91(1H),6.51(1H),5.36(1H),4.28(2H),4.00(2H),3.93(4H),3.22(1H),2.61(2H),2.47(3H),2.16(3H),2.14-2.04(2H),1.82(2H),1.75(3H),1.44(3H),1.36-1.23(2H).

[0366] Example 21: (R)-4-Fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)benzamide

Chem.

[0367] Step B: Methyl 1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-methyl 2-amino-4-fluoro-5-(tetrahydro-2H-pyran-4-yl)benzoate To a solution of methyl 2-amino-5-(3,6-dihydro-2H-pyran-4-yl)-4-fluoro-benzoate (230 mg, 0.91 mmol) in MeOH (3 mL) and EtOH (10 mL) was added Pd / C (30.0 mg, 0.028 mmol, 10 wt%). The reaction mixture was stirred at room temperature for 2 h under a H2 atmosphere (1 atm). The reaction mixture was filtered and the filtrate was concentrated to dryness to give the crude title compound (230 mg, crude). The crude product was used directly in the next step without further purification. MS obsd.(ESI + ): 254.2 [(M+H) + .

[0368] Step C: 2-Amino-4-fluoro-5-(tetrahydro-2H-pyran-4-yl)benzoic acid Methyl 2-amino-4-fluoro-5-tetrahydropyran-4-yl-benzoate (220 mg, crude product) was dissolved in MeOH (15 mL) and THF (5 mL). Then LiOH (1 M, 5 mL) was added to the solution. The reaction mixture was stirred at 50 °C for 2 h. After the reaction was complete, HCl (1 M, 5 mL) was added to the mixture. The mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (205 mg, crude), which was used without further purification. MS obsd.(ESI + ): 240.3 [(M+H) + .

[0369] Step D (R)-2-Amino-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)benzamide 2-Amino-4-fluoro-5-tetrahydropyran-4-yl-benzoic acid (205 mg, crude product) and HATU (491 mg, 1.29 mmol) were dissolved in DMF (10 mL). The mixture was stirred at room temperature for 0.5 h. Then DIPEA (223 mg, 1.72 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (210 mg, 1.03 mmol) were added to the mixture. The mixture was stirred at room temperature for 1.5 h. The mixture was poured into water (100 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (eluting with 0 - 25% EtOAc in PE) to give the title compound (313.5 mg, 85% yield). MS obsd.(ESI + ): 425.4 [(M+H) + .

[0370] Step E: (R)-4-Fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)benzamide (Example 21) To a solution of (R)-2-amino-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-5-(tetrahydro-2H-pyran-4-yl)benzamide (310 mg, 0.73 mmol) in AcOH (10 mL) was added 1-methylpiperidin-4-one (124 mg, 1.10 mmol) at 0 °C. Then, NaBH(OAc)3 (310 mg, 1.46 mmol) was added to the mixture. The mixture was stirred at 0 °C for 1 h. Then, the reaction mixture was poured into water (50 mL) and the mixture was adjusted to pH = 10 using solid Na2CO3. The mixture was extracted with EtOAc (15 mL × 4). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (88.6 mg, 23% yield). MS obsd.(ESI + ):522.2[(M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ: 8.69 (1H), 7.95 (1H), 7.74 (1H), 7.68 (1H), 7.57 (1H), 7.42 (1H), 6.45 (1H), 5.38 (1H), 3.97 (2H), 3.44 (2H), 3.25 (1H), 2.87 (1H), 2.57 (2H), 2.48 (3H), 2.13 (3H), 2.06 (2H), 1.91 - 1.80 (4H), 1.60 (2H), 1.45 (3H), 1.39 - 1.23 (2H).

[0371] Example 22: (R)-5-(4-Acetylpiperazin-1-yl)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide

Chemical Structure

[0372] Step B: Methyl 5-(4-acetylpiperazin-1-yl)-2-amino-4-fluorobenzoate To a solution of methyl 5-(4-acetylpiperazin-1-yl)-4-fluoro-2-nitrobenzoate (472 mg, 1.45 mmol) in AcOH (10 mL) was added iron powder (810 mg, 14.51 mmol). The mixture was stirred at 50 °C for 1 h. The mixture was filtered. The filtrate was concentrated in vacuo and saturated aqueous NaHCO3 was added to the residue. The mixture was extracted with DCM (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0 - 50% EtOAc in PE) to afford the title compound (393 mg, 91% yield). MS obsd.(ESI + ): 296.3 [(M + H) + .

[0373] Step C: Lithium 2-amino-4-fluoro-5-(piperazin-1-yl)benzoate A solution of methyl 5-(4-acetylpiperazin-1-yl)-2-amino-4-fluorobenzoate (200 mg, 0.67 mmol) in THF (4 mL) and water (0.5 mL) was added with lithium hydroxide (65 mg, 2.71 mmol). The mixture was stirred at 80 °C for 3 h. The solvent was removed in vacuo to afford the crude title compound (166 mg, crude). The crude product was used directly in the next step without further purification. MS obsd.(ESI + ): for the free acid 246.3 [(M+H) + .

[0374] Step D: (R)-5-(4-acetylpiperazin-1-yl)-2-amino-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)benzamide To a solution of acetic acid (37 mg, 0.62 mmol) in DMF (5 mL) were added HATU (234 mg, 0.62 mmol) and N,N-diisopropylethylamine (239 mg, 1.85 mmol). The mixture was stirred at room temperature for 0.5 h. Then lithium 2-amino-4-fluoro-5-(piperazin-1-yl)benzoate (166 mg, crude) was added to the mixture and stirred at room temperature for 1 h. Then HATU (350 mg, 0.92 mmol) was added. The mixture was stirred at room temperature for 0.5 h. Then N,N-diisopropylethylamine (158 mg, 1.23 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (187 mg, 0.92 mmol) were added and the mixture was stirred for a further 1 h. The reaction was quenched with water and extracted with DCM (3×80 mL). The combined organic layers were washed with water (3×50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluting with 0-5% MeOH in DCM) to afford the title compound (261 mg). MS obsd.(ESI + ): 467.2 [(M+H) + .

[0375] Step E: (R)-5-(4-Acetylpiperazin-1-yl)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide (Example 22) To a solution of (R)-5-(4-acetylpiperazin-1-yl)-2-amino-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)benzamide (261 mg, 0.56 mmol) and 1-methylpiperidin-4-one (633 mg, 5.60 mmol) in AcOH (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.60 mmol). The mixture was stirred at room temperature for 1 h. At this point, an equivalent amount of 1-methylpiperidin-4-one and sodium triacetoxyborohydride were added to the mixture, and the mixture was stirred for an additional 1 h. The reaction mixture was concentrated, diluted with water, and stirred for 0.5 h. Then, saturated NaHCO3 solution was added dropwise to the mixture until the solution reached about pH 8. The mixture was extracted with DCM (3 × 50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (eluting with 0-20% MeOH in DCM), followed by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (95.8 mg, 30% yield). MS obsd.(ESI + ):564.5[(M+H) + . 1 H NMR(400MHz,DMSO-d6)δ:8.65(1H),7.72(2H),7.57(1H),7.43-7.39(2H),6.54(1H),5.37(1H),3.62-3.55(4H),3.29-3.20(1H),2.96-2.84(4H),2.59-2.56(2H),2.47(3H),2.13(3H),2.09(1H),2.05(4H),1.82(2H),1.44(3H),1.37-1.23(2H).

[0376] Example 23: (R)-N-(1-(2-Methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide [Chemical formula] Step A: 5-Bromo-2-((1-methylpiperidin-4-yl)amino)benzoic acid To a stirred mixture of 5-bromo-2-fluorobenzoic acid (2 g, 9.13 mmol) and 1-methylpiperidin-4-amine (1.15 g, 10.05 mmol) in DMSO (25 mL) was added N-ethyl-N-isopropyl-propan-2-amine (2.35 g, 18.26 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 48 h. The reaction mixture was quenched with water (50 ml). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (0 - 60%) to give the title compound (320 mg, yield 11%). MS obsd.(ESI + ): 313.25 [M+H] + .

[0377] Step B: (R)-5-Bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide A stirred mixture of 5-bromo-2-((1-methylpiperidin-4-yl)amino)benzoic acid (320 mg, 1.02 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (207.0 mg, 1.02 mmol) in DMF (4 mL) was added with HATU (388.7 mg, 1.02 mmol) and N-ethyl-N-isopropyl-propan-2-amine (259.29 mg, 2.04 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (0 - 50%) to afford the title compound (300 mg, 0.60 mmol, 59% yield). MS obsd.(ESI + ): 498.10[M+H] + .

[0378] Step C: (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide (Example 23) To a stirred mixture of (R)-5-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide (150 mg, 0.30 mmol) and morpholine (131 mg, 1.50 mmol) in dioxane (3 mL) were added Pd2(dba)3 (27.5 mg, 0.03 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (14.3 mg, 0.03 mmol) and cesium carbonate (196 mg, 0.6 mmol). The resulting mixture was stirred at 100 °C for 3 h under a N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (DCM / MeOH = 10 / 1). Further purification by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / NH4HCO3), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 35%B - 55%B in 7 min, 55%B). Thereby, the title compound (40.2 mg, yield 26%) was obtained. 19 F NMR(376MHz,DMSO-d6)δ-58.706.MS obsd.(ESI + ):505.30[M+H] + .

[0379] Examples 24 and 25: 4-Cyano-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-morpholino-2-(((R)-quinidin-3-yl)amino)benzamide and 4-Cyano-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-morpholino-2-(((S)-quinidin-3-yl)amino)benzamide (stereochemistry not assigned)

Chem.

[0380] The mixture was separated by preparative SFC (Regis (R,R) Whelk-O1 (25 * 250 mm, 10 um), CO2 / EtOH [0.5% NH3 (7M in MeOH)] = 60 / 40) to afford the title compound. Example 24: First elution peak. MS obsd. (ESI + ): 528.8 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 9.00 (1H), 7.65 (1H), 7.54 (2H), 7.47 (1H), 7.36 (1H), 7.22 (1H), 6.98 (1H), 5.38 (1H), 3.80 - 3.74 (4H), 3.52 (1H), 3.23 (1H), 3.06 - 2.98 (4H), 2.72 - 2.57 (4H), 2.20 (1H), 1.81 (1H), 1.59 (2H), 1.51 (4H), 1.31 (1H). Example 25: Second elution peak. MS obsd. (ESI + ): 528.8 [M + H] + . 11H NMR (400 MHz, DMSO-d6) δ: 9.01 (1H), 7.64 (1H), 7.53 (1H), 7.45 (2H), 7.35 (1H), 7.22 (1H), 6.99 (1H), 5.37 (1H), 3.81 - 3.72 (4H), 3.54 (1H), 3.24 (1H), 3.02 (4H), 2.63 (4H), 2.23 (1H), 1.78 (1H), 1.63 - 1.54 (2H), 1.51 (3H), 1.43 (1H), 1.25 (1H).

[0381] Examples 26 and 27: N-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-5-(3,3-difluoropyrrolidin-1-yl)-4-fluoro-2-(((S)-quinucidin-3-yl)amino)benzamide and N-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-5-(3,3-difluoropyrrolidin-1-yl)-4-fluoro-2-(((R)-quinucidin-3-yl)amino)benzamide (diastereomers not assigned)

Chemical formula

[0382] Steps B - D: (R)-2-Amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(3,3-difluoropyrrolidin-1-yl)-4-fluorobenzamide For example, it is synthesized according to the procedures described in the seven Steps B - D. MS obsd. (ESI + ): 432.1 [M + H] + .

[0383] Step E: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(3,3-difluoropyrrolidin-1-yl)-4-fluoro-2-(((R)-quinolin-3-yl)amino)benzamide and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(3,3-difluoropyrrolidin-1-yl)-4-fluoro-2-(((S)-quinolin-3-yl)amino)benzamide (Examples 26 and 27) A solution of (R)-2-amino-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(3,3-difluoropyrrolidin-1-yl)-4-fluorobenzamide (500 mg, 1.16 mmol) in AcOH (15 mL) was added quinuclidin-3-one hydrochloride (1.9 g, 11.59 mmol) and sodium cyanoborohydride (437 mg, 6.95 mmol), and the mixture was stirred at 60 °C for 16 h. The mixture was concentrated under vacuum, and the residue was dissolved in water (50 mL) and neutralized with aqueous sodium carbonate solution. The mixture was extracted with DCM (80 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (MeOH / DCM, 0 - 20%) followed by preparative HPLC (0.5% NH4HCO3 / ACN) to give the title compound as a mixture of diastereomers (85 mg, 13% yield). MS obsd.(ESI + ):541.0[M+H] + .

[0384] The mixture was further separated by chiral SFC (column name: Daicel OZ (25*250mm, 10um); CO2 / MeOH [0.2% NH3 (7M in MeOH)]) to afford the title compound. Example 26: The first elution isomer. MS obsd.(ESI + ):541.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.68(1H),7.90(1H),7.65(1H),7.52(1H),7.39-7.08(3H),6.48(1H),5.39(1H),3.59(2H),3.41(3H),3.23(1H),2.66(4H),2.44(2H),2.24(1H),1.82(1H),1.63-1.52(3H),1.49(3H),1.31(1H). Example 27: The second elution isomer. MS obsd.(ESI + ):541.0[M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.69 (1H), 7.81 (1H), 7.63 (1H), 7.52 (1H), 7.39 - 7.08 (3H), 6.48 (1H), 5.37 (1H), 3.59 (2H), 3.41 (3H), 3.23 (1H), 2.71 - 2.57 (4H), 2.49 - 2.40 (2H), 2.25 (1H), 1.78 (1H), 1.56 (2H), 1.52 - 1.41 (4H), 1.25 (1H).

[0385] Examples 28 and 29: 5-(Azetidin-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((S)-quinuclidin-3-yl)amino)benzamide and 5-(azetidin-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((R)-quinuclidin-3-yl)amino)benzamide (diastereomers not assigned)

Chem.

[0386] Examples 30 and 31: N-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)benzamide and N-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((1-methylpiperidin-4-yl)amino)-5-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)benzamide (diastereomers not assigned)

Chem.

[0387] Examples 32 and 33: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(pyrrolidin-1-yl)-2-(((S)-quinolinidin-3-yl)amino)benzamide and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(pyrrolidin-1-yl)-2-(((R)-quinolinidin-3-yl)amino)benzamide (diastereomers are not assigned)

Chemical Structure

[0388] The following examples were synthesized according to a similar procedure as described in Example 5 using appropriate reagent substitutions through the following general scheme, Steps A - E (all reagents used are commercially available or synthetically reported).

Chemical formula

Table 5 - 1

Table 5 - 2

Table 5 - 3

[0389] Examples 42 and 43: N-((R)-1-(3-(1,1-Difluoroethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(((S)-quinucidin-3-yl)amino)benzamide and N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(((R)-quinucidin-3-yl)amino)benzamide (diastereomers not assigned)

Chem.

[0390] Examples 44 and 45: N-((R)-1-(3-Cyano-2-methylphenyl)ethyl)-4-fluoro-5-morpholino-2-(((S)-quinucidin-3-yl)amino)benzamide and N-((R)-1-(3-cyano-2-methylphenyl)ethyl)-4-fluoro-5-morpholino-2-(((R)-quinucidin-3-yl)amino)benzamide (diastereomers not assigned)

Chem.

Claims

1. A compound of formula (I), 【Chemical Formula 63】 or a pharmaceutically acceptable salt thereof, wherein R １ is C １～１２ alkyl, C ３～６ cycloalkyl, 3- to 10-membered heterocyclyl, or 3- to 10-membered (C １～３ alkylene)-heterocyclyl, and R ２ is hydrogen, halo, cyano, C １～３ alkyl, C １～３ alkoxy, or C １～３ haloalkyl, and R ３ is C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl, 3- to 10-membered heterocyclyl, 3- to 10-membered (-O-) heterocyclyl, 5- to 10-membered heteroaryl, -C(O)R ７ , -C(O)NR ８ R ９ and R ４ is hydrogen, C １～３ alkyl, or C １～３ haloalkyl, and R ５ is independently selected from halo, cyano, hydroxy, C １～３ alkyl, C １～３ alkoxy, C １～３ haloalkyl, and NH ２ and the like, R ７ is hydrogen, C １～３ alkyl, or C １～３ alkoxy, and R ８ and R ９ are each independently selected from hydrogen and C １～３ alkyl, or R ８ and R ９ optionally together form a 5- to 8-membered heterocyclyl, n is an integer of 0, 1, 2 or 3, Each heterocyclyl and heteroaryl is optionally substituted with 1 to 3 substituents each independently selected from halo, OH, C １～３ alkyl, C １～３ alkoxy, and C １～３ haloalkyl, oxo, and -C(O)R ６ wherein R ６ is hydrogen or C １～３ alkyl, Each alkyl and cycloalkyl is optionally substituted with 1 to 3 substituents each independently selected from halo, OH, amine, cyano, C １～３ alkyl, C １～３ alkoxy, and C １～３ haloalkyl, oxo, and -C(O)R １０ wherein R １０ is hydrogen, OH, C １～３ alkyl, or C １～３ alkoxy, a compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. R １ The compound according to claim 1, wherein R is a 3- to 10-membered heterocyclyl.

3. R １ The compound according to claim 2, wherein R is a 6-membered heterocyclyl.

4. R １ is azepanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, quinuclidinyl, 4H-pyran, azetidinyl, oxetanyl, octahydrocyclopenta[c]pyrrol, 2-azaspiro[3.3]heptanyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 4-azaspiro[2.5]octanyl, 6-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.1]octanyl, hexahydro-1H-cyclopenta[c]pyrrolyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, or hexahydro-1H-pyrrolidinyl, optionally substituted with one or more C １～３ alkyl, the compound according to claim 2

5. R １ The compound according to claim 4, wherein R is tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

6. R １ is a piperidinyl optionally substituted with one or more C １～３ alkyl, the compound according to claim 5.

7. R ２ is hydrogen, halo, cyano, or C １～３ haloalkyl, the compound according to claim 1.

8. R ３ The compound according to claim 1, wherein R is a 3- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl.

9. R ３ The compound according to claim 8, wherein R is a 4- to 6-membered heterocyclyl.

10. R ３ is azepanyl, 1,3-dioxolan, 1,4-dioxolanil, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, quinuclidinyl, 4H-pyranyl, azetidinyl, oxetanyl, octahydrocyclopenta[c]pyrrol, 2-azaspiro[3.3]heptanyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 4-azaspiro[2.5]octanyl, 6-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.1]octanyl, hexahydro-1H-cyclopenta[c]pyrrolyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 1,3-oxa-7-azabicyclo[3.3.1]nonanyl, hexahydro-1H-pyrrolidinyl, 2-oxa-7-azaspiro[4.4]nonanyl, or 6-oxa-1-azaspiro[3.4]octanyl, optionally substituted with one or more halo, OH, or C １～３ alkyl, the compound according to claim 8.

11. R ３ is piperidinyl substituted with one or more halos, OH, or C １～３ alkyl, the compound according to claim 10.

12. R ３ is morpholinyl substituted with one or more halos, OH, or C １～３ alkyl, the compound according to claim 10.

13. R ３ The compound according to claim 1, wherein R is oxazolyl, thiazolyl, pyrazolyl, pyridyl, or pyridone.

14. R ３ is -C(O)R ７ and R ７ is C １～３ alkoxy, the compound according to claim 1.

15. R ３ is -C(O)NR ８ R ９ and i) R ８ is hydrogen or C １～３ alkyl, and R ９ is C １～３ alkyl, or ii) R ８ and R ９ which optionally together form a 5- to 8-membered heterocycle, the compound according to claim 1.

16. R ４ is C １～３ alkyl, the compound according to claim 1.

17. R ４ The compound according to claim 1, wherein R is methyl.

18. R ５ is halo, CN, C １～３ alkyl, or C １～３ haloalkyl, the compound according to claim 1.

19. (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide, 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, (R)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide, (R)-4-cyano-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(4-methylpiperazin-1-yl)-2-((1-methylpiperidin-4-yl)amino)benzamide, 5-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, (R)-5-(2,2-dioxide-2-thia-6-azaspiro[3.3]heptan-6-yl)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(((R)-tetrahydrofuran-3-yl)oxy)benzamide N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(((S)-tetrahydrofuran-3-yl)oxy)benzamide (R)-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide (R)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-(oxazol-5-yl)benzamide (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(piperidin-4-ylamino)benzamide N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(((R)-quinuclidin-3-yl)amino)benzamide N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(((S)-quinuclidin-3-yl)amino)benzamide N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-5-morpholinobenzamide N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-5-morpholinobenzamide 5-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, (R)-5-(6-acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide, (R)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)benzamide, (R)-5-(4-acetylpiperazin-1-yl)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide, (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide, 4-cyano-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-morpholino-2-(((R)-quinucidin-3-yl)amino)benzamide, 4-cyano-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-morpholino-2-(((S)-quinucidin-3-yl)amino)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(3,3-difluoropyrrolidin-1-yl)-4-fluoro-2-(((S)-quinucidin-3-yl)amino)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(3,3-difluoropyrrolidin-1-yl)-4-fluoro-2-(((R)-quinucidin-3-yl)amino)benzamide, 5-(azetidin-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((S)-quinucidin-3-yl)amino)benzamide, 5-(Azetidin-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((R)-quinucidin-3-yl)amino)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-((R)-2-oxa-7-azaspiro[4.4]nonan-7-yl)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-((S)-2-oxa-7-azaspiro[4.4]nonan-7-yl)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(pyrrolidin-1-yl)-2-(((S)-quinucidin-3-yl)amino)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(pyrrolidin-1-yl)-2-(((R)-quinucidin-3-yl)amino)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-((S)-6-oxa-1-azaspiro[3.4]octan-1-yl)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-((R)-6-oxa-1-azaspiro[3.4]octan-1-yl)benzamide, 5-((R)-4,4-Difluoro-2-methylpyrrolidin-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, 5-((S)-4,4-Difluoro-2-methylpyrrolidin-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, 5-(3-Oxa-7-azabicyclo[3.3.1]nonan-7-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, 5-(3-Oxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-5-(2,2-difluoromorpholino)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, 5-(9-Oxa-3-azabicyclo[3.3.1]nonan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, N-((R)-1-(3-(1,1-Difluoroethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(((S)-quinuclidin-3-yl)amino)benzamide, N-((R)-1-(3-(1,1-Difluoroethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholino-2-(((R)-quinuclidin-3-yl)amino)benzamide, N-((R)-1-(3-Cyano-2-methylphenyl)ethyl)-4-fluoro-5-morpholino-2-(((S)-quinuclidin-3-yl)amino)benzamide, N-((R)-1-(3-Cyano-2-methylphenyl)ethyl)-4-fluoro-5-morpholino-2-(((R)-quinuclidin-3-yl)amino)benzamide, (R)-N-(1-(3-Cyano-2-methylphenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide, (R)-2-((2-Aminoethyl)amino)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholinobenzamide, (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-5-morpholinobenzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-(((R)-1-(dimethylamino)propan-2-yl)amino)-4-fluoro-5-morpholinobenzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-(((S)-1-(dimethylamino)propan-2-yl)amino)-4-fluoro-5-morpholinobenzamide, (R)-2-(((2-cyanopropan-2-yl)amino)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-morpholinobenzamide, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-(((1-(dimethylamino)-2-methylpropan-2-yl)amino)-4-fluoro-5-morpholinobenzamide, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-(((3-(dimethylamino)bicyclo[1.1.1]pentan-1-yl)amino)-4-fluoro-5-morpholinobenzamide, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-(((1,3-dimethylazetidin-3-yl)amino)-4-fluoro-5-morpholinobenzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-5-morpholinobenzamide, (R)-4-fluoro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-(((1-methylpiperidin-4-yl)amino)-5-(pyridin-4-yl)benzamide, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((1-methylpiperidin-4-yl)amino)-5-(pyridin-4-yl)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(pyridin-4-yl)-2-(((R)-quinucidin-3-yl)amino)benzamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(pyridin-4-yl)-2-(((S)-quinucidin-3-yl)amino)benzamide (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-((1-methylpiperidin-4-yl)amino)benzamide (R)-4-fluoro-5-(isoxazol-4-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)benzamide (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((1-methylpiperidin-4-yl)amino)benzamide (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-5-(3-fluoropyridin-4-yl)-2-((1-methylpiperidin-4-yl)amino)benzamide (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(2-methylpyridin-4-yl)benzamide (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(pyridazin-4-yl)benzamide (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(pyrimidin-4-yl)benzamide (R)-5-cyclopropyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide (R)-5-(bicyclo[1.1.1]pentan-1-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide 5-(Bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((R)-quinolin-3-yl)amino)benzamide, 5-(Bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-(((S)-quinolin-3-yl)amino)benzamide, Methyl (R)-5-(((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-2-fluoro-4-((1-methylpiperidin-4-yl)amino)benzoate, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(1,3,4-oxadiazol-2-yl)benzamide, (R)-N1-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-N3-methyl-6-((1-methylpiperidin-4-yl)amino)isophthalamide, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(4,4-difluoropiperidine-1-carbonyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)benzamide, (R)-N1-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-N3,N3-dimethyl-6-((1-methylpiperidin-4-yl)amino)isophthalamide, (R)-N1-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-N3-isopropyl-6-((1-methylpiperidin-4-yl)amino)isophthalamide, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-fluoro-2-((1-methylpiperidin-4-yl)amino)-5-(morpholine-4-carbonyl)benzamide, Methyl (R)-3-(((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-4-((1-methylpiperidin-4-yl)amino)benzoate, (R)-4-(difluoromethyl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-((1-methylpiperidin-4-yl)amino)-5-morpholinobenzamide, 4-chloro-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-morpholino-2-(((R)-quinucidin-3-yl)amino)benzamide, 4-chloro-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-morpholino-2-(((S)-quinucidin-3-yl)amino)benzamide, a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

21. A method for treating cancer in a subject in need of cancer treatment, the method comprising administering to the subject an effective amount of the compound according to any one of claims 1 to 19.

22. The method according to claim 21, wherein the cancer is a Ras pathway-related cancer.

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