Heterocyclic compounds and methods of use

Abstract

This application relates to compounds of formula (I) as defined herein, and pharma- ceutically acceptable salts thereof. This application also describes pharmaceutical compositions comprising the compounds of formula (I), and pharma- ceutically acceptable salts thereof, and methods of using the compounds and compositions for inhibiting certain protein-protein interactions and for treating cancer. Also provided herein are pharmaceutical compositions comprising the compounds of formula (I), or pharma- ceutically acceptable salts thereof, and at least one pharma- ceutically acceptable excipient.

Description

[Technical Field]

[0001] This application relates to heterocyclic compounds that are useful for treating proliferative disorders such as cancer. [Background technology]

[0002] Cancer is characterized by abnormal cell growth and proliferation. Ras proteins are key components of signal transduction networks that control cell proliferation, differentiation, and survival. See, for example, Fernandes-Medarde and Santos, Genes Cancer, Vol. 2, No. 3, pp. 344-358 (2011). Ras is a GTPase that acts as a molecular switch between an active GTP-bound state and an inactive GDP-bound state. GTP-bound Ras can activate several downstream signal transduction pathways involved in cell cycle progression, survival, and apoptosis. Guanine nucleotide exchange factors (GEFs), such as SOS1, are required for Ras activation by promoting the exchange of GDP (inactive Ras) for GTP (active Ras). SOS1 itself is activated by Ras through an allosteric interaction, 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). Ras mutations occur in many human cancers, but currently, no drugs targeting Ras proteins are approved. See, for example, Hillig, et al., Proc. Nat. Acad. Sci., Vol. 117, No. 7, pp. 2551–2560 (2019). Therefore, there remains a need for novel therapeutic approaches that disrupt Ras signaling. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Fernandes-Medarde and Santos, Genes Cancer, Vol. 2, No. 3, pp. 344-358 (2011) [Non-patent document 2] Bandaru,et al.,Cold Spring Harb.Perspect Med.,Vol.9,No.2,a031534(2019) [Non-patent document 3] Hillig,et al.,Proc.Nat.Acad.Sci.,Vol.117,No.7,pp.2551-2560(2019) Summary of the Invention [Means for solving the problem]

[0004] It has now been discovered that certain heterocyclic compounds are inhibitors of SOS1 activity and are useful in treating a variety of diseases and disorders, including cancer.

[0005] Thus, as used herein, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and X are as defined herein.

[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, comprising contacting the cells with an effective amount of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

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

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

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

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

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

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

[0015] Provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with a dysregulation of the expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or 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 thereof, 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, wherein the subject has been determined to have a cancer associated with dysregulation of the expression or activity or level of a Ras pathway gene, a Ras pathway protein, or any of them.

[0017] Provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with a Ras gene, a Ras protein, or dysregulation of the expression or activity or levels 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.

[0018] Also provided herein is a method for treating cancer in a subject in need thereof, 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, wherein the subject has been determined to have a cancer associated with dysregulation of the expression or activity or level of a Ras gene, a Ras protein, or any of them.

[0019] Also provided herein is a method for treating cancer in a subject in need thereof, 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, wherein the subject has been determined to have a cancer associated with dysregulation of the expression or activity or level of the SOS1 gene, SOS1 protein, or any of them.

[0020] Provided herein is a method for treating cancer in a subject in need thereof, comprising: (a) determining that the cancer is associated with dysregulation of the SOS1 gene, the SOS1 protein, or the expression or activity or levels 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.

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

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

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

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

[0026] Also provided is a method for inhibiting metastasis in a subject with a particular cancer in need of treatment, 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 comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

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

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

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

[0030] 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 and / or the inhibition of metastasis associated with certain cancers.

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

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

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

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

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

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

[0037] Other features and advantages of the invention will become apparent from the following detailed description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0038] Unless otherwise specified, 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; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are 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] definition The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the depicted structure. A compound identified herein by name or structure as one particular tautomeric form is intended to include other tautomeric forms unless otherwise specified.

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

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

[0042] The term "halo" refers to the halogens, 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 "C1-C6 alkyl" refers to a straight or branched saturated hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0044] The term "C1-C6 alkylene" refers to a straight or branched divalent hydrocarbon (alkyl) chain containing 1, 2, 3, 4, 5, or 6 carbon atoms, respectively, connecting the rest of the molecule to a radical group consisting only of carbon and hydrogen. The alkylene can have 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule can be through one carbon or any two carbons within the chain.

[0045] The term "C1-C6 haloalkyl" refers to a C1-C6 alkyl as defined herein substituted with at least one independently selected halogen atom at each occurrence, such as fluorine, chlorine, bromine, and iodine. The halogen atom(s) may be present at any position on the alkyl group. For example, C1-C6 haloalkyl may refer to chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloroethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, difluoroethyl, such as 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, or trifluoropropyl.

[0046] As used herein, the term "heteroaryl" refers to a 5-10 membered monocyclic or bicyclic group in which at least one ring in the system is aromatic and one or more carbon atoms in at least one ring in the system is replaced by a heteroatom independently selected from N, O, and S. Non-limiting examples of heteroaryl groups include furanyl, furazanyl, thiofuranyl, 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, Examples include 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.

[0047] As used herein, the term "cycloalkyl" refers to a C-C 10 "Cycloalkyl" refers to saturated or partially unsaturated monocyclic or bicyclic carbon groups having 3 to 10 carbon atoms, such as cycloalkyl groups and C3-C6 cycloalkyl groups. Bicyclic cycloalkyl groups include fused, spiro, and bridged ring systems. Non-limiting examples of cycloalkyl groups include phenyl, 2,3-dihydro-1H-indene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexyl, spiro[3.3]heptanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and spiro[2.5]octyl.

[0048] The term "heterocyclyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or bicyclic ring system having 3 to 10 ring atoms that is not aromatic and has at least one heteroatom in the ring selected from N, O, and S. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. Heterocyclyl groups may be referred to, for example, as "5- to 10-membered heterocyclyl groups," which are ring systems containing 5, 6, 7, 8, 9, or 10 atoms, with at least one atom being a heteroatom. Heterocyclyl groups can have, for example, 1, 2, 3, or more heteroatoms. In some embodiments, heterocyclyl groups have 1 or 2 independently selected heteroatoms. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, and as defined, include oxo and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. A heterocyclyl group may be attached to the remainder of the molecule through any carbon atom or through a heteroatom such as nitrogen.Exemplary heterocyclyl groups include azepanyl, 1,3-dioxolane, 1,4-dioxolanyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidionyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, quinuclidinyl, 4H-pyranyl, azetidinyl, oxetanyl, octahydrocyclopenta[c]pyrrole, 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-diazabi Examples include, but are not limited to, cyclo[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.

[0049] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation due to the ring itself, e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0050] The compounds of formula (I) include pharmaceutically acceptable salts thereof. In addition, the compounds of formula (I) also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, but that may be useful as intermediates for preparing and / or purifying compounds of formula (I) and / or for separating enantiomers of compounds of formula (I).

[0051] It will further be understood that the compounds of formula (I) or their salts may be isolated in the form of a solvate, and therefore 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 unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0052] In some embodiments, the compounds of Formula (I) include the compounds of Examples 1-313, as well as stereoisomers and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the compounds of Examples 1-313 are in free base form. In some embodiments, the compounds of Examples 1-313 are in the form of pharmaceutically acceptable salts.

[0053] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt can be obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid. In some embodiments, a pharmaceutically acceptable salt 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 a salt containing an amino acid (e.g., arginine and lysine), or by other methods previously determined. The pharmacologically acceptable salt is not specifically limited, so long as it can be used in medicine. A compound described herein having a base Examples of salts include those with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, those with organic bases such as methylamine, ethylamine, and ethanolamine, those with basic amino acids such as lysine and ornithine, and ammonium salts. The salts may be acid addition salts, for example, 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.

[0054] The compounds provided herein may also contain unnatural proportions of atomic isotopes in one or more of the atoms that constitute such compounds. That is, when an atom is specifically referred to in connection with a compound according to formula (I), it includes all isotopes and isotopic mixtures of that atom, whether naturally occurring or synthetically produced, in either natural abundance or isotopically enriched form. 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 mentioned, the atom is 11 C. 12 C. 13 C. 14 C, or mixtures thereof, and when nitrogen is mentioned, the atom 13 N, 14 N, 15 N, or mixtures thereof, and when oxygen is mentioned, the atom is 14 O. 15 O. 16 O. 17 O. 18 O, or mixtures thereof, and when fluoro is mentioned, 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 replaced with deuterium ( 2 Some of the aforementioned isotopes are radioactive, and therefore the compounds provided herein also include compounds with one or more isotopes of one or more atoms, including radioactive compounds, and mixtures thereof, in which one or more non-radioactive atoms are replaced by one of their radioactively enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, for example, cancer therapeutic agents, research reagents, for example, assay reagents, and diagnostic agents, for example, in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0055] 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. IC for inhibiting SOS1-Ras interaction 50 The values ​​are shown in Table A. hSOS1 K in surface plasmon resonance (SPR) SOS1 binding assay D The values ​​are shown in Table B.

[0056] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood-brain barrier and inhibiting SOS1 activity in 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, compounds can be used to treat cancers (e.g., Ras pathway-related cancers (e.g., SOS1-related cancers, Ras-related cancers (e.g., KRas-related cancers, HRas-related cancers, and / or NRas-related cancers), EGFR-related cancers, ErbB2-related cancers, ErbB3-related cancers, ErbB4-related cancers, NF1-related cancers, PDGFR-A-related cancers, PDGFR-B-related cancers, FGFR1-related cancers, FGFR2-related cancers, FGFR3-related cancers, IGF1-related cancers, and the like). Treatment of a subject with a cancer (e.g., a Ras pathway-related brain tumor or a CNS cancer) (e.g., a Ras pathway-related brain tumor ...

[0057] The compounds of formula (I) or pharmaceutically acceptable salts thereof are useful in treating diseases or disorders that can be treated with SOS1 inhibitors, for example, Ras pathway-related diseases or disorders (e.g., SOS1-related diseases or disorders), Ras-related diseases or disorders (e.g., rheumatoid arthritis ... , 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 ROS-related disease or disorder, INSR-related disease or disorder, ALK-related disease or disorder, ROS-related disease or disorder, TrkA-related disease or disorder, TrkB-related disease or disorder, TrkC-related disease or disorder, RET-related disease or disorder, c-MET-related disease or disorder, VEGFR1-related disease or disorder, VEGFR2-related disease or disorder, VEGFR3-related disease or disorder, AXL-related disease or disorder, SHP2-related disease or disorder, RAF-related disease or disorder (e.g., a BRAF-related disease or disorder), PI3K-related disease or disorder, AKT-related disease or disorder, mTOR-related disease or disorder, MEK-related disease or disorder, ERK-related disease or disorder, or a combination thereof.

[0058] The compounds of formula (I) or pharmaceutically acceptable salts thereof are useful for treating diseases and disorders that can be treated by SOS1 inhibitors, such as Ras pathway-associated cancers, including hematological cancers and solid tumors.

[0059] As used herein, the term "treat" or "treatment" refers to curative or palliative measures. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, a decrease in the extent of the disease, a stabilization of the disease state (i.e., does not worsen), a delay or slowing of disease progression, an 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.

[0060] 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 is experiencing and / or exhibiting at least one symptom of the disease or disorder being treated and / or prevented.

[0061] In some embodiments, the subject is diagnosed with a genetic abnormality in 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, 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 a combination thereof), Ras pathway proteins (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1 The subject has been identified or diagnosed with a cancer involving dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them (Ras pathway-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor(s) that is positive for dysregulation of a Ras pathway gene, a Ras pathway protein, or the expression, activity, or level of any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be one whose tumor has a dysregulation of a Ras pathway gene, Ras pathway protein, or their expression or activity or levels (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).In some embodiments, the subject is suspected of having a Ras pathway-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them (a Ras pathway-associated cancer) based on histological examination.

[0062] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the Ras gene, Ras protein, or expression or activity or levels of any of them (Ras-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the Ras gene, Ras protein, or expression or activity or levels of any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have tumor(s) that are positive for dysregulation of the Ras gene, Ras protein, or expression or activity or levels of any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has dysregulation of the Ras gene, Ras protein, or expression or activity or levels thereof (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a Ras-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of a Ras gene, a Ras protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulated expression or activity or levels of a Ras gene, a Ras protein, or any of them (Ras-associated cancer) based on histological examination.

[0063] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the KRas gene, KRas protein, or expression or activity or levels of any of them (KRas-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the KRas gene, KRas protein, or expression or activity or levels of any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have tumor(s) that are positive for dysregulation of the KRas gene, KRas protein, or expression or activity or levels of any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor that has dysregulation of the KRas gene, KRas protein, or expression or activity or levels thereof (e.g., identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the KRas gene, KRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulated expression or activity or levels of the KRas gene, KRas protein, or any of them (KRas-associated cancer) based on histological examination.

[0064] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the HRas gene, HRas protein, or expression or activity or levels of any of them (HRas-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the HRas gene, HRas protein, or expression or activity or levels of any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor(s) are positive for dysregulation of the HRas gene, HRas protein, or expression or activity or levels of any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has dysregulation of the HRas gene, HRas protein, or expression or activity or levels thereof (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an HRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (an HRas-associated cancer) based on histological examination.

[0065] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the NRas gene, NRas protein, or expression or activity or levels of any of them (NRas-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the NRas gene, NRas protein, or expression or activity or levels of any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have tumor(s) that are positive for dysregulation of the NRas gene, NRas protein, or expression or activity or levels of any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has dysregulation of the NRas gene, NRas protein, or expression or activity or levels (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an NRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the NRas gene, NRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulated expression or activity or levels of the NRas gene, NRas protein, or any of them (an NRas-associated cancer) based on histological examination.

[0066] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the SOS1 gene, SOS1 protein, or expression or activity or levels of any of them (SOS1-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the SOS1 gene, SOS1 protein, or expression or activity or levels of any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has dysregulation of the SOS1 gene, SOS1 protein, or expression or activity or levels (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an SOS1-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulation of the expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer determined to be associated with dysregulation of the expression or activity or level of the SOS1 gene, SOS1 protein, or any of them (SOS1-associated cancer) based on histological examination.

[0067] The term "pediatric subject," as used herein, refers to a subject under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subpopulations, including neonates (birth to 1 month), infants (1 month to 2 years), children (2 to 12 years), and adolescents (12 to 21 years, up to but not including their 22nd birthday). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is from birth to 28 days of age, from 29 days of age to less than 2 years of age, from 2 years of age to less than 12 years of age, or from 12 years of age to 21 years of age (up to but not including the 22nd birthday).

[0068] In certain embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof are useful for preventing diseases and disorders defined herein (e.g., autoimmune diseases, inflammatory diseases, and cancer). The term "preventing," as used herein, means preventing the onset, recurrence, or spread, in whole or in part, of a disease or condition described herein, or a symptom thereof.

[0069] In certain embodiments, the compounds of Formula (I) or pharmaceutically acceptable salts thereof are useful for preventing diseases and disorders as defined herein (e.g., Ras pathway-associated diseases or disorders, as described herein (e.g., autoimmune diseases, inflammatory diseases, and cancer). The term "preventing," as used herein, means preventing the onset, recurrence, or spread, in whole or in part, of a disease or condition described herein, or a symptom thereof.

[0070] Abnormal cell growth and proliferation are hallmarks 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 viral oncogene homolog), HRas (V-Ha-Ras Harvey rat sarcoma viral oncogene homolog), and / or NRas (neuroblastoma RAS viral (V-Ras) oncogene homolog), sometimes referred to as KRAS, HRAS, and NRAS, or K-Ras, H-Ras, and N-Ras, respectively) are membrane-bound guanosine triphosphate (GTP) / guanosine diphosphate (GDP)-binding (G) proteins involved in many oncogene signaling cascades. Each of these proteins is approximately 21 kD in size. KRas has two common isoforms known as KRas4A and KRas4B.

[0071] Mature Ras proteins typically associate with cell membranes 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, Ras proteins are bound to GDP. See, e.g., Adjei, J. Nat'l. Cancer Inst. 93.14(2001):1062-1074.

[0072] Activation of Ras proteins can be initiated through multiple types of cell surface receptors, including receptor tyrosine kinases (TKIs) (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3, AXL), T cell receptors, B cell receptors, monocyte colony-stimulating factor receptors, G protein-coupled receptors (GPCRs), and integrin family proteins. Activation of one of these types of cell surface receptors generally leads to the activation of one or more guanine nucleotide exchange factors (GEFs), which directly or indirectly promote the Ras protein to release GDP, allowing GTP to bind. Non-limiting examples of GEFs include SOS (Son of Sevenless homolog) protein and RASGRF1 (Ras protein-specific guanine nucleotide releasing factor 1, sometimes also known as Cdc25). For example, upon activation, dimerization, and autophosphorylation of EGFR, the receptor can bind to the SH2 domain of the adaptor protein growth factor receptor-bound protein 2 (GRB2), which can then bind to SOS proteins (e.g., SOS1 or SOS2, sometimes also called SOS-1 and SOS-2, respectively), thereby colocalizing the SOS proteins with Ras family proteins at the cell membrane.For example, and Coumoul,Biochem.Pharmacol.82.9(2011):1049-1056.Kortum,et al. Proc. Nat. Acad. Sci. 108.30(2011):12407-12412; U.S. Application Publication Nos. 2019 / 0358230 and 2019 / 0194192, and PCT Publication Nos. WO2018 / 172250 and WO2019 / 201848.

[0073] Upon activation by GTP binding, Ras proteins can bind to and activate numerous downstream effectors, including RAF family proteins, phosphatidylinositol 3-kinase (PI3K), and RAL family proteins. See, e.g., Gurung and Bhattacharjee. Oncology & Hematology Review, 2015;11(2):147-52(2015). For example, signal transduction via the Ras-RAF-MAPK pathway has been implicated in many cancers, including, but not limited to, pancreatic cancer, thyroid cancer (e.g., papillary thyroid cancer), colon cancer, lung cancer (e.g., non-small cell lung cancer), melanoma, biliary tract 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, signaling through the Ras-PI3K / AKT / mammalian target of rapamycin (mTOR) pathway has been shown to play a role in a number of cancers, including, but not limited to, melanoma, ovarian cancer, cervical cancer, endometrial cancer, breast cancer, prostate cancer, brain cancer (e.g., glioblastoma), lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, bladder cancer, colon cancer, head and neck cancer, leukemia, thyroid cancer, lymphoma, intestinal cancer, gastric cancer, and combinations thereof.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.

[0074] Although Ras proteins have intrinsic GTPase activity, it is typically not physiologically relevant. Instead, hydrolysis of bound GTP is required for the production of neurofibromatosis type 1 (NF1) or p120 GAP The binding of GTPase-activating proteins (GAPs) such as ATP is enhanced (e.g., by up to about 5 orders of magnitude). See, e.g., Adjei, Journal of the National Cancer Institute 93.14(2001):1062-1074; Downward, Nature Reviews Cancer 3.1(2003):11-22; Scheffzek, et al. Science 277.5324(1997):333-339.

[0075] Activating mutations in Ras family proteins (particularly at residues G12, G13, and / or Q61) are estimated to be present in up to approximately 30% of all human cancers. Generally, activating mutations in Ras family proteins render the Ras protein insensitive to the activity of GAPs. See, for example, Santarpia, et al. Expert Opinion on Therapeutic Targets 16.1 (2012): 103-119. Illustrative, non-limiting examples of Ras mutations are presented in Tables 1 (KRas mutations), 2 (HRas mutations), and 3 (NRas mutations).

[0076] As used herein, the term "Ras pathway-associated disease or disorder" refers to a disease or disorder associated with or involving dysregulation of a gene in the Ras pathway, a protein in the Ras pathway, or the expression, activity, or levels of any (e.g., one or more) thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of a gene in the Ras pathway, a protein in the Ras pathway, or any of the foregoing described herein). Non-limiting examples of Ras pathway-associated diseases or disorders include, for example, neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Leopard syndrome, capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome, hereditary gingival fibromatosis, and cancer.

[0077] In some embodiments, the Ras pathway-associated disease or disorder is a Ras pathway-associated cancer. As used herein, the term "Ras pathway-associated cancer" refers to a cancer associated with or having dysregulation of the expression, activity, or level of a gene in the Ras pathway, a protein in the Ras pathway, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression, activity, or level of a gene in the Ras pathway, a protein in the Ras pathway, or any of them described herein). Non-limiting examples of Ras pathway-associated cancers are described herein. In some embodiments, the Ras pathway-associated cancer can be a KRas-associated cancer, an HRas-associated cancer, an NRas-associated cancer, an SOS1-associated cancer, an EGFR-associated cancer, an ErbB2-associated cancer, an ErbB3-associated cancer, an ErbB4-associated cancer, an NF1-associated cancer, a PDGFR-A-associated cancer, a PDGFR-B-associated cancer, an FGFR1-associated cancer, an FGFR2-associated cancer, an FGFR3-associated cancer, an IGF1 R-associated cancer, an INSR-associated cancer, an ALK-associated cancer, a ROS-associated cancer, a TrkA-associated cancer, a TrkB-associated cancer, a TrkC-associated cancer, a RET-associated cancer, a c-MET-associated cancer, a VEGFR1-associated cancer, a VEGFR2-associated cancer, a VEGFR3-associated cancer, an AXL-associated cancer, a SHP2-associated cancer, a RAF-associated cancer (e.g., a BRAF-associated cancer), a PI3K-associated cancer, an AKT-associated cancer, an mTOR-associated cancer, a MEK-associated cancer, an ERK-associated cancer, or a combination thereof.

[0078] The term "Ras-associated cancer," as used herein, refers to a cancer associated with or having dysregulation of the expression, activity, or levels of a Ras gene, a Ras protein, or any (e.g., one or more) thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of a Ras gene, a Ras protein, or any (e.g., one or more) thereof described herein). Non-limiting examples of Ras-associated cancers are described herein. In some embodiments, the Ras-associated cancer may be a KRas-associated cancer, an HRas-associated cancer, an NRas-associated cancer, or a combination thereof.

[0079] The phrase "dysregulated expression or activity or levels of a Ras gene, a Ras protein, or any of them" refers to a genetic mutation (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 comprising a deletion of at least one amino acid compared to the wild-type Ras protein, a mutation in a Ras gene that results in the expression of a Ras protein with one or more point mutations compared to the wild-type Ras protein, a mutation in a Ras gene that results in the expression of a Ras protein with at least one inserted amino acid compared to the wild-type Ras protein, a gene duplication that results in an increased level of a Ras protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of a Ras protein in a cell), a Ras protein (e.g., that results in a Ras protein having a deletion of at least one amino acid in the Ras protein compared to the wild-type Ras protein or that results in a Ras protein having an insertion of at least one amino acid in the Ras protein compared to the wild-type Ras protein). This refers to increased expression (e.g., increased levels) of wild-type Ras protein in mammalian cells due to alternatively spliced ​​versions of mRNA, or aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or 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 a protein encoded by a Ras gene that does not contain the mutation. In some embodiments of any of the methods described herein, dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them can be selected from the group consisting of a G12 mutation, a G13 mutation, a Q61 mutation, and combinations thereof.

[0080] Table 1 lists some non-limiting exemplary KRas mutations. Table 1A lists non-limiting exemplary KRas fusions. In some embodiments of any of the methods described herein, the dysregulation of the expression or activity or level of the KRas gene, KRas protein, or any of them may be selected from the group consisting of a G12 mutation (e.g., G12I, G12A, G12C, G12D, G12E, G12F, G12L, G12N, G12R, G12S, G12T, G12V, G12W, or G12Y), a G13 mutation (e.g., G13A, G13C, G13D, G13E, G13F, G13I, G13M, G13N, G13P, G13R, G13S, G13V, or G13Y), a Q61 mutation (e.g., Q61D, Q61E, Q61H, Q61K, Q61L, Q61P, Q61R), and combinations thereof.

[0081] Table 2 lists some non-limiting exemplary HRas mutations. In some embodiments of any of the methods described herein, the dysregulation of the HRas gene, HRas protein, or expression or activity or level of any of them may be selected from the group consisting of a G12 mutation (e.g., G12A, G12C, G12D, G12R, G12S, G12V), a G13 mutation (e.g., G13A, G13C, G13D, G13R, G13S, G13V), a Q61 mutation (e.g., Q61H, Q61K, Q61L, Q61P, Q61R, Q61*), and combinations thereof.

[0082] Table 3 lists some non-limiting exemplary HRas mutations. In some embodiments of any of the methods described herein, the dysregulation of the HRas gene, HRas protein, or expression or activity or level of any of them may be selected from the group consisting of a G12 mutation (e.g., G12A, G12C, G12D, G12R, G12S, G12V, G12W, G12N), a G13 mutation (e.g., G13A, G13C, G13D, G13R, G13S, G13V), a Q61 mutation (e.g., Q61E, Q61H, Q61K, Q61L, Q61P, Q61R, Q61E, Q61N), and combinations thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 2] [Table 3] [Table 4]

[0083] However, Ras proteins are often considered "undruggable," and no direct Ras inhibitors have been approved by the U.S. Food and Drug Administration. Therefore, other targets in the Ras signaling pathway have been targeted to suppress aberrant signaling through these pathways, including both upstream and downstream targets of Ras family proteins. See, e.g., 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.

[0084] Guanine nucleotide exchange factors, which promote the exchange of GDP for bound GTP by Ras family proteins, may be suitable targets for reducing signaling through the Ras pathway. Inhibition of GEFs may promote the inactive (GDP-bound) state of Ras family proteins and thus reduce signaling through the pathway. See, e.g., 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.

[0085] SOS1 consists of a central "catalytic" core of approximately 500 residues (SOSATcat ), which is sufficient for Ras activation activity. SOS1 has a primary (sometimes referred to as the "catalytic" site) Ras-binding site (e.g., containing a Cdc25 homology domain) that can bind to the nucleotide-binding site of the Ras protein, thereby promoting the release of the bound nucleotide (e.g., GDP) and allowing another nucleotide (e.g., GTP) to be released. SOS1 can bind to two Ras molecules in a ternary complex, and binding of the Ras·GTP complex to a second (sometimes referred to as the "allosteric" site) site on SOS1 further activates the catalytic activity of SOS1 in a positive feedback mechanism. See, e.g., Margarit, et al. Cell 112.5(2003):685-695; Freedman, et al. Proc. Nat. Acad. Sci. 103.45(2006):16692-16697. Furthermore, it has been shown that small molecule binders of SOS1 can regulate its GEF activity. See, e.g., Burns, et al. Proc. Nat. Acad. Sci. 111.9 (2014):3401-3406. In some cases, small molecule binders of SOS1 can negatively regulate its GEF activity with Ras proteins, and such molecules may also be referred to herein as "SOS1 inhibitors" and may be referred to as inhibiting "SOS1 activity." Some SOS1 inhibitors have been shown to bind proximal to the primary Ras binding site, causing, for example, movement of the side chain of Tyr884, reducing the favorable stacking interaction with Arg73 of KRas. Furthermore, the antiproliferative activity of some such SOS1 inhibitors has been demonstrated. See, e.g., Hillig, et al., Proc. Nat. Acad. Sci. 116.7(2019):2551-2560, U.S. Patent Application Publication Nos. 2019 / 0358230 and 2019 / 0194192, and PCT Publication Nos. WO2018 / 172250 and WO2019 / 201848.

[0086] The term "SOS1-associated cancer," as used herein, refers to cancer that is associated with or has dysregulation of the expression, activity, or levels of the SOS1 gene, SOS1-GEF (also referred to herein as the SOS1 protein), or any (e.g., one or more) thereof (e.g., any of the types of dysregulation of the expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them described herein). Non-limiting examples of SOS1-associated cancers are described herein.

[0087] The phrase "dysregulated expression or activity or levels of the SOS1 gene, SOS1 protein, or any of them" refers to a genetic mutation (e.g., an SOS1 gene translocation resulting in the expression of a fusion protein, a mutation in the SOS1 gene resulting in the expression of an SOS1 protein containing at least one amino acid deletion compared to the wild-type SOS1 protein, a mutation in the SOS1 gene resulting in the expression of an SOS1 protein with one or more point mutations compared to the wild-type SOS1 protein, a mutation in the SOS1 gene resulting in the expression of an SOS1 protein with at least one inserted amino acid compared to the wild-type SOS1 protein, a gene duplication resulting in an increased level of SOS1 protein in a cell, or refers to an increase in expression (e.g., increased level) of wild-type SOS1 protein in mammalian cells due to a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of SOS1 protein in the cell, an alternative splice version of SOS1 mRNA (e.g., resulting in an SOS1 protein having a deletion of at least one amino acid in the SOS1 protein compared to the wild-type SOS1 protein or resulting in an SOS1 protein having an insertion of at least one amino acid in the SOS1 protein compared to the wild-type SOS1 protein), or aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them can be a mutation in the SOS1 gene that encodes an SOS1 protein that is constitutively active or has increased activity compared to a protein encoded by an SOS1 gene that does not contain the mutation. Non-limiting examples of SOS1 protein point mutations / insertions / deletions are listed in Table 4. Table 4A lists non-limiting exemplary SOS1 fusions. [Table 5-1] [Table 5-2] [Table 6]

[0088] The term "wild-type" describes a nucleic acid (e.g., an SOS1 gene or mRNA) or protein (e.g., an SOS1 protein) found in a subject who does not have a disease or disorder associated with the nucleic acid or protein (e.g., an SOS1-associated disease or disorder) (and optionally does not have an increased risk of developing a disease or disorder associated with the nucleic acid or protein and / or is not suspected of having a disease or disorder associated with the nucleic acid or protein), or found in cells or tissues from a subject who does not have a disease or disorder associated with the nucleic acid or protein (e.g., a cancer associated with the nucleic acid or protein) (and optionally does not have an increased risk of developing a disease or disorder associated with the nucleic acid or protein and / or is not suspected of having a disease or disorder associated with the nucleic acid or protein).

[0089] The term "regulatory agency" refers to a national agency that approves pharmaceutical agents for medical use in a country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0090] compound As used herein, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is C1-C6 alkyl, 4- to 10-membered heterocyclyl, or C3-C 10 cycloalkyl, wherein each alkyl, heterocyclyl, and cycloalkyl is selected from one or more R a and optionally substituted with R aare each independently C-C alkyl, C-C haloalkyl, C-C cycloalkyl, halogen, —C(O)C-C alkyl, or —C(O)—C-C cycloalkyl, each cycloalkyl optionally substituted with one or more halogens; R 2 is a C6 aryl or a 5- to 10-membered heteroaryl, and each aryl and heteroaryl is selected from one or more R b and optionally substituted with R b are each independently halogen, C1-C3 haloalkyl, C1-C3 alkyl, or C3 cycloalkyl; R 3 -H, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkylene-O-NH-C(NH)(NH2), C3-C 10 Cycloalkyl, C1-C6 alkylene-5-10 membered heteroaryl, C1-C6 alkylene-4-10 membered heterocyclyl, C1-C6 alkylene-(C3-C 10 cycloalkyl), or C3-C 10 cycloalkyl, and each alkylheterocyclyl, cycloalkyl, and heteroaryl may be one or more R c and optionally substituted with R c are each independently C1-C6 alkyl, -OH, -O-(C1-C6 alkyl), C1-C6 alkylene-O-CH3, halogen, C1-C6 alkylene-5 to 10-membered heterocyclyl, -N(CH3)(CH3), C3-C 10 cycloalkyl, C1-C6 haloalkyl, wherein each heterocyclyl, cycloalkyl, and alkyl is optionally substituted with one or more deuterium, C1-C6 alkyl, —OH, halogen, CN, or C1-C6 haloalkyl; R 4 is -H, -CH3, -CN, -OMe, or halogen; R 5 is C1-C3 alkyl or C1-C3 haloalkyl; Compounds of formula (I), or pharmaceutically acceptable salts thereof, are provided wherein X is NH or S.

[0091] In some embodiments, R 1 is a 4- to 10-membered heterocyclyl. In some embodiments, R 1 is one or more R a In some embodiments, R is a 4- to 10-membered heterocyclyl optionally substituted with 1 is one R a is a 4- to 10-membered heterocyclyl substituted with

[0092] In some embodiments, R 1 is a 4- to 6-membered heterocyclyl. In some embodiments, R 1 is one or more R a In some embodiments, R is a 4- to 6-membered heterocyclyl optionally substituted with 1 is one R a is a 4- to 6-membered heterocyclyl substituted with

[0093] In some embodiments, R 1 is one or more R aazepanyl, 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, pyrrolidionyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, quinuclidinyl, 4H-pyran, azetidinyl, oxetanyl, octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]he optionally substituted with butanyl, 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.

[0094] In some embodiments, R 1 is tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl. 1 is one or more R a In some embodiments, R is tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl optionally substituted with 1 is one R a and tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl substituted with .

[0095] In some embodiments, R 1 is tetrahydrofuranyl, tetrahydropyranyl, or azetidinyl.

[0096] In some embodiments, R 1 is C3-C 10 In some embodiments, R 1 is one or more R a C3-C optionally substituted with 10 In some embodiments, R 1 is one R a C3-C substituted with 10 It is cycloalkyl.

[0097] In some embodiments, R 1 is C or C cycloalkyl. In some embodiments, R 1 is one or more R a In some embodiments, R 1 is one R a is a C3 or C4 cycloalkyl substituted with

[0098] In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is one or more R a In some embodiments, R is cyclopropyl optionally substituted with 1 is one R a is a cyclopropyl substituted with

[0099] In some embodiments, R a is C1-C3 alkyl. In some embodiments, R a is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R a is methyl.

[0100] In some embodiments, R a is halogen. In some embodiments, R a is Cl, F, or Br. In some embodiments, R a is F.

[0101] In some embodiments, R a is C1-C3 haloalkyl. In some embodiments, R a is fluoromethyl. In some embodiments, R a is difluoromethyl. In some embodiments, R a is trifluoromethyl.

[0102] In some embodiments, R a is C-C cycloalkyl optionally substituted with one or more halogens. In some embodiments, R a is a C cycloalkyl optionally substituted with one or more halogens. In some embodiments, R a is a C4 cycloalkyl optionally substituted with one or more halogens. In some embodiments, R a is a C cycloalkyl optionally substituted with one or more halogens. In some embodiments, R a is a C6 cycloalkyl optionally substituted with one or more halogens.

[0103] In some embodiments, R a is —C(O)C1-C3 alkyl. In some embodiments, R a is -C(O)CH3.

[0104] In some embodiments, R a is —C(O)—C-C cycloalkyl optionally substituted with one or more halogens. In some embodiments, R a is —C(O)-cyclopropyl optionally substituted with one or more halogens.

[0105] In some embodiments, R 1 teeth, [ka] is selected from.

[0106] In some embodiments, R 1 is one or more R a In some embodiments, R 1 is C alkyl optionally substituted with C-C cycloalkyl. In some embodiments, R 1 is isopropyl. In some embodiments, R 1 is cyclopropylpropan-2-yl.

[0107] In some embodiments, R 2 is one or more R b In some embodiments, R 2 is one or more R b R is phenyl optionally substituted with b The group(s) can be at any of the five available positions within the phenyl ring.

[0108] In some embodiments, R 2 is one R b and phenyl substituted by one R b The group is R 2 It can be in the ortho, meta, or para position relative to the bond connecting R to the rest of the molecule. 2 are two independently selected R b and two independently selected R b The groups can be in the ortho, meta, or para positions relative to each other. 2 are three independently selected R b and phenyl substituted by three independently selected R bThe groups can be located at any combination of the five available positions on the phenyl ring. 2 is unsubstituted phenyl.

[0109] In some embodiments, R 2 teeth [ka] is selected from.

[0110] In some embodiments, R 2 is a 5- to 10-membered heteroaryl, optionally substituted with one or more R b In some embodiments, R 2 is one or more R b is a 9-membered heteroaryl optionally substituted with

[0111] In some embodiments, R 2 teeth, [ka] is.

[0112] In some embodiments, R b is halogen. In some embodiments, R b is F, Cl, Br, or I. In some embodiments, R b is F.

[0113] In some embodiments, R b is C1-C3 haloalkyl. In some embodiments, R bis chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, e.g., 1-chloroethyl and 2-chloroethyl, trichloroethyl, e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, e.g., 1-fluoromethyl and 2-fluoroethyl, difluoroethyl, e.g., 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, or trifluoropropyl. In some embodiments, R b is trifluoromethyl, difluoromethyl, or 1,1-difluoroethyl.

[0114] In some embodiments, R b is C1-C3 alkyl. In some embodiments, R b is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R b is methyl.

[0115] In some embodiments, R b is a C3 cycloalkyl.

[0116] In some embodiments, R 3 is -H.

[0117] In some embodiments, R 3 is a 4- to 10-membered heterocyclyl. In some embodiments, R 3 is one or more R c In some embodiments, R is a 4- to 10-membered heterocyclyl optionally substituted with 3 is one R c is a 4- to 10-membered heterocyclyl substituted with

[0118] In some embodiments, R 3 is a 4- to 6-membered heterocyclyl. In some embodiments, R3 is one or more R c In some embodiments, R is a 4- to 6-membered heterocyclyl optionally substituted with 3 is one R c is a 4- to 6-membered heterocyclyl substituted with

[0119] In some embodiments, R 3 is one or more R c azepanyl, 1,3-dioxolane, 1,4-dioxolanyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidionyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, quinuclidinyl, 4H-pyranyl, azetidinyl, oxetanyl, octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heteroaryl, optionally substituted with butanyl, 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.

[0120] In some embodiments, R 3 is one or more R ctetrahydropyranyl, azepanyl, azetidinyl, 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

[0121] In some embodiments, R 3 is one or more R c In some embodiments, R is piperidinyl optionally substituted with 3 is one R c In some embodiments, R 3 is piperidinyl.

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

[0123] In some embodiments, R 3 is one or more R c In some embodiments, R 3 is one or more R c In some embodiments, R 3 is one or more R c In some embodiments, R 3 is one or more R c In some embodiments, R 3 is one or more R c In some embodiments, R 3 is one or more R cisopropyl optionally substituted with

[0124] In some embodiments, R 3 teeth, [ka] is selected from.

[0125] In some embodiments, R 3 is C1-C6 alkylene-O-NH-C(NH)(NH2). In some embodiments, R 3 is -CH2-O-NH-C(NH)(NH2).

[0126] In some embodiments, R 3 is one or more R c C3-C optionally substituted with 10 In some embodiments, R 3 is one or more R c In some embodiments, R 3 is one or more R c In some embodiments, R 3 is one or more R c In some embodiments, R 3 is one or more R c In some embodiments, R 3 is one or more R c is a C6 cycloalkyl optionally substituted with

[0127] In some embodiments, R 3 is one or more R cis selected from phenyl, 2,3-dihydro-1H-indene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexyl, spiro[3.3]heptane, and bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and spiro[2.5]octyl, optionally substituted with

[0128] In some embodiments, R 3 is one or more R c cyclobutyl or cyclopentyl optionally substituted with

[0129] In some embodiments, R 3 teeth, [ka] is selected from.

[0130] In some embodiments, R 3 is at least one R c In some embodiments, R is a C1-C6 alkylene-5-10 membered heteroaryl optionally substituted with 3 is at least one R c In some embodiments, R 3 is at least one R c is a CH2-5 membered heteroaryl optionally substituted with

[0131] In some embodiments, R 3 teeth, [ka] is.

[0132] In some embodiments, R 3 is at least one R c In some embodiments, R is C1-C6 alkylene-4-10 membered heterocyclyl optionally substituted with 3is at least one R c In some embodiments, R 3 is at least one R c is CH2-6 membered heterocyclyl optionally substituted with

[0133] In some embodiments, R 3 teeth, [ka] is selected from.

[0134] In some embodiments, R 3 is at least one R c C1-C6 alkylene-(C3-C 10 In some embodiments, R 3 is at least one R c In some embodiments, R 3 is at least one R c is CH2-6-membered cycloalkyl optionally substituted with

[0135] In some embodiments, R c is C1-C6 alkyl optionally substituted with one or more C1-C6 alkyl, —OH, halogen, CN, or C1-C6 haloalkyl. c is methyl, ethyl, n-propyl, or isopropyl optionally substituted with one or more C1-C6 alkyl, —OH, halogen, CN, or C1-C6 haloalkyl. c is methyl.

[0136] In some embodiments, R c is -OH.

[0137] In some embodiments, R cis —O—(C1-C6 alkyl) optionally substituted with one or more C1-C6 alkyl, —OH, halogen, CN, or C1-C6 haloalkyl. In some embodiments, R c is —O—(C1-C3 alkyl) optionally substituted with one or more C1-C6 alkyl, —OH, halogen, CN, or C1-C6 haloalkyl. c is -O-CH3.

[0138] In some embodiments, R c is C-C alkylene-O-CH optionally substituted with one or more C-C alkyl, —OH, halogen, CN, or C-C haloalkyl. c is C-C alkylene-O-CH optionally substituted with one or more C-C alkyl, —OH, halogen, CN, or C-C haloalkyl. c is -CH2CH2-O-CH3.

[0139] In some embodiments, R c is halogen. In some embodiments, R c is Cl, F, Br, or I. In some embodiments, R c is F.

[0140] In some embodiments, R c is C1-C6 alkylene-5-10 membered heterocyclyl optionally substituted with one or more C1-C6 alkyl, —OH, halogen, CN, or C1-C6 haloalkyl. c is —CH—CH-5-10 membered heterocyclyl optionally substituted with one or more C-C alkyl, —OH, halogen, CN, or C-C haloalkyl. c is -CH2-CH2-5-membered heterocyclyl optionally substituted with one or more C1-C6 alkyl, -OH, halogen, CN, or C1-C6 haloalkyl.

[0141] In some embodiments, R c is -N(CH3)(CH3).

[0142] In some embodiments, R c is a C3-C optionally substituted with one or more C1-C6 alkyl, —OH, halogen, CN, or C1-C6 haloalkyl; 10 In some embodiments, R c is C-C cycloalkyl optionally substituted with one or more C-C alkyl, —OH, halogen, CN, or C-C haloalkyl. c is a C3 cycloalkyl optionally substituted with one or more C1-C6 alkyl, -OH, halogen, CN, or C1-C6 haloalkyl.

[0143] In some embodiments, R c is C1-C6 haloalkyl. In some embodiments, R c is C1-C3 haloalkyl. In some embodiments, R c is chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl, e.g., 1-chloroethyl and 2-chloroethyl, trichloroethyl, e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, e.g., 1-fluoromethyl and 2-fluoroethyl, difluoroethyl, e.g., 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, or trifluoropropyl. In some embodiments, R c is trifluoromethyl, difluoromethyl, or 1,1-difluoroethyl.

[0144] In some embodiments, R 4is —H. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is CN. In some embodiments, R 4 is -OMe. In some embodiments, R 4 is a halogen.

[0145] In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is a deuterated C1-C3 alkyl.

[0146] In some embodiments, R 5 is C1-C3 haloalkyl. In some embodiments, R 5 is fluoromethyl, difluoromethyl, trifluoromethyl, trichloroethyl, such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, difluoroethyl, such as 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, fluoropropyl, or trifluoropropyl. 5 is trifluoromethyl, difluoromethyl, or 1,1-difluoroethyl.

[0147] In some embodiments, X is NH. In some embodiments, X is S.

[0148] In some embodiments, in Formula I [ka] teeth, [ka] is.

[0149] In some embodiments, the compound is a compound selected from Examples 1-313.

[0150] Treatment method Provided herein are methods of treating cancer (e.g., a Ras pathway-associated cancer) in a subject in need thereof, 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-associated cancer. In some embodiments, the cancer is a Ras-associated cancer. In some embodiments, the cancer is a KRas-associated cancer. In some embodiments, the cancer is an HRas-associated cancer. In some embodiments, the cancer is an NRas-associated cancer. In some embodiments, the cancer is an SOS1-associated cancer.

[0151] For example, Ras pathway-related cancers (e.g., SOS1-related cancers, Ras-related cancers (e.g., KRas-related cancers, HRas-related cancers, and / or NRas-related cancers), EGFR-related cancers, ErbB2-related cancers, ErbB3-related cancers, ErbB4-related cancers, NF1-related cancers, PDGFR-A-related cancers, PDGFR-B-related cancers, FGFR1-related cancers, FGFR2-related cancers, FGFR3-related cancers, IGF1-related cancers,

[0013] Provided herein are methods for treating a Ras-associated cancer (e.g., a BRAF-associated cancer, a PI3K-associated cancer, an AKT-associated cancer, an mTOR-associated cancer, a MEK-associated cancer, an ERK-associated cancer, or a combination thereof) comprising: a) detecting dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them in a sample from the subject in need of such treatment; and b) administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them comprises one or more fusion proteins.

[0152] For example, provided herein are methods for treating a Ras-associated cancer in a subject in need thereof, comprising: a) detecting dysregulation of expression, activity, or level of a Ras gene, a Ras protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of expression, activity, or level of a Ras gene, a Ras protein, or any of them comprises one or more fusion proteins.

[0153] For example, provided herein are methods for treating a KRas-associated cancer in a subject in need thereof, comprising: a) detecting dysregulation of expression, activity, or level of a KRas gene, a KRas protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of expression, activity, or level of a KRas gene, a KRas protein, or any of them comprises one or more fusion proteins.

[0154] For example, provided herein are methods for treating an HRas-associated cancer in a subject in need thereof, comprising: a) detecting dysregulation of the expression, activity, or level of an HRas gene, an HRas protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the HRas gene, the HRas protein, or any of them comprises one or more fusion proteins.

[0155] For example, provided herein are methods for treating an NRas-associated cancer in a subject in need thereof, comprising: a) detecting dysregulated expression, activity, or level of an NRas gene, an NRas protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulated expression, activity, or level of an NRas gene, an NRas protein, or any of them comprises one or more fusion proteins.

[0156] For example, provided herein are methods for treating an SOS1-associated cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them comprises one or more fusion proteins.

[0157] Also provided are methods for treating cancer in a subject in need thereof, the methods comprising: (a) detecting a Ras pathway-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have a Ras pathway-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them in the subject or a biopsy sample from 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.

[0158] Also provided are methods for treating cancer in a subject in need thereof, the methods comprising: (a) detecting a Ras-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have a Ras-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or levels of a Ras gene, a Ras protein, or any of them in the subject or in a biopsy sample from 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.

[0159] Also provided are methods for treating cancer in a subject in need thereof, the methods comprising: (a) detecting a KRas-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have a KRas-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or levels of the KRas gene, KRas protein, or any of them in the subject or in a biopsy sample from 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.

[0160] Also provided are methods for treating cancer in a subject in need thereof, the methods comprising: (a) detecting an HRas-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have an HRas-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or levels of the HRas gene, HRas protein, or any of them in the subject or a biopsy sample from 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.

[0161] Also provided are methods for treating cancer in a subject in need thereof, the methods comprising: (a) detecting an NRas-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have an NRas-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or levels of the NRas gene, NRas protein, or any of them in the subject or a biopsy sample from 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.

[0162] Also provided are methods for treating cancer in a subject in need thereof, the methods comprising: (a) detecting SOS1-associated cancer in the subject; and (b) administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have SOS1-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or levels of the SOS1 gene, SOS1 protein, or any of them in the subject or in a biopsy sample from 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.

[0163] Also provided are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have a Ras pathway-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them in the subject or in a biopsy sample from 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.

[0164] Also provided are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of a Ras gene, a Ras protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have a Ras-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or level of a Ras gene, a Ras protein, or any of them in the subject or in a biopsy sample from 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.

[0165] Also provided are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of the KRas gene, KRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have a KRas-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or level of the KRas gene, KRas protein, or any of them in the subject or in a biopsy sample from 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.

[0166] Also provided are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have an HRas-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them in the subject or in a biopsy sample from 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.

[0167] Also provided are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of the NRas gene, NRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have an NRas-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or level of the NRas gene, NRas protein, or any of them in the subject or in a biopsy sample from 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.

[0168] Also provided are methods for treating cancer in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject determined to have a cancer associated with dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor, or radiation therapy. In some embodiments, the subject is determined to have an SOS1-associated cancer by use of a regulatory agency-approved, e.g., FDA-approved, test or assay to identify dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them in the subject or in a biopsy sample from 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.

[0169] Also provided are methods for treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of a Ras pathway gene, a Ras pathway protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or level of a Ras pathway gene, a Ras pathway protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is suspected of having a Ras pathway-associated cancer, exhibits one or more symptoms of a Ras pathway-associated cancer, or is at high risk for developing a Ras pathway-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or break-down FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0170] Also provided are methods for treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of a Ras gene, a Ras protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or level of a Ras gene, a Ras protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is suspected of having a Ras-associated cancer, exhibits one or more symptoms of a Ras-associated cancer, or is at high risk for developing a Ras-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0171] Also provided are methods for treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of a KRas gene, a KRas protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or level of a KRas gene, a KRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is suspected of having a KRas-associated cancer, exhibits one or more symptoms of a KRas-associated cancer, or is at high risk for developing a KRas-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0172] Also provided are methods for treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is suspected of having an HRas-associated cancer, exhibits one or more symptoms of an HRas-associated cancer, or is at high risk for developing an HRas-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0173] Also provided are methods for treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the NRas gene, NRas protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or level of the NRas gene, NRas protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is suspected of having an NRas-associated cancer, exhibits one or more symptoms of an NRas-associated cancer, or is at high risk for developing an NRas-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0174] Also provided are methods for treating a subject, comprising: performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them; and administering (e.g., specifically or selectively administering) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them. Some embodiments of these methods further comprise administering to the subject another anti-cancer agent (e.g., a small molecule or immunotherapy). In some embodiments of these methods, the subject has previously been treated with another anti-cancer treatment, e.g., at least partial tumor resection or radiation therapy. In some embodiments, the subject is suspected of having an SOS1-associated cancer, exhibits one or more symptoms of an SOS1-associated cancer, or is at high risk for developing an SOS1-associated cancer. In some embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, for example, an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art.

[0175] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a Ras pathway-associated cancer in a subject identified or diagnosed as having the cancer through performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them, wherein the presence of dysregulated expression or levels of a Ras pathway gene, a Ras pathway protein, or any of them identifies the subject as having a Ras pathway-associated cancer. 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 treating a Ras pathway-associated cancer in a subject identified or diagnosed with the cancer through performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of a Ras pathway gene, a Ras pathway protein, or any of them, wherein the presence of dysregulated expression or level of a Ras pathway gene, a Ras pathway protein, or any of them identifies the subject as having a Ras pathway-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that the subject has been determined to have dysregulated expression, activity, or level of a Ras pathway gene, a Ras pathway protein, or any of them through performance of the assay, and that the 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 separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy.

[0176] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a Ras-associated cancer in a subject identified or diagnosed as having such cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression or activity or levels of a Ras gene, a Ras protein, or any of them, wherein the presence of dysregulated expression or levels of a Ras gene, a Ras protein, or any of them identifies the subject as having a Ras-associated 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 treating a Ras-related cancer in a subject identified or diagnosed with the cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of a Ras gene, a Ras protein, or any of them, wherein the presence of dysregulated expression or level of a Ras gene, a Ras protein, or any of them identifies the subject as having a Ras-related cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that the subject has been determined to have dysregulated expression, activity, or level of a Ras gene, a Ras protein, or any of them through performance of an assay, and that the 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 separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy.

[0177] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a KRas-associated cancer in a subject identified or diagnosed as having such cancer through performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression or activity or levels of the KRas gene, KRas protein, or any of them, wherein the presence of dysregulated expression or levels of the KRas gene, KRas protein, or any of them identifies the subject as having a KRas-associated 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 treating a KRas-associated cancer in a subject identified or diagnosed with the cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the KRas gene, KRas protein, or any of them, wherein the presence of dysregulated expression or level of the KRas gene, KRas protein, or any of them identifies the subject as having a KRas-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that the subject has been determined to have dysregulated expression, activity, or level of the KRas gene, KRas protein, or any of them through performance of the assay, and that the 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 separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy.

[0178] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an HRas-associated cancer in a subject identified or diagnosed as having such cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them, wherein the presence of dysregulated expression or levels of the HRas gene, HRas protein, or any of them identifies the subject as having an HRas-associated cancer. Also provided is 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 treating an HRas-associated cancer in a subject identified or diagnosed with the cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the HRas gene, HRas protein, or any of them, wherein the presence of dysregulated expression or level of the HRas gene, HRas protein, or any of them identifies the subject as having an HRas-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that the subject has been determined to have dysregulated expression, activity, or level of the HRas gene, HRas protein, or any of them through performance of the assay, and should be administered the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy.

[0179] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an NRas-associated cancer in a subject identified or diagnosed as having such cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulated expression or activity or levels of the NRas gene, NRas protein, or any of them, wherein the presence of dysregulated expression or levels of the NRas gene, NRas protein, or any of them identifies the subject as having an NRas-associated 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 treating an NRas-associated cancer in a subject identified or diagnosed with the cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the NRas gene, NRas protein, or any of them, wherein the presence of dysregulated expression or level of the NRas gene, NRas protein, or any of them identifies the subject as having an NRas-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that the subject has been determined to have dysregulated expression, activity, or level of the NRas gene, NRas protein, or any of them through performance of the assay, and that the 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 separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy.

[0180] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an SOS1-associated cancer in a subject identified or diagnosed as having such cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them, wherein the presence of dysregulation of the expression or level of the SOS1 gene, SOS1 protein, or any of them identifies the subject as having an SOS1-associated cancer. Also provided is 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 treating an SOS1-associated cancer in a subject identified or diagnosed with the cancer through the step of performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them, wherein the presence of dysregulated expression or level of the SOS1 gene, SOS1 protein, or any of them identifies the subject as having an SOS1-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record (e.g., a computer-readable medium) that the subject has been determined to have dysregulated expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them through performance of the assay, and that the 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 separate FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy.

[0181] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed with cancer involving dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may be a subject with tumor(s) that are positive for dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a Ras pathway-associated cancer. In some embodiments, provided herein are methods for treating a Ras pathway-associated cancer in a subject in need thereof, comprising: a) detecting dysregulation of expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them comprises one or more Ras pathway protein point mutations / insertions / deletions.

[0182] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed with cancer involving dysregulated expression, activity, or levels of the Ras gene, Ras protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulated expression, activity, or levels of the Ras gene, Ras protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may be a subject with tumor(s) that are positive for dysregulated expression, activity, or levels of the Ras gene, Ras protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulated expression, activity, or levels of the Ras gene, Ras protein, or 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 are methods for treating a Ras-associated cancer in a subject in need thereof, comprising: a) detecting dysregulation of the expression, activity, or level of a Ras gene, a Ras protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of a Ras gene, a Ras protein, or any of them comprises one or more Ras protein point mutations / insertions / deletions.

[0183] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed with cancer involving dysregulation of the KRas gene, KRas protein, or any of their expression, activity, or levels. 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, KRas protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject may be a subject with tumor(s) that are positive for dysregulation of the KRas gene, KRas protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulation of the KRas gene, KRas protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a KRas-associated cancer. In some embodiments, provided herein are methods for treating a KRas-associated cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the expression, activity, or level of a KRas gene, a KRas protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of a KRas gene, a KRas protein, or any of them comprises one or more KRas protein point mutations / insertions / deletions. Non-limiting examples of KRas protein point mutations / insertions / deletions are listed in Table 1.

[0184] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed with cancer involving dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may be a subject with tumor(s) that are positive for dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject is suspected of having an HRas-associated cancer. In some embodiments, provided herein are methods for treating an HRas-associated cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the HRas gene, HRas protein, or any of them comprises one or more HRas protein point mutations / insertions / deletions. Non-limiting examples of HRas protein point mutations / insertions / deletions are listed in Table 2.

[0185] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed with cancer involving dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may be a subject with tumor(s) that are positive for dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them. In some embodiments of any of the methods or uses described herein, the subject is suspected of having an NRas-associated cancer. In some embodiments, provided herein are methods for treating an NRas-associated cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the expression, activity, or level of an NRas gene, an NRas protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the NRas gene, the NRas protein, or any of them comprises one or more NRas protein point mutations / insertions / deletions. Non-limiting examples of NRas protein point mutations / insertions / deletions are listed in Table 3.

[0186] In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having cancer associated with dysregulation of the SOS1 gene, SOS1 protein, or any of their expression, activity, or levels. 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, SOS1 protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject may be a subject with tumor(s) that are positive for dysregulation of the SOS1 gene, SOS1 protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject may be a subject whose tumor has dysregulation of the SOS1 gene, SOS1 protein, or any of their expression, activity, or levels. In some embodiments of any of the methods or uses described herein, the subject is suspected of having an SOS1-associated cancer. In some embodiments, provided herein are methods for treating an SOS1-associated cancer in a subject in need thereof, the method comprising: a) detecting dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them in a sample from the subject; and b) administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of the expression, activity, or level of the SOS1 gene, SOS1 protein, or any of them comprises one or more SOS1 protein point mutations / insertions / deletions. Non-limiting examples of SOS1 protein point mutations / insertions / deletions are listed in Table 4.

[0187] In some embodiments, cancers with dysregulated expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit. In some embodiments, tumors with dysregulated expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit.

[0188] In some embodiments, cancers with dysregulated expression or activity or levels of Ras genes, Ras proteins, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit. In some embodiments, tumors with dysregulated expression or activity or levels of Ras genes, Ras proteins, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit.

[0189] In some embodiments, cancers with dysregulated expression or activity or levels of the KRas gene, KRas protein, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit. In some embodiments, tumors with dysregulated expression or activity or levels of the KRas gene, KRas protein, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit.

[0190] In some embodiments, cancers with dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit. In some embodiments, tumors with dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit.

[0191] In some embodiments, cancers with dysregulated expression or activity or levels of the NRas gene, NRas protein, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit. In some embodiments, tumors with dysregulated expression or activity or levels of the NRas gene, NRas protein, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit.

[0192] In some embodiments, cancers with dysregulated expression or activity or levels of the SOS1 gene, SOS1 protein, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit. In some embodiments, tumors with dysregulated expression or activity or levels of the SOS1 gene, SOS1 protein, or any of them are determined using a regulatory agency approved, e.g., FDA approved, assay or kit.

[0193] In some embodiments of any of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them. Also provided is a method of treating a subject, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject with clinical records indicating that the subject has dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them.

[0194] In some embodiments of any of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor with dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them. Also provided is a method of treating a subject, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject with clinical records indicating that the subject has dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them.

[0195] In some embodiments of any of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the KRas gene, KRas protein, or any of them. Also provided is a method of treating a subject, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject with clinical records indicating that the subject has dysregulated expression or activity or levels of the KRas gene, KRas protein, or any of them.

[0196] In some embodiments of any of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor with dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them. Also provided is a method of treating a subject, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject with clinical records indicating that the subject has dysregulated expression, activity, or levels of the HRas gene, HRas protein, or any of them.

[0197] In some embodiments of any of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor with dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them. Also provided is a method of treating a subject, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject with clinical records indicating that the subject has dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them.

[0198] In some embodiments of any of the methods or uses described herein, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the SOS1 gene, SOS1 protein, or any of them. Also provided is a method of treating a subject, comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject with clinical records indicating that the subject has dysregulated expression or activity or levels of the SOS1 gene, SOS1 protein, or any of them.

[0199] In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of a Ras pathway gene, a Ras pathway protein, or any of them. In some such embodiments, the methods also include administering to the subject determined to have dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include determining that the subject has dysregulated expression or levels of a Ras pathway gene, a Ras pathway protein, or any of them via an assay performed on a sample obtained from the subject. In such embodiments, the methods also include administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of a Ras gene, a Ras protein, or any of them. In some such embodiments, the methods also include administering to the subject determined to have dysregulated expression, activity, or levels of a Ras gene, a Ras protein, or any of them an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include determining that the subject has dysregulated expression or levels of a Ras gene, a Ras protein, or any of them via an assay performed on a sample obtained from the subject. In such embodiments, the methods also include administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of the KRas gene, KRas protein, or any of them. In some such embodiments, the methods also include administering to the subject determined to have dysregulated expression, activity, or levels of the KRas gene, KRas protein, or any of them an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include determining that the subject has dysregulated expression or levels of the KRas gene, KRas protein, or any of them via an assay performed on a sample obtained from the subject. In such embodiments, the methods also include administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the methods provided herein comprise performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of the HRas gene, HRas protein, or any of them. In some such embodiments, the methods also comprise administering to the subject determined to have dysregulated expression, activity, or levels 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. In some embodiments, the methods comprise determining that the subject has dysregulated expression or levels of the HRas gene, HRas protein, or any of them via an assay performed on a sample obtained from the subject. In such embodiments, the methods also comprise administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of the NRas gene, NRas protein, or any of them. In some such embodiments, the methods also include administering to the subject determined to have dysregulated expression, activity, or levels of the NRas gene, NRas protein, or any of them an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include determining that the subject has dysregulated expression or levels of the NRas gene, NRas protein, or any of them via an assay performed on a sample obtained from the subject. In such embodiments, the methods also include administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the methods provided herein comprise performing an assay on a sample obtained from the subject to determine whether the subject has dysregulated expression or levels of the SOS1 gene, the SOS1 protein, or any of them. In some such embodiments, the methods also comprise administering to the subject determined to have dysregulated expression, activity, or levels of the SOS1 gene, the SOS1 protein, or any of them an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods comprise determining that the subject has dysregulated expression or levels of the SOS1 gene, the SOS1 protein, or any of them via an assay performed on a sample obtained from the subject. In such embodiments, the methods also comprise administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0205] 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, leukemias (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, juvenile myelomonocytic leukemia (JMML), and hairy cell leukemia) and lymphomas (e.g., non-Hodgkin's lymphoma, Hodgkin's cutaneous T-cell lymphoma, and Burkitt's lymphoma).

[0206] 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 carcinoma, biliary tract cancer, breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ), gastric cancer, small intestine cancer, colon cancer, colorectal cancer, peritoneal cancer, ovarian cancer, uterine cancer, liver cancer, uterine cancer, endometrial cancer, prostate cancer (including benign prostatic hyperplasia), testicular cancer, bladder cancer, urinary tract cancer, uterine cancer, head and neck cancer, brain cancer (e.g., glioblastoma, brainstem and substem glioma, brain and brain astrocytoma, medulloblastoma, and ependymoma), squamous cancer, and malignant tumors.

[0207] In some embodiments, the subject is a human.

[0208] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in treating Ras pathway-associated cancers.

[0209] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having a Ras pathway-associated cancer, e.g., any of the exemplary Ras pathway-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0210] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having a Ras pathway-associated cancer, e.g., any of the exemplary Ras pathway-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0211] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in treating Ras-associated cancers.

[0212] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having a Ras-associated cancer, e.g., any of the exemplary Ras-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0213] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having a Ras-associated cancer, e.g., any of the exemplary Ras-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0214] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in treating KRas-associated cancers.

[0215] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having a KRas-associated cancer, e.g., any of the exemplary KRas-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0216] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having a KRas-associated cancer, e.g., any of the exemplary KRas-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0217] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in treating HRas-associated cancers.

[0218] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having an HRas-associated cancer, e.g., any of the exemplary HRas-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0219] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having an HRas-associated cancer, e.g., any of the exemplary HRas-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0220] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in treating NRas-associated cancers.

[0221] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having an NRas-associated cancer, e.g., any of the exemplary NRas-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0222] Accordingly, also provided herein are methods for treating a subject diagnosed or identified as having an NRas-associated cancer, e.g., any of the exemplary NRas-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of Formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0223] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also useful in treating SOS1-associated cancers.

[0224] Accordingly, also provided herein is a method for treating a subject diagnosed or identified as having an SOS1-associated cancer, e.g., any of the exemplary SOS1-associated cancers disclosed herein, comprising administering to the subject an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula (I) is selected from Examples 1-313, or a pharmaceutically acceptable salt thereof.

[0225] Dysregulation of the expression, activity, or levels of a Ras pathway protein, a Ras pathway gene, or any of them (e.g., one or more) can contribute to tumorigenesis. For example, a fusion protein can have increased activity compared to a wild-type Ras pathway protein (e.g., in the case of SOS1, increased Ras activity and / or increased GEF activity due to more favorable binding), increased expression (e.g., increased levels) of a wild-type Ras pathway protein in a mammalian cell can result from aberrant 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.

[0226] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) penetrance. 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, IGFR1 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 a combination thereof) activity in the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in effective amounts. For example, treating a subject with cancer (e.g., a Ras pathway-related cancer, such as a Ras pathway-related brain or CNS cancer) can include administering (e.g., orally administering) a compound to the subject. In some such embodiments, the compounds provided herein are useful for treating primary or metastatic brain tumors. For example, the compounds can be used to treat one or more gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendroglioma, ependymoma, and mixed glioma, meningioma, medulloblastoma, ganglioglioma, schwannoma (schwannoma), and craniopharyngioma (see, e.g., the tumors listed in Louis, DNet al. Acta Neuropathol 131(6), 803-820 (June 2016)). In some embodiments, the brain tumor is a primary brain tumor.In some embodiments, the subject has been previously treated with another anti-cancer agent, e.g., another Ras pathway inhibitor (e.g., a compound that is not 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 a combination thereof), or a combination 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, e.g., another Ras pathway inhibitor (e.g., a compound that is not a compound of Formula (I), or an inhibitor of another Ras pathway gene or protein).

[0227] 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 a compound to penetrate a model surface barrier can be represented by fluorescence intensity at a given depth below the surface. In some assays, such as calcein-AM-based assays, the fluorescent label is non-fluorescent until it penetrates live cells, where it is hydrolyzed by intracellular esterases to generate a fluorescent compound that is retained intracellularly and can be quantified spectrophotometrically. Non-limiting examples of fluorescent labels that can be used in the assays described herein include Cy5, rhodamine, infrared IRDye® CW-800 (LICOR#929-71012), far-infrared IRDye® 650 (LICOR#929-70020), sodium fluorescein (Na—F), Lucifer Yellow (LY), 5′-carboxyfluorescein, and calcein-acetoxymethyl ester (calcein-AM). In some embodiments, a BBB model (e.g., a tissue or cell aggregate) can be sectioned, and a compound described herein can be detected in one or more sections using mass spectrometry (e.g., MALDI-MSI analysis).In some embodiments, the ability of compounds described herein to cross the BBB via transcellular transport systems, such as receptor-mediated transport (RMT), carrier-mediated transport (CMT), or activated efflux transport (AET), can be demonstrated by assays known in the art. See, e.g., 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, e.g., Doan et al. 2002. J Pharmacol Exp Ther. 303(3):1029-1037). Alternative in vivo assays for identifying compounds that cross the blood-brain barrier include 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 is 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 / ).

[0228] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them (a Ras pathway-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has dysregulation of expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a Ras pathway-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0229] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the Ras gene, Ras protein, or expression or activity or levels of any of them (Ras-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the Ras gene, Ras protein, or expression or activity or levels of any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have tumor(s) that are positive for dysregulation of the Ras gene, Ras protein, or expression or activity or levels of any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has dysregulation of the Ras gene, Ras protein, or expression or activity or levels thereof (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a Ras-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of a Ras gene, a Ras protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0230] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the KRas gene, KRas protein, or expression or activity or levels of any of them (KRas-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the KRas gene, KRas protein, or expression or activity or levels of any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 1. The subject can be a subject with tumor(s) that are positive for dysregulation of the KRas gene, KRas protein, or expression or activity or levels of any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has a dysregulated KRas gene, KRas protein, or expression or activity or levels thereof (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with a dysregulated KRas gene, KRas protein, or expression or activity or levels of either thereof (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0231] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the HRas gene, HRas protein, or any of their expression, activity, or levels (HRas-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the HRas gene, HRas protein, or any of their expression, activity, or levels (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 2. The subject may be a subject with tumor(s) that are positive for dysregulation of the HRas gene, HRas protein, or any of their expression, activity, or levels (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has dysregulation of the HRas gene, HRas protein, or any of their expression, activity, or levels (e.g., whose tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an HRas-associated cancer, hi some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the HRas gene, HRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0232] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the expression or activity or levels of the NRas gene, NRas protein, or any of them (NRas-associated cancer) (e.g., as determined using a regulatory agency approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the expression or activity or levels of the NRas gene, NRas protein, or any of them (e.g., as determined using a regulatory agency approved, e.g., FDA-approved, assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 3. The subject may be a subject who has tumor(s) that are positive for dysregulation of the expression or activity or levels of the NRas gene, NRas protein, or any of them (e.g., identified as positive using a regulatory agency approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has dysregulation of the NRas gene, NRas protein, or their expression or activity or levels (e.g., whose tumor is identified as such using a regulatory agency approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an NRas-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with dysregulated expression or activity or levels of the NRas gene, NRas protein, or any of them (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0233] In some embodiments, the subject has been identified or diagnosed with a cancer involving dysregulation of the SOS1 gene, SOS1 protein, or expression or activity or levels of any of them (SOS1-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for dysregulation of the SOS1 gene, SOS1 protein, or expression or activity or levels of any of them (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 4. The subject may be a subject with tumor(s) that are positive for dysregulation of the SOS1 gene, SOS1 protein, or expression or activity or levels of any of them (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be a subject whose tumor has a dysregulation of the SOS1 gene, SOS1 protein, or expression or activity or levels thereof (e.g., the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an SOS1-associated cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with a dysregulation of the SOS1 gene, SOS1 protein, or expression or activity or levels of either thereof (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0234] In some embodiments of any of the methods or uses described herein, the assay used to determine whether a subject has dysregulated expression, activity, or levels of a Ras pathway gene, or a Ras pathway protein, or any of them, using a sample from the subject can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, separate FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the 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 dysregulated expression, activity, or levels of a Ras pathway gene, a Ras pathway protein, or any of them. In some embodiments, the sample is a biological sample or biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is suspected of having a Ras pathway-associated cancer, has one or more symptoms of a Ras pathway-associated cancer, or is at increased risk of developing a Ras pathway-associated cancer.

[0235] In some embodiments, dysregulation of expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them can be identified using liquid biopsy (variously referred to as fluid biopsy or fluid-phase biopsy). See, e.g., Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment,” Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or dysregulation of expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them. Liquid biopsies can be performed on biological samples relatively easily obtained from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulation of expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them at an earlier stage than traditional methods. In some embodiments, the biological sample used in the liquid biopsy can include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, the liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, the liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using the liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using highly 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 the expression, activity, or levels of Ras pathway genes, Ras pathway proteins, or any of them.

[0236] In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using highly 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 the expression, activity, or levels of Ras pathway genes, Ras pathway proteins, or any of them.

[0237] 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 genes, or any number in between) 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., commercially available test panels designed to detect dysregulation of the expression or activity or levels of Ras pathway genes, Ras pathway proteins, or any of them). Liquid biopsy can be used to detect dysregulation of expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them, including, but not limited to, point mutations or single nucleotide variants (SNVs), copy number variants (CNVs), gene fusions (e.g., translocations or rearrangements), insertions, deletions, or any combination thereof. In some embodiments, liquid biopsy can be used to detect germline mutations. In some embodiments, liquid biopsy can be used to detect somatic mutations. In some embodiments, liquid biopsy can be used to detect primary genetic mutations (e.g., primary mutations or primary fusions associated with the early onset of a disease, e.g., cancer). In some embodiments, dysregulation of expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them identified using 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 expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them described herein can be detected using liquid biopsy. In some embodiments, genetic mutations identified via liquid biopsy may be used to identify subjects as candidates for particular treatments.For example, detection of dysregulation of the expression or activity or levels of a Ras pathway gene, a Ras pathway protein, or any of them in a subject can indicate that the subject will respond to treatment comprising administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0238] 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 (e.g., a 1% to about 99% reduction, a 1% to about 50% reduction, a 1% to about 10% reduction, a 50% to about 99% reduction, or a 75% to about 95% reduction) in the dysregulated allele frequency (AF) of a Ras pathway gene in cfDNA obtained from the subject at a second time point compared to the dysregulated allele frequency (AF) of the Ras pathway gene in cfDNA obtained from the subject at the first time point 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 dysregulated allele frequency (AF) of a Ras pathway gene in cfDNA obtained from the subject at a second time point compared to the dysregulated allele frequency (AF) 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 the subject in whom the compound of Formula (I) or a pharmaceutically acceptable salt thereof has been determined to be effective. Some embodiments of these methods can further include administering a different treatment (e.g., a treatment that does not include administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof as monotherapy) to the subject in whom the compound of Formula (I) or a pharmaceutically acceptable salt thereof has been determined to be ineffective.

[0239] In some examples of these methods, the time difference between the first and second time points can be about 1 day to about 1 year, about 1 day to about 1 month, about 1 day to about 5 days, about 1 month to about 3 months, about 3 months to about 6 months, or about 7 months to about 9 months. In some embodiments of these methods, the subject can be previously identified as having a cancer with a dysregulated Ras pathway gene (e.g., any of the examples of dysregulated Ras pathway genes described herein). In some embodiments of these methods, the subject can be previously diagnosed with any of the types of cancer described herein. In some embodiments of these methods, the subject can have one or more metastases (e.g., one or more brain metastases).

[0240] In some of the above embodiments, the cfDNA comprises ctDNA, such as Ras pathway-associated (e.g., SOS1, Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGFR1 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 a combination thereof)-associated) ctDNA. For example, the cfDNA is ctDNA, such as Ras pathway-associated ctDNA. In some embodiments, at least some portion of the cfDNA is determined to be Ras pathway-associated ctDNA, e.g., a sequenced and / or quantified amount of total cfDNA is determined to have a Ras pathway fusion and / or Ras pathway overexpression.

[0241] combination In the field of medical oncology, it is common practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology, in addition to the compositions provided herein, other components of such conjoint treatment or therapy may 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, surgery may be open surgery or minimally invasive surgery. Thus, the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be useful as adjuvants for cancer treatment, i.e., they may 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 may be used prior to the administration of the additional therapeutic agent or therapy. For example, a subject in need thereof may be administered one or more doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time, followed by 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 tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof may be administered one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof over a period of time, followed by 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 tumor size (e.g., tumor burden) prior to one or more rounds of radiation therapy.

[0242] "Ras pathway targeted therapeutic agent," as used herein, includes any compound that exhibits inactivation activity (e.g., active site (e.g., competitive) inhibition, allosteric inhibition, inhibition of dimerization, inhibition of expression, inhibition of protein-protein interaction, and induction of degradation) of any protein in the Ras pathway. Non-limiting examples of proteins in the Ras pathway include any one of proteins in the Ras-RAF-MAPK pathway or the PI3K / AKT pathway, such as Ras (e.g., KRas, HRas, and / or NRas), EGFR, ErbB2, ErbB3, ErbB4, NF1, PDGFR-A, PDGFR-B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1, VEGFR2, VEGFR3, AXL, SHP2, RAF (e.g., BRAF), PI3K, AKT, mTOR, MEK, ERK, or a combination thereof. In some embodiments, the Ras pathway-targeting therapeutic agent may be selective for a protein in the Ras pathway. For example, a Ras pathway-targeting therapeutic agent may be selective for a Ras protein (e.g., KRas, HRas, and / or NRas, or a mutant form of any of these). Such agents may also be referred to as "Ras modulators." In some embodiments, a Ras modulator is a covalent inhibitor. In some embodiments, a Ras pathway-targeting therapeutic agent may be selective for a particular Ras protein (e.g., KRas, HRas, or NRas), or a mutant form thereof (e.g., a G12 mutant, a G13 mutant, or a Q61 mutant). Non-limiting examples of KRas-targeting 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.

[0243] The compound of Formula (I), or a pharmaceutically acceptable salt thereof, may 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 compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be used prior to the administration of the additional therapeutic agent or therapy. For example, a subject in need thereof may be administered one or more doses of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time, followed by 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 tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, a subject in need thereof may be administered one or more doses of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time, followed by 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 tumor size (e.g., tumor burden) prior to one or more rounds of radiation therapy.

[0244] In some embodiments, the one or more additional therapies or therapeutic agents are independently an EGFR inhibitor (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, and olmutinib), an ErbB2 / Her2 inhibitor (e.g., afatinib, lapatinib, trastuzumab, and pertuzumab), an ALK inhibitor (e.g., crizotinib, alectinib, entrectinib, brigatinib), a ROS1 inhibitor (e.g., crizotinib, entrectinib, lorlatinib, ceritinib, and merestinib). , MEK inhibitors (e.g., trametinib, cobimetinib, binimetinib, selumetinib, rifametinib), RAS (KRas, HRas, and / or NRas) inhibitors (e.g., MRTX849, LY3499446, JNJ-74699157, AMG510, and AZD4785), Bcr-Abl inhibitors (e.g., imatinib, dasatinib, nilotinib), FGFR1, 2, or 3 inhibitors (e.g., nintedanib), MET inhibitors (e.g., capmatinib), AXL inhibitors (e.g., sitravatinib), RET inhibitors (e.g., sunitinib and selpercatinib), ERK inhibitors (e.g., ulixertinib), Shp2 inhibitors (e.g., RLY-1971, RMC-4630, TNO155, and JAB-3068), Bcl-2 inhibitors (e.g., ABT-263, obatoclax, ABT-737, and navitoclax), mTOR inhibitors (e.g., everolimus and tacrolimus), Trk inhibitors (e.g., larotrectinib and entrectinib), checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and and pidilizumab) or other immunotherapies (e.g., monoclonal antibodies), PARP inhibitors (e.g., olaparib), PI3K inhibitors (e.g., buparisib), BET inhibitors (e.g., GSK1210151A), Raf inhibitors (e.g., encorafenib), MCL-1 inhibitors (e.g., AZD5991), AKT inhibitors (e.g., miltefosine), PDK1 inhibitors (e.g., GSK2334470), and other chemotherapeutic agents, such as taxanes (e.g., paclitaxel and docetaxel), platinum-based agents (e.g., cisplatin and carboplatin),The inhibitor is selected from cytotoxic drugs (e.g., 5-fluorouracil, capecitabine, floxuridine, cytarabine, and gemcitabine), farnesyltransferase inhibitors, topoisomerase inhibitors (e.g., topotecan and irinotecan), DNA synthesis inhibitors (e.g., capecitabine and gemcitabine hydrochloride (Gemzar®)), alkylating agents (e.g., temozolomide and Temodar®), dactinomycin (actinomycin-D, also known as Cosmegen®), carmustine (BiCNU®), bendamustine®, and lomustine (CeeNU®)), and cytotoxic drugs (e.g., vincristine, cytarabine, and Pemced).

[0245] Osimertinib (AZD9291, merectinib, TAGRISSO®), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZA®, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRE®), LSA®), loserinib (CO-1686), olmutinib (OLITA®, HM61713, BI-1482694), nacotinib (ASP8273), nazartin (EGF816, NVS-816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBWW2992, GILOTRIF®), dacomitin (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAbEGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin, and acetylshikonin) Luarcanin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), Y H25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, valintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602 epidermal growth factor receptor (EGFR) inhibitors such as Sym004, MAb-425, modotuximab (TAB-H49), futuximab (992DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG595, BDTX-189, avatinib, Disruptin, CL-387785, EGFR Bi-armed autologous T cells, and EGFR CAR-T therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0246] Human epidermal growth factor receptor 2 (HER2 receptor) (also known as Neu, ErbB-2, CD340, or p185) inhibitors, 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 ( For example, NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanspicin (17-AAG), IPI-504, PF299, pelitinib, S-22261, and AEE-788.

[0247] In some embodiments, the FGFR inhibitor is selected from infigratinib, AZD4547, erdafitinib (JNJ-42756493), nintedanib dovitinib, ponatinib, and TAS120.

[0248] In some embodiments, the ALK inhibitor is selected from alectinib, crizotinib (XALKORI®), ceritinib, AP26113, ASP3026, TSR-011, PF-06463922, X-396, and CEP-37440.

[0249] In some embodiments, the ROS1 inhibitor is selected from crizotinib (XALKORI®), ceritinib, lorlatinib, brigatinib, cabozantinib, and repotrectinib.

[0250] In some embodiments, the mTOR inhibitor is selected from everolimus, tacrolimus rapamycin, perifosine, and temsirolimus.

[0251] In some embodiments, the Trk inhibitor is selected from larotrectinib, lestaurtinib, and entrectinib.

[0252] In some embodiments, the RET inhibitor is selected from sunitinib (Sutent®), selpercatinib (RETEVMO®), vandetanib (Caprelsa®), motesanib (AMG706), sorafenib, regorafenib, and danusertib.

[0253] In some embodiments, the MET inhibitor is selected from capmatinib, tepotinib, savolitinib, crizotinib, cabozantinib, tivantinib, bozitinib, merestinib, glesatinib, sitravatinib, onartuzumab, and emibetuzumab.

[0254] In some embodiments, the AXL inhibitor is selected from sitravatinib, bemcentinib, duvelmatinib, DS-1205, SLC-391, INCB081776, ONO-7475, and BA3011.

[0255] In some embodiments, the Shp2 inhibitor is selected from TNO155, BBP-398, JAB-3068, RMC-4360, and RLY-1971.

[0256] In some embodiments, the RAF inhibitor is a BRAF inhibitor, such as vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), encorafenib (BRAFTOVI®), BMS-908662, sorafenib, LGX818, PLX3603, RAF265, RO5185426, GSK2118436, ARQ736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, and LXH254.

[0257] In some embodiments, the PI3K inhibitor is bupallisib (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), pilalalisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), selavelisib (TAK-117, M LN1117, INK1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), boctalisib (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.

[0258] In some embodiments, the AKT inhibitor is miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, MK-2206, ede Selected from rufosine, miltefosine, perifosine, erucirfocoline, elfosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine, API-1, ARQ092, BAY1125976, 3-oxo-tirucaric acid, lactoquinomycin, GSK2141795, ONC201, tricirubine, A674563, and AT7867.

[0259] 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 hyfothemycin.

[0260] In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, L Selected from TT-462, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5-7-oxozeaenol, 5-iodoversidine, GDC0994, and ONC201.

[0261] In some embodiments, PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289.

[0262] In some embodiments, the RAS inhibitor is MRTX849, LY3499446, JNJ-74699157, AMG 510, ARS3248, ARS853, ARS1620, AZD4785, JNJ-74699157, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

[0263] In some embodiments, the PDK-1 inhibitor is selected from GSK2334470, JX06, SNS-510, and AR-12.

[0264] 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.

[0265] In some embodiments, the MCL-1 inhibitor is AZD5991.

[0266] In some embodiments, the Bcl-2 protein family inhibitor is selected from ABT-263, tetrocarcin A, antimycin, gossypol ((-)BL-193), obatoclax, HA14-1, obrymersen (Genasense®), (-)-gossypol acetate (AT-101), ABT-737, and navitoclax.

[0267] In some embodiments, the Bcr / Abl kinase inhibitor is selected from imatinib (Gleevec®), inilotinib, nilotinib (Tasigna®), dasatinib (BMS-345825), bosutinib (SKI-606), ponatinib (AP24534), bafetinib (INNO406), danusertib (PHA-739358), AT9283, saracatinib (AZD0530), and PF-03814735.

[0268] In some embodiments, the checkpoint inhibitor is selected from ipilimumab (YERVOY®), pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), IMP701 (LAG525), CPI-444, MBG453, enoblitzumab, JNJ-61610588, and indoximod. See, e.g., Marin-Acevedo, et. al., J Hematol Oncol. 11:39 (2018).

[0269] In some embodiments, the immunotherapy is an antibody therapy (e.g., a monoclonal antibody). In some embodiments, the antibody therapy is selected from the group consisting of bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), rituximab (MabThera™, Rituxan®), edrecolomab (Panorex®), daratumab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-6 75,206), ramucirumab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), necitumumab (Portrazza™), cirumutuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, urelumab, pidilizumab, and amatuximab.

[0270] In some embodiments, the other chemotherapeutic agent is selected from anthracyclines, alkylating agents, taxanes, platinum-based agents, eribulin (HALAVEN™), farnesyltransferase inhibitors, topoisomerase inhibitors, DNA synthesis inhibitors, and cytotoxic agents.

[0271] In some embodiments, the taxane is selected from paclitaxel, docetaxel, cabazitaxel, abraxane, and taxotere.

[0272] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0273] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedoplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.

[0274] In some embodiments, the farnesyltransferase inhibitor is selected from lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277.

[0275] In some embodiments, the topoisomerase inhibitor is a topoisomerase I inhibitor (e.g., irinotecan (Camptosar®), topotecan (Hycamtin®), and 7-ethyl-10-hydroxycampothecin (SN38)), or a topoisomerase II inhibitor (e.g., etoposide (Toposar®, VePesid®, and Etopophos®), teniposide (VM-26, Vumon®), and tafluposide).

[0276] In some embodiments, the DNA synthesis inhibitor is selected from capecitabine (Xeloda®), gemcitabine hydrochloride (Gemzar®), nelarabine (Arranon® and Atriance®), and sapacitabine.

[0277] In some embodiments, the alkylating agent is temozolomide (Temodar® and Temodal®), dactinomycin (actinomycin-D, also known as Cosmegen®), melphalan (Alkeran®), altretamine (Hexalen®), carmustine (BiCNU®), bendamustine (Treanda®), busulfan (Busulfex® and Myleran®), lomustine (CeeNU®). , chlorambucil (Leukeran®), cyclophosphamide (Cytoxan® and Neosar®), dacarbazine (DTIC-Dome®), altretamine (Hexalen®), ifosfamide (Ifex®), prednummustine, procarbazine (Matulane®), mechloroethamine (Mustargen®), streptozocin (Zanosar®), and triiotepa (Thioplex®).

[0278] In some embodiments, the cytotoxic agent is selected from bleomycin, cytarabine, dacarbazine, methotrexate, mitomycin C, pemetrexed, and vincristine.

[0279] Also provided herein are (i) pharmaceutical combinations for treating cancer in a subject in need thereof, comprising (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate, or sequential use for 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 together effective for the treatment of cancer, (ii) pharmaceutical compositions comprising such combinations, (iii) uses of such combinations for the preparation of medicaments for the treatment of cancer, and (iv) commercial packages or products comprising such combinations as combined preparations for simultaneous, separate, or sequential use, and methods for treating cancer in a subject in need thereof. In some embodiments, the cancer is a Ras pathway-associated cancer.

[0280] As used herein, the term "pharmaceutical combination" 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 active ingredients. The term "fixed combination" means that a 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 a subject simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that a 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 that can be administered to a subject in need thereof simultaneously, simultaneously, or sequentially with variable intervening time limits, such that such administration provides effective levels of the two or more compounds in the subject's body. This also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0281] Therefore, also provided herein is a method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating 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, such that the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective for treating cancer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate doses. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered sequentially in any order as separate doses in jointly effective amounts, for example, daily or intermittent doses. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dose. In some embodiments, the cancer is a Ras pathway-associated cancer.

[0282] Therefore, also provided herein is a method for inhibiting, preventing, or assisting in the prevention of cancer metastasis or reducing symptoms in a subject in need thereof, 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 a method can be used to treat one or more of the cancers described herein. For example, see U.S. Publication No. 2013 / 0029925, WO 2014 / 083567, and U.S. 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-associated cancer. In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent, as described herein.

[0283] The term "metastasis" is an art-recognized term that refers to the formation of additional tumors (e.g., solid tumors) in a subject at a site distant from the primary tumor, wherein the additional tumors contain the same or similar cancer cells as the primary tumor.

[0284] Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having a Ras pathway-associated cancer, comprising selecting, identifying, or diagnosing the subject as having a Ras pathway-associated cancer and administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having a Ras pathway-associated cancer. Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having a Ras pathway-associated cancer, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject having a Ras pathway-associated cancer. The reduced risk of developing metastasis or additional metastases in a subject having a Ras pathway-associated cancer can be compared to the risk of developing metastasis or additional metastases in the subject before treatment, or compared to a subject or population of subjects having a similar or identical Ras pathway-associated 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, AMG 510, 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 received one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0285] Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having a Ras-associated cancer, comprising selecting, identifying, or diagnosing the subject as having a Ras-associated cancer and administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having a Ras-associated cancer. Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having a Ras-associated cancer, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. The reduced risk of developing metastasis or additional metastases in a subject having a Ras-associated cancer can be compared to the risk of developing metastasis or additional metastases in the subject before treatment, or compared to a subject or population of subjects having a similar or identical Ras-associated 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, AMG 510, 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 received one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0286] Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having a KRas-associated cancer, comprising selecting, identifying, or diagnosing the subject as having a KRas-associated cancer and administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having a KRas-associated cancer. Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having a KRas-associated cancer, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. The reduced risk of developing metastasis or additional metastases in a subject having a KRas-associated cancer can be compared to the risk of developing metastasis or additional metastases in the subject before treatment, or compared to a subject or population of subjects with a similar or identical KRas-associated 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, AMG 510, 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 received one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0287] Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having an HRas-associated cancer, comprising selecting, identifying, or diagnosing the subject as having an HRas-associated cancer and administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having an HRas-associated cancer. Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having an HRas-associated cancer, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject. The reduced risk of developing metastasis or additional metastases in a subject having an HRas-associated cancer can be compared to the risk of developing metastasis or additional metastases in the subject before treatment, or compared to a subject or population of subjects with a similar or identical HRas-associated 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, AMG 510, 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 received one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0288] Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having an NRas-associated cancer, comprising selecting, identifying, or diagnosing the subject as having an NRas-associated cancer and administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having an NRas-associated cancer. Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having an NRas-associated cancer, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject. The reduced risk of developing metastasis or additional metastases in a subject having an NRas-associated cancer can be compared to the risk of developing metastasis or additional metastases in the subject before treatment, or compared to a subject or population of subjects with a similar or identical NRas-associated cancer that has not received treatment or that has received a different treatment. In some embodiments, the additional therapeutic agent is selected from MRTX849, LY3499446, JNJ-74699157, AMG 510, 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 received one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0289] Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having an SOS1-associated cancer, comprising selecting, identifying, or diagnosing the subject as having an SOS1-associated cancer and administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject selected, identified, or diagnosed as having an SOS1-associated cancer. Also provided is a method for reducing the risk of developing metastasis or additional metastases in a subject having an SOS1-associated cancer, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. The reduced risk of developing metastasis or additional metastases in a subject having an SOS1-associated cancer can be compared to the risk of developing metastasis or additional metastases in the subject before treatment, or compared to a subject or population of subjects with a similar or the same SOS1-associated 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, AMG 510, 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 received one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition.

[0290] The phrase "risk of developing metastases" refers to the risk that a subject with a primary tumor will develop additional tumors (e.g., solid tumors) at sites distant from the primary tumor in the subject over a period of time, where the additional tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing metastases in a subject with cancer are described herein.

[0291] The phrase "risk of developing additional metastases" refers to the risk that a subject who has a primary tumor and one or more additional tumors at sites distant from the primary tumor (where the one or more additional tumors contain the same or similar cancer cells as the primary tumor) will develop one or more additional tumors distant from the primary tumor, where the additional tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0292] Treatment of a subject with cancer with a multikinase inhibitor (MKI) or a target-specific kinase inhibitor (e.g., a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROS1 inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, a RET inhibitor, or a Ras inhibitor) can result in dysregulation of Ras pathway genes, Ras pathway proteins, or their expression, activity, or levels in the cancer. See, for example, 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.

[0293] Treatment of a subject having cancer with an SOS1 inhibitor in combination with a multikinase inhibitor or a target-specific kinase inhibitor (e.g., a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROS1 inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, a RET inhibitor, or a RAS inhibitor) may result in an enhanced therapeutic effect compared to treatment of the same or a similar subject with the SOS1 inhibitor as monotherapy, or with the multikinase inhibitor or the target-specific kinase inhibitor as 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.

[0294] Provided herein are methods of treating a subject having cancer (e.g., any of the cancers described herein) and who has previously been administered a multikinase inhibitor (MKI) or a target-specific kinase inhibitor (e.g., a Ras inhibitor, a BRAF inhibitor, an EGFR inhibitor, a MEK inhibitor, an ALK inhibitor, a ROS1 inhibitor, a MET inhibitor, an aromatase inhibitor, a RAF inhibitor, a RET inhibitor, or a Ras inhibitor) (e.g., as monotherapy), the methods comprising administering to the subject (i) an effective dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as monotherapy, or (ii) an effective dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and effective doses of the previously administered MKI or the previously administered target-specific kinase inhibitor.

[0295] Also provided is a method for inhibiting SOS1 activity in a mammalian cell, the method comprising contacting the mammalian cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell with SOS1 activity. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer described herein. In some embodiments, the mammalian cancer cell is a Ras pathway-associated cancer cell.

[0296] Also provided is a method for inhibiting Ras activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell with Ras activity. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer described herein. In some embodiments, the mammalian cancer cell is a Ras pathway-associated cancer cell.

[0297] Also provided is a method for inhibiting SOS1-Ra (e.g., KRas, HRas, and / or NRas) protein-protein interaction in a mammalian cell, the method comprising contacting the mammalian cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell having SOS1-Ra (e.g., KRas, HRAs, and / or NRas) protein-protein interaction. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer described herein. In some embodiments, the mammalian cancer cell is a Ras pathway-associated cancer cell.

[0298] Also provided is a method for inhibiting Ras pathway activity in a mammalian cell, comprising contacting the mammalian cell with a compound of Formula (I). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having a mammalian cell with Ras pathway activity. In some embodiments, the mammalian cell is a mammalian cancer cell. In some embodiments, the mammalian cancer cell is any cancer described herein. In some embodiments, the mammalian cancer cell is a Ras pathway-associated cancer cell.

[0299] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in an in vivo system. For example, "contacting" an SOS1 protein with a compound provided herein includes administering a compound provided herein to a subject, such as a human, having an SOS1 protein, and introducing a compound provided herein into a sample containing, for example, a mammalian cell or purified preparation containing an SOS1 protein.

[0300] Also provided herein is a method of inhibiting the proliferation of mammalian cells in vitro or in vivo, 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.

[0301] The phrase "effective amount" refers to an amount sufficient, when administered to a subject in need of such treatment, to (i) treat a Ras pathway-associated disease or disorder (such as a Ras pathway-associated 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 an amount, will vary depending on factors such as the particular compound, the disease state and its severity, and the individual characteristics (e.g., body weight) of the subject in need of treatment, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0302] Pharmaceutical Compositions When used as a pharmaceutical, the compounds of formula (I), including their pharmaceutically acceptable salts, can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ophthalmic, and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., intratracheal or intranasal, by inhalation or insufflation of powders or aerosols, 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 a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and the like may be necessary or desirable.

[0303] The present invention also provides pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient in combination with one or more pharmaceutically acceptable excipients. For example, a pharmaceutical composition prepared using a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, for example, 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 compositions are formulated for oral administration. In some embodiments, the compositions are solid oral dosage forms. In some embodiments, the compositions are formulated as tablets or capsules.

[0304] Further provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by intimately mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a 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.

[0305] Suitable pharmaceutically acceptable carriers are well known in the art, and descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Society.

[0306] Methods for formulating pharmaceutical compositions are described in numerous publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al., Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al., and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al. and published by Marcel Dekker, Inc.

[0307] When preparing compositions in oral dosage form, any of the usual pharmaceutical media can be used. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc.; for solid oral preparations such as powders, capsules, and tablets, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or 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 can also be coated with a substance such as sugar to modify the primary absorption site, or enteric coated. For parenteral administration, the carrier usually consists of sterile water, and other ingredients may be added to increase solubility or preservation. Injection suspensions or solutions may also be prepared using aqueous carriers with appropriate additives. The pharmaceutical compositions herein will contain the amount of active ingredient necessary to deliver an effective dose as described herein per dosage unit, e.g., tablet, capsule, powder, injection, teaspoon, etc.

[0308] Compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human and other subjects, each unit containing a predetermined quantity of the active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0309] In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient.

[0310] In some embodiments, the compositions provided herein contain 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.

[0311] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient.

[0312] The daily dosage of a 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 adult per day, 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 active ingredient, for symptomatic adjustment of dosage to the subject being treated. An effective amount of 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 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. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered on a regimen of 1 to 4 times per day, or in a single daily dose.

[0313] Active compound can be effective in a wide dosage range, and is generally administered in a pharmaceutically effective amount.The optimal dosage to be administered can be easily determined by those skilled in the art.Therefore, it will be understood that the amount of compound actually administered will usually be determined by a doctor and will vary according to relevant circumstances, including administration method, the actual compound to be administered, the strength of the preparation, the condition to be treated, and the progression of the disease state.In addition, factors related to the specific subject being treated, including subject's response, age, weight, diet, administration time, and the severity of subject's symptoms, will result in the need to adjust dosage.

[0314] In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. In some embodiments, such administration may be once daily or twice daily (BID).

[0315] Those skilled in the art will recognize that both in vivo and in vitro tests using suitable, known, and generally accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0316] Those skilled in the art will further recognize that human clinical trials, including first-in-human dose ranging and efficacy studies in healthy subjects and / or subjects afflicted with a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0317] Provided herein are pharmaceutical kits useful for treating Ras pathway-related diseases or disorders, such as cancer, comprising one or more containers containing a pharmaceutical composition comprising, for example, an effective amount of a compound provided herein. Such kits can further comprise, if desired, one or more of a variety of conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as an insert or label, indicating the amount of components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. [Example]

[0318] Abbreviation ℃=Celsius temperature 1 H NMR = proton nuclear magnetic resonance spectrum ACN or MeCN = acetonitrile AcOH = acetic acid Boc = tert-butoxycarbonyl con.=concentration d = doublet DAST = diethylaminosulfur trifluoride DCM = dichloromethane DIPEA or DIEA = N,N-diisopropylethylamine DMF = N,N-dimethylformamide DMF-DMA = dimethylformamide dimethyl acetal DMSO = dimethyl sulfoxide DPPA = diphenylphosphoryl azide EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et = ethyl EtOAc or EA = ethyl acetate EtOH = methanol ESI = electrospray ionization g = grams(s) HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazole tetramethyluronium hr=hour(s) HOBt = 1-hydroxybenzotriazole HPLC = High-Performance Liquid Chromatography IPA = 2-propanol LCMS = Liquid Chromatography-Mass Spectrum M=mass MTBA = methyl tert-butyl ether m / z=mass-to-charge ratio Me = methyl MeCN = acetonitrile MeOH = methanol MeONa = sodium methoxide mg = milligram(s) mL = milliliters mmol = millimoles (multiple) mol = mole(s) MS = mass spectrum NBS = N-bromosuccinimide obsd. = observed Pd(OAc)2 = palladium(II) acetate Pd(dppf)Cl2 = (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride PE = petroleum ether ppm=parts per million rt=room temperature s = singlet SPhos-Pd-G3 = (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Tf = trifluoromethanesulfonyl T3P = propylphosphonate anhydride t = triplet TBAF = tetrabutylammonium fluoride TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography UPCC = Ultra Performance Convergence Chromatography

[0319] Materials and Methods The compounds provided herein, including the salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0320] The reactions for preparing the compounds provided herein can be carried out in a suitable solvent that can be easily selected by those 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, at a temperature ranging from the freezing temperature of the solvent 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 specific reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0321] Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one of ordinary skill in the art. Protecting group chemistry 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 th Ed., Wiley-Interscience Publication, 2001, and Peturssion, S. et al., "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 74(11), 1297 (1997).

[0322] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectroscopy, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" KF Blom, et al., J. Combi. Chem. 6(6), 874 (2004)), normal phase silica chromatography, and supercritical fluid chromatography (SFC).

[0323] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible light), mass spectroscopy, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" KF Blom, et al., J. Combi. Chem. 6(6), 874 (2004)), normal phase silica chromatography, and supercritical fluid chromatography (SFC).

[0324] 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 stain. NMR spectra were obtained on a Bruker Neo 400M spectrometer operating at 400 MHz. Chemical shifts are reported in parts per million (δ) from the tetramethysilane 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 by DAD (254 nm, 210 nm, and 280 nm). Chiral HPLC was performed on a Waters Acquity UPC2 system or other designated columns containing base 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 by DAD (254 nm). Preparative HPLC was performed on a Gilson Trilution LC system using a Welch XB-C18 column (5 μm, 21.2 × 150 mm). Flash chromatography was performed on a Biotage Isolera Prime system using Welch WelFlash flash columns (40-63 μm). All synthesized compounds had a purity of 95% or higher unless otherwise specified.

[0325] Example 1: (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] Step A: Methyl 4-hydroxy-6-oxo-1-tetrahydropyran-4-yl-pyridine-3-carboxylate To a solution of dimethyl 3-oxopentanedioate (7.83 g, 44.9 mmol, 6.6 mL) in MeOH (30 mL) was added N,N-dimethylformamide dimethyl acetal (6.43 g, 53.9 mmol, 7.2 mL). The reaction mixture was stirred at ambient temperature for 2 hours. 4-Aminotetrahydropyran (5.00 g, 49.4 mmol) was added, and the resulting mixture was stirred for 24 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (PE: EtOAc = 1:1) to give the title compound (3.6 g, 31% yield). MS obsd. (ESI+) 254.1 [M+H] + .

[0326] Step B: Methyl 4-chloro-6-oxo-1-tetrahydropyran-4-yl-pyridine-3-carboxylate To a solution of methyl 4-hydroxy-6-oxo-1-tetrahydropyran-4-yl-pyridine-3-carboxylate (2.0 g, 7.9 mmol) in acetonitrile (15 mL) was added phosphorus oxychloride (32.7 g, 213 mmol) at room temperature. The resulting mixture was stirred at 95 °C for 6 hours. The mixture was then concentrated in vacuo. The residue was treated with aqueous NaCO and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (960 mg, 45% yield). MS obsd. (ESI+) 35 Cl / 37 Cl 272.1 / 274.1[M+H]+ .

[0327] Step C: 4-chloro-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylic acid A solution of methyl 4-chloro-6-oxo-1-tetrahydropyran-4-yl-pyridine-3-carboxylate (2.0 g, 7.36 mmol) and LiOH (264 mg, 11.0 mmol) in THF (15.0 mL) and HO (5.0 mL) was stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo. The residue was dissolved in HO (100 mL) and the pH was adjusted to approximately 3. The mixture was extracted with EtOAc, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the title compound (1.82 g, crude). This material was used in the subsequent step without further purification. MS obsd. (ESI+) 258.1 [M+H] + .

[0328] Step D: (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide To a solution of 4-chloro-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylic acid (1.80 g, crude, assumed 7.0 mmol) in DMF (50 mL) was added HATU (4.0 g, 10.5 mmol), and the mixture was stirred for 30 min. Then, (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (2.10 g, 10.5 mmol) and DIPEA (2.70 g, 20.9 mmol) were added, and the mixture was stirred for 1 h. The reaction was quenched with HO and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-6% MeOH in DCM) to give the title compound (3.0 g). MS obsd. (ESI+) 35 Cl / 37 Cl 443.5 / 445.2[M+H]+ .

[0329] Step E: (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (Example 1): To a solution of (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (206 mg, 0.47 mmol) and 1-methylpiperidin-4-amine (80 mg, 0.70 mmol) in DMSO (4.2 mL) was added triethylamine (142 mg, 1.4 mmol). The reaction was stirred in a sealed vial in a microwave reactor at 120 °C for 10 h. The mixture was then diluted with water and extracted with EtOAc (4 × 30 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 20–30% MeOH in DCM) to give the title compound (150 mg, 61% yield). MS obsd.(ESI+)521.6[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:8.75(1H),8.12(2H),7.71(1H),7.59(1H),7.43(1H),5.34(1H),5.26(1H),4.86(1H),4.02( 2H), 3.47(2H), 3.22(1H), 2.56(2H), 2.46(3H), 2.13(3H), 2.05(4H), 1.83(2H), 1.66(2H), 1.45(3H), 1.41-1.27(2H).

[0330] Example 2: (R)-4-((2-(dimethylamino)ethyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (67 mg, 0.15 mmol) and N',N'-dimethylethane-1,2-diamine (20 mg, 0.23 mmol) in DMSO (1.5 mL) was added triethylamine (46 mg, 0.45 mmol). The reaction was stirred in a sealed tube in a microwave reactor at 120 °C for 6 h. The mixture was then diluted with HO and extracted with EtOAc (4 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 5-10% MeOH in DCM) followed by preparative HPLC (MeCN / 0.1% aqueous NH4HCO3) to give (R)-4-((2-(dimethylamino)ethyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (19.7 mg, 26% yield). MS obsd. (ESI+) 495.2 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ:8.71(1H),8.07(2H),7.71(1H),7.58(1H),7.43(1H),5.32(1H),5.21(1H),4.8 6(1H),4.02(2H),3.47(2H),3.04(2H),2.46(3H),2.38(2H),2.11(6H),2.05(2H),1.65(2H),1.45(3H).

[0331] The following examples can be synthesized in a similar manner to Example 2, starting with (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide and varying the amine reagent used. [Table 7-1] [Table 7-2]

[0332] Example 12: (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(methylamino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] To a round-bottom flask was added (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (35 mg, 0.079 mmol) and methylamine (33% in EtOH, 1 mL), and the mixture was stirred at 70° C. for 2 h. The solvent was evaporated, and the residue was purified by preparative HPLC (ACN / water / 0.1% NH4CO3) to give the title compound (20.3 mg, 58% yield). MS obsd. (ESI+) 438.5 [M+H] + .

[0333] Example 13: 4-(((1S,3S)-3-hydroxycyclopentyl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] To a mixture of (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (50 mg, 0.11 mmol) in DMSO (2 mL) was added (1S,3S)-3-aminocyclopentanol (11.4 mg, 0.11 mmol) and potassium carbonate (46.8 mg, 0.34 mmol). The mixture was stirred at 130 °C under microwave heating for 1 hour. The mixture was cooled to room temperature and diluted with EtOAc (6 mL). The organic mixture was washed with HO (4 mL × 3) and brine (4 mL × 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (acetonitrile: 0.1% NH4HCO3 in water = 10% to 95%) to give the title compound (15.8 mg, 28% yield). MS obsd. (ESI+) 508.5 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.75(1H),8.12(2H),7.70(1H),7.58(1H),7.43(1H),5.31(1H),5.19(1H),4.87(1H),4.56(1H),4.16(1H),4.02(2H),3.7 8(1H),3.48(2H),2.45(3H),2.17-1.98(3H),1.93(1H),1.87-1.74(1H),1.66(2H),1.50(1H),1.44(3H),1.33-1.25(1H).

[0334] Example 14: 4-(((1R,3R)-3-hydroxycyclopentyl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] Prepared according to a procedure similar to Example 13, using (1R,3R)-3-aminocyclopentanol instead of (1S,3S)-3-aminocyclopentanol. MS obsd. (ESI+) 508.4 [M+H]+ .

[0335] Example 15: (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)-1,6-dihydropyridine-3-carboxamide [ka] 1-(2,2,2-Trifluoroethyl)piperidin-4-amine, dihydrochloride (57.60 mg, 0.23 mmol) and potassium carbonate (62.4 mg, 0.45 mmol) were dissolved in DMSO (5 mL) at room temperature, and the mixture was stirred at this temperature for 5 minutes. Then, (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (50 mg, 0.11 mmol) was added to the mixture. The resulting solution was stirred at 120 °C for 24 hours. The mixture was then poured into water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (0% to 10% MeOH in DCM) to give the title compound (6.30 mg, 4% yield). MS obsd. (ESI+) 589.6 [M+H] + .

[0336] Example 16: (R)-4-((1-(2-fluoroethyl)piperidin-4-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] Prepared according to a procedure similar to Example 15 using 1-(2-fluoroethyl)piperidin-4-amine dihydrochloride. MS obsd. (ESI+) 553.7 [M+H] + .

[0337] Example 17: (R)-5-Bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (200 mg, 0.38 mmol) in AcOH (5 mL) was added molecular bromine (92 mg, 0.57 mmol) and potassium acetate (57 mg, 0.57 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated in vacuo. The residue was purified by preparative TLC (eluted with 10:1 DCM:MeOH) to give the title compound (120 mg, 53% yield). MS obsd. (ESI+) 79 Br / 81 Br 599.2 / 601.2[M+H] + .

[0338] Example 18: (R)-5-Methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)-5-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (40 mg, 0.066 mmol) in MeOH (3.0 mL) was added sodium methoxide (72 mg, 1.33 mmol) at room temperature. The reaction was heated in a sealed tube in a microwave reactor at 80° C. for 2 hours. The mixture was then quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluted with 2% MeOH in DCM) to give the title compound (7.0 mg, 18% yield). MS obsd.(ESI+)551.3[M+H] + .

[0339] Example 19: (R)-5-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)-5-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (40 mg, 0.066 mmol) in water (0.2 mL) and 1,4-dioxane (0.8 mL), SPhos-Pd-G3 (10.4 mg, 0.013 mmol) and methylboronic acid (12 mg, 0.2 mmol) were added at room temperature. The mixture was stirred in a sealed tube at 100° C. for 16 hours. The reaction mixture was concentrated to dryness and the residue was purified by preparative TLC (10% MeOH in DCM) followed by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (2.25 mg, 6% yield). MS obsd. (ESI+) 535.6 [M+H]+ .

[0340] Example 20: (R)-5-cyano-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)-5-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (50 mg, 0.08 mmol) in N,N-dimethylacetamide (0.99 mL) was added zinc cyanide (29.3 mg, 0.25 mmol), zinc powder (0.5 mg, 0.08 mmol), and Pd(dppf)Cl (18 mg, 0.025 mmol) at room temperature. The reaction mixture was then stirred at 120 °C under a N atmosphere for 4 hours. The mixture was diluted with water and extracted with DCM (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH=10 / 1) followed by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (4 mg, 9% yield). MS obsd. (ESI+) 546.2 [M+H] + .

[0341] Example 21: (R)-4-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] Step A: tert-Butyl (R)-6-((5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate A mixture of (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (50 mg, 0.11 mmol) and tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (71 mg, 0.34 mmol) in DMSO (1 mL) was sealed in a microwave tube and heated to 100 °C for 16 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel chromatography (eluting with 0-20% MeOH in DCM) to give the title compound (65 mg, 93% yield). MS obsd. (ESI+) 619.7 (M+H). + .

[0342] Step B: (R)-4-((2-azaspiro[3.3]heptan-6-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide A mixture of tert-butyl (R)-6-((5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (65 mg, 0.11 mmol) in TFA (5.0 mL) and DCM (5.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo. The residue was diluted with water (50 mL), and the resulting mixture was adjusted to pH 10 with aqueous sodium bicarbonate. The aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give the title compound (48 mg, crude). The compound was used without further purification. MS obsd.(ESI+)519.6(M+H) + .

[0343] Step C: (R)-4-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide A mixture of (R)-4-((2-azaspiro[3.3]heptan-6-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (48 mg, assumed crude, 0.09 mmol), paraformaldehyde (27 mg), and sodium cyanoborohydride (29 mg, 0.46 mmol) in EtOH (5 mL) was stirred at room temperature for 16 hours. The resulting mixture was then poured into ice water and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in DCM) to give the title compound (24 mg, 50% yield). MS obsd.(ESI+)533.2(M+H) + . 1H NMR(400MHz,DMSO-d6)δ 8.80(1H),8.21(1H),8.15(1H),7.70(1H),7.58(1H),7.43(1H),5.36-5.24(1H),5.13(1H),4.85(1H),4. 02(4H),3.86(2H),3.76-3.66(1H),3.47(2H),2.74-2.57(5H),2.46(3H),2.03(4H),1.65(2H),1.45(3H).

[0344] The following example can be synthesized in a similar manner to Example 21 (Steps A-C), starting with (R)-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide and modifying the amine reagent used in Step A. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7]

[0345] Example 41: (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, [ka] Step A: (R)-4-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide To a solution of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (531 mg, 2.81 mmol) in DMF (10.0 mL) was added HATU (1.1 g, 2.81 mmol), and the mixture was stirred at room temperature for 30 minutes. 4-Chloro-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylic acid (482 mg, 1.87 mmol) and DIPEA (725 mg, 5.61 mmol) were then added to the mixture, which was stirred at room temperature for 1 hour. The crude reaction mixture was combined with a mixture from a separate reaction carried out under identical conditions on a 0.097 mmol scale. The combined reaction mixture was quenched with water and extracted with EtOAc. The organic layer was then washed with water, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (840 mg, crude), which was used without further purification. MS obsd.(ESI+) 35 Cl / 37 Cl 429.5 / 431.2[M+H] + .

[0346] Step B: (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, [ka] To a solution of 1-methylpiperidin-4-amine (107 mg, 0.93 mmol) in DMSO (4.0 mL) was added DIPEA (121 mg, 0.93 mmol) and (R)-4-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (100 mg, assumed crude, 0.23 mmol). The reaction was stirred at 80 °C for 1 h. The reaction mixture was combined with crude material from a separate reaction carried out under identical conditions on a 0.058 mmol scale. The combined reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (eluting with 10% MeOH in DCM) gave the title compound (31 mg, 20% yield). MS obsd. (ESI+) 507.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:8.77(1H),8.14-8.10(2H),7.63(1H),7.53(1H),7.37-7.10(2H),5.35-5.27(2H),4.87(1H), 4.02(2H),3.47(2H),3.23(1H),2.59(2H),2.16(3H),2.10-1.99(4H),1.84(2H),1.66(2H),1.49(3H),1.40-1.30(2H).

[0347] Example 42: (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxamide [ka] Step A: Methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxylate To a solution of methyl 4-chloro-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (100 mg, 0.37 mmol) in DMSO (2 mL) was added tetrahydropyran-4-amine (186 mg, 1.84 mmol). The reaction was stirred at 105 °C for 2 hours. The mixture was diluted with water and extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na SO . The mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to give methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxylate (120 mg, 96% yield). MS obsd.(ESI+)337.3[M+H] + .

[0348] Step B: 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxylic acid To a solution of methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxylate (126 mg, 0.37 mmol) in MeOH (4 mL) and water (1 mL) was added LiOH·HO (30.6 mg, 0.74 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was acidified with 1 M aqueous HCl and extracted with DCM (3 × 30 mL). The combined organic layers were dried over NaSO. The mixture was filtered and concentrated in vacuo to give 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxylic acid (115 mg, crude), which was used without further purification. MS obsd.(ESI+)323.3[M+H] + .

[0349] Step C: (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxamide (Example 42): [ka] To a solution of 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxylic acid (115 mg, assumed composition, 0.35 mmol) and HATU (176 mg, 0.46 mmol) in DMF (5 mL) was added DIPEA (138 mg, 1.07 mmol) at room temperature. The reaction was stirred at room temperature for 10 minutes. (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (94 mg, 0.46 mmol) was added to the reaction mixture, and the reaction was stirred at room temperature for 1 hour. Water was then added to the mixture, and the mixture was extracted into DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with 0% to 15% MeOH in DCM) followed by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxamide (79.4 mg). MS obsd. (ESI+) 508.5 [(M+H) + ].

[0350] Example 43: (R)-4-(Azetidin-3-ylamino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] Step A: Methyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate A mixture of tert-butyl 3-aminoazetidine-1-carboxylate (475 mg, 2.76 mmol), methyl 4-chloro-6-oxo-1-tetrahydropyran-4-yl-pyridine-3-carboxylate (250 mg, 0.92 mmol), and triethylamine (279 mg, 2.76 mmol) in DMSO (3 mL) was sealed in a microwave tube. The resulting mixture was heated to 120 °C in a microwave reactor for 2 h. The mixture was then diluted with water and extracted with EtOAc (80 mL × 3). The combined organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 30-100% EA in PE) to give the title compound (260 mg, 69% yield). MS obsd. (ESI+) 408.5 [(M+H) + ].

[0351] Step B: 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylic acid To a mixture of methyl 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (260 mg, 0.64 mmol) in MeOH (5 mL) and THF (5 mL) was added 1 M NaOH (1.0 M, 6.38 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (50 mL) and adjusted to pH 3 with 1 M aqueous HCl. The resulting mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (220 mg, crude). This material was used in the next step without further purification. MS obsd. (ESI+) 394.5 [(M+H) + ].

[0352] Step C: tert-Butyl (R)-3-((5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-4-yl)amino)azetidine-1-carboxylate To a mixture of (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (112 mg, 0.55 mmol), 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylic acid (180 mg, assumed crude, 0.45 mmol), and triethylamine (93 mg, 0.91 mmol) in DMF (8.0 mL) was added HATU (261 mg, 0.69 mmol) in portions. The resulting mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine and subsequently dried over Na2SO4. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in DCM) to give the title compound (100 mg, 37% yield). MS obsd. (ESI+) 579.7 [(M+H) + ].

[0353] Step D: (R)-4-(Azetidin-3-ylamino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (Example 43) [ka] To a mixture of tert-butyl (R)-3-((5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-4-yl)amino)azetidine-1-carboxylate (100 mg, 0.17 mmol) in 1,4-dioxane (0.5 mL) was added HCl / 1,4-dioxane (4 M, 0.43 mL). The resulting mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo, and the residue was neutralized with 7 M ammonia / methanol solution. The mixture was again concentrated in vacuo. The residue was purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (13.1 mg, 15% yield). MS obsd. (ESI+) 479.5 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ 8.80(1H),8.40(1H),8.15(1H),7.71(1H),7.58(1H),7.43(1H),5.36-5.29(1H),5.00(1H),4.86(1H),4. 10(1H),4.02(2H),3.67(2H),3.47(2H),3.28-3.19(2H),2.47(3H),2.09-1.99(2H),1.66(2H),1.46(3H).

[0354] Example 44: N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-4-(pyrrolidin-3-ylamino)-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] Prepared in a manner similar to Example 43 using tert-butyl 3-aminopyrrolidine-1-carboxylate in Step A. MS obsd. (ESI+) 493.5 [(M+H) + ].

[0355] Example 45: (R)-4-((1,4-dimethylpiperidin-4-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] Step A: Methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate To a solution of methyl 4-hydroxy-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (850 mg, 3.36 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.80 g, 5.04 mmol) in dry DMF (50 mL) was added potassium carbonate (1.39 g, 10.08 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water, and the mixture was extracted three times with 100 mL of DCM. The combined organic layers were washed with water (4 × 100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography on a silica gel column (eluted with 0–40% EA in PE) to give the title compound (1.01 g, approximately 71% pure), which was used without further purification. MS obsd.(ESI+)386.5[(M+H) + ].

[0356] Step B: Methyl 4-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate To a solution of methyl 6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate (200 mg, assumed ∼71% purity, 0.36 mmol) in DMSO (1 mL) was added tert-butyl 4-amino-4-methyl-piperidine-1-carboxylate (334 mg, 1.56 mmol). The mixture was stirred in a microwave reactor at 120 °C for 3.5 h. The mixture was then quenched with water and extracted with DCM (3 × 80 mL). The combined organic layers were washed with water (3 × 50 mL), dried over NaSO, concentrated in vacuo, and purified by silica gel chromatography (eluting with 0–10% MeOH in DCM) to afford the impure title compound (125 mg, ∼46% purity), which was used without further purification. MS obsd.(ESI+)450.5[(M+H) + ].

[0357] Step C: Lithium 4-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate To a solution of methyl 4-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (125 mg, assumed purity 46%, 0.27 mmol) in MeOH (5 mL) and water (1 mL) was added lithium hydroxide (10 mg, 0.42 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo to give the crude title compound (120 mg, crude). The crude product was used in the next step without further purification. MS obsd. (ESI+) 436.5 [(M+H) + ].

[0358] Step D: tert-Butyl (R)-4-methyl-4-((5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-4-yl)amino)piperidine-1-carboxylate To a solution of lithium 4-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (120 mg, crude) in DMF (5 mL) was added HATU (157 mg, 0.41 mmol). The mixture was stirred at room temperature for 20 minutes. Then, ((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (84 mg, 0.41 mmol) and N,N-diisopropylethylamine (107 mg, 0.82 mmol) were added, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with DCM (3 × 80 mL). The combined organic layers were washed with water (3 × 50 mL), dried over NaSO, filtered, and concentrated. Purification by silica gel chromatography (eluting with 0–10% MeOH in DCM) afforded the impure title compound (155 mg, approximately 67% purity). The compound was used without further purification. MS obsd. (ESI+) 621.7 [(M+H) + ].

[0359] Step E: (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((4-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide trifluoroacetate To a solution of tert-butyl (R)-4-methyl-4-((5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-4-yl)amino)piperidine-1-carboxylate (155 mg, approx. 67% purity) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the crude title compound (130 mg, crude). The crude product was used in the next step without further purification. MS obsd. (ESI+) 521.6 [(M+H) + ].

[0360] Step F: (R)-4-((1,4-dimethylpiperidin-4-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (Example 45) [ka] To a solution of crude (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((4-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide trifluoroacetate (130 mg, crude) in MeOH (10 mL) was added paraformaldehyde (75 mg). The mixture was stirred at room temperature for 15 minutes. Sodium cyanoborohydride (94 mg, 1.50 mmol) was then added, and the mixture was stirred for 16 hours. The reaction was quenched with water and extracted with DCM (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-20% MeOH in DCM) followed by preparative HPLC (ACN / water / 0.05% NH4HCO3) to give the title compound (53 mg) as a white solid. MS obsd. (ESI+) 535.6 [(M+H) + ]. 1H NMR(400MHz,DMSO-d6)δ:8.75(1H),8.18(1H),8.00(1H),7.72(1H),7.59(1H),7.44(1H),5.34(1H),5.31(1H),4.8 1(1H),4.01(2H),3.47(2H),2.46(3H),2.38(2H),2.05-1.87(9H),1.66(2H),1.59-1.50(2H),1.47(3H),1.27(3H).

[0361] Example 46: (R)-4-((2-(guanidinooxy)ethyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide [ka] Step A: Methyl 4-((5-((tert-butoxycarbonyl)amino)-9,9-dimethyl-7-oxo-3,8-dioxa-4,6-diazadec-5-en-1-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate To a solution of methyl 6-oxo-1-tetrahydropyran-4-yl-4-(trifluoromethylsulfonyloxy)pyridine-3-carboxylate (60 mg, 0.16 mmol) in DMSO (2 mL) was added [N,N'-di-(tert-butoxycarbonyl)]-2-aminoethoxyguanidine (100 mg, 0.31 mmol, prepared according to the procedure described in J. Med. Chem. 2010, 53, 1843-1856) at room temperature. The reaction was stirred at 80 °C for 2 h. The mixture was extracted with DCM (3 × 15 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated. The residue was combined with the crude material from a reaction performed on a 0.2 mmol scale, and the combined mixture was purified via silica gel chromatography (eluting with 0% to 10% MeOH in DCM) to give the title compound (206 mg). MS obsd.(ESI+)554.5[(M+H) + ].

[0362] Step B: Lithium 4-((5-((tert-butoxycarbonyl)amino)-9,9-dimethyl-7-oxo-3,8-dioxa-4,6-diazadec-5-en-1-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate To a solution of methyl 4-((5-((tert-butoxycarbonyl)amino)-9,9-dimethyl-7-oxo-3,8-dioxa-4,6-diazadec-5-en-1-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (200 mg, 0.36 mmol) in THF / HO (4:1, 2.5 mL) was added LiOH·HO (29.6 mg, 0.72 mmol). The reaction was stirred at room temperature for 10 h. The mixture was then concentrated in vacuo to give the crude title compound (190 mg), which was used in the next step without further purification. MS obsd. (ESI+) 540.5 [(M+H) + ].

[0363] Step C: tert-Butyl N-[(tert-butoxycarbonylamino)-[2-[[5-[[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-tetrahydropyran-4-yl-4-pyridyl]amino]ethoxyamino]methylene]carbamate To a solution of lithium 4-((5-((tert-butoxycarbonyl)amino)-9,9-dimethyl-7-oxo-3,8-dioxa-4,6-diazadec-5-en-1-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxylate (190 mg, crude) in DMF (3 mL) was added triethylamine (143 mg, 1.41 mmol), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (85 mg, 0.42 mmol), and 2,4,6-tripropyl-1,3,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50 wt% in ethyl acetate, 443 mg, 0.70 mmol). The reaction was stirred at room temperature for 1 hour. To this mixture was added water (30 mL), and the mixture was extracted with DCM (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with 0% to 10% MeOH in DCM) to give the title compound (136 mg). MS obsd. (ESI + ):725.5[(M+H) + ]

[0364] Step D: (R)-4-((2-(guanidinooxy)ethyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide (Example 46) [ka] To a solution of tert-butyl N-[(tert-butoxycarbonylamino)-[2-[[5-[[(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-tetrahydropyran-4-yl-4-pyridyl]amino]ethoxyamino]methylene]carbamate (126 mg, 0.17 mmol, 1.0 equiv) in DCM (4.5 mL) was added TFA (1.5 mL) at room temperature. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (46 mg, 50% yield). MS obsd. (ESI + ):525.6[(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.75(1H),8.25(1H),8.07(1H),7.71(1H),7.58(1H),7.43(1H),5.32(1H),5.24(1H),4.98(2H),4.86(1H ),4.34(2H),4.02(2H),3.72(2H),3.47(2H),3.15(2H),2.46(3H),2.12-1.96(2H),1.66(2H),1.45(3H).

[0365] Examples 47 and 48: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-1-((S)-3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-1-((R)-3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (unassigned diastereomer) [ka] Step A: Methyl 4-hydroxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate To a solution of dimethyl 3-oxopentanedioate (500 mg, 2.87 mmol) in MeOH (10.0 mL) was added DMF-DMA (411 mg, 3.45 mmol). The mixture was stirred at room temperature for 2 hours. Then, 3-methyltetrahydrofuran-3-amine (334 mg, 3.30 mmol) was added. The mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure. Water was added to the residue, and the suspension was adjusted to pH=11. The solution was washed with EtOAc. The aqueous phase was collected and acidified with saturated citric acid to pH=4. It was then extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (238 mg, crude). The crude material was used in the following step without further purification. MS obsd. (ESI+) 254.4 [M+H] + .

[0366] Step B: Methyl 1-(3-methyltetrahydrofuran-3-yl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate To a solution of methyl 4-hydroxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate (188 mg, assumed crude, 0.74 mmol) and PhN(Tf) (398 mg, 1.11 mmol) in dry DMF (7.5 mL) was added KCO (308 mg, 2.23 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched by adding 5 mL of saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (3 × 5 mL). The organic layer was washed with brine and dried over anhydrous NaSO. The crude material was combined with crude material from a separate reaction carried out under identical conditions on a 0.099 mmol scale. The solvent was removed, and the residue was purified by silica gel chromatography (eluting with 0–20% EtOAc in PE) to give the title compound (271 mg). MS obsd.(ESI+)386.5[M+H] + .

[0367] Step C: Methyl 4-((1-methylpiperidin-4-yl)amino)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate: To a solution of methyl 1-(3-methyltetrahydrofuran-3-yl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate (221 mg, 0.57 mmol) in DMSO (5.0 mL) was added 1-methylpiperidin-4-amine (262 mg, 2.29 mmol). The reaction was stirred at 80° C. for 1 h. The crude material was combined with crude material from a separate reaction carried out under identical conditions on a 0.065 mmol scale. The combined reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4. The mixture was filtered and concentrated to give the title compound (264 mg, crude) as a white solid. MS obsd. (ESI+) 350.6 [M+H] + .

[0368] Step D: 4-((1-methylpiperidin-4-yl)amino)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid A solution of methyl 1-(3-methyltetrahydrofuran-3-yl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate (239 mg, crude, assumed 0.68 mmol) in HO (1.0 mL) and THF (3.0 mL) was added to LiOH (25 mg, 1.03 mmol), and the reaction mixture was stirred at room temperature for 2 h. The mixture was directly concentrated in vacuo. The crude residue was combined with crude material from another reaction carried out under identical conditions on a 0.071 mmol scale. The residue was dissolved in HO, the solution was adjusted to pH 3 with aqueous HCl, and the mixture was extracted with EtOAc. The aqueous phase was then concentrated in vacuo to give the title compound (250 mg, crude) as a white solid. MS obsd. (ESI+) 336.2 [M+H] + .

[0369] Step E: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-1-((S)-3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-1-((R)-3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (Examples 47 and 48, diastereomers unassigned) [ka] To a solution of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (190 mg, 1.01 mmol) in DMF (5.0 mL) was added HATU (383 mg, 1.01 mmol), and the mixture was stirred at room temperature for 0.5 h. Then, 4-((1-methylpiperidin-4-yl)amino)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (225 mg, crude, assumed 0.67 mmol) and DIPEA (347 mg, 2.68 mmol) were added, and the mixture was stirred for an additional 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was then washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification via silica gel chromatography (eluting with 0-10% MeOH in DCM) gave the title compound (47 mg, 0.09 mmol). MS obsd. (ESI+) 507.8 [M+H] + .

[0370] The individual diastereomers were purified via chiral SFC: (Column: Daicel IG (25 x 250 mm, 10 μm), Mobile phase: CO2 / EtOH [0.5% NH3 (7 M in MeOH)] = 75 / 25). Absolute structures were not determined.

[0371] Example 47: MS obsd.(ESI+)507.6[M+H]+ Analytical chiral UPCC: (Column: IG-3, 4.6 x 100 mm 3 um, Flow rate: 3.0 mL / min, Co-solvent: EtOH (1% 7M NH3 in MeOH), Temperature: 40 °C) Retention time = 1.5 min

[0372] Example 48: MS obsd.(ESI+)507.6[M+H] + Analytical chiral UPCC: (Column: IG-3, 4.6 x 100 mm 3 um, Flow rate: 3.0 mL / min, Co-solvent: EtOH (1% 7M NH3 in MeOH), Temperature: 40 °C) Retention time = 2.1 min

[0373] Example 49: (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] Step A: Methyl 1-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate To a solution of dimethyl 3-oxopentanedioate (6 g, 34.45 mmol, 5.06 mL) in MeOH (89 mL) was added 1,1-dimethoxy-N,N-dimethyl-methanamine (4.93 g, 41.34 mmol, 5.54 mL) at room temperature, and the mixture was stirred for 2 h. In a separate flask, a solution of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride (4.95 g, 34.45 mmol) and DIPEA (9.80 g, 75.80 mmol, 13.20 mL) in 3 mL of MeOH was stirred at room temperature for 2 h. At this point, the free base amine solution was added to the reaction mixture, and the combined mixture was stirred for 2 h. The solvent was removed under reduced pressure. Water was added to the residue, and the suspension was adjusted to pH 11 using KCO (aq). The solution was extracted with EtOAc, and the organic layer was discarded. The aqueous layer was collected and acidified to pH 4 with saturated citric acid. The aqueous phase was then extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (6.6 g, crude). This material was used without further purification. MS obsd. (ESI+) 260.0 [(M+H) + ].

[0374] Step B: Methyl 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate To a solution of methyl 1-(1-(difluoromethyl)cyclopropyl)-4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.07 g, assumed crude, 5.79 mmol) in dry DMF (25 mL) was added potassium carbonate (1.60 g, 11.57 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, 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 (1.4 g, 62% yield). MS obsd. (ESI+) 392.0 [(M+H) + ].

[0375] Step C: Methyl 1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylate To a solution of methyl 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-((((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate (350 mg, 0.90 mmol) in DMSO (0.5 mL) was added 1-methyl-piperidin-4-amine (408 mg, 3.58 mmol). The mixture was stirred at 80° C. for 1 h. The mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated to give the crude title compound (260 mg, crude). This material was used in the next step without further purification. MS obsd. (ESI+) 356.6 [M+H] + .

[0376] Step D: 1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid To a suspension of methyl 1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylate (130 mg, crude, assumed 0.36 mmol) in HO (0.75 mL) was added LiOH (17 mg, 0.73 mmol) and THF (0.75 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH = 1 with 4 M aqueous HCl. The solvent was removed to give the crude title compound (120 mg, crude), which was used without further purification. MS obsd. (ESI+) 342.4 [M+H] + .

[0377] Step E: (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide (Example 49) [ka] To a solution of 1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (100 mg, assumed crude, 0.29 mmol) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (79 mg, 0.35 mmol) in DMF (5.0 mL) was added HATU (167 mg, 0.44 mmol) and DIPEA (151 mg, 1.17 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography (0-20% MeOH in DCM) to give the title compound (Example 49, 47 mg). MS obsd. (ESI+) 513.6 (M+H). + . 1H NMR(400MHz,CD3OD)δ ppm:8.02(1H),7.57-7.49(2H),7.29(1H),7.14-6.86(1H),6.29-6.00(1H),5.44(1H),5.37(1H),3. 40(1H),2.83-2.72(2H),2.42-2.32(2H),2.33(3H),2.03(2H),1.61-1.49(5H),1.45(2H),1.31(2H).

[0378] Example 50: (R)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a solution of 1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (96 mg, assumed crude, 0.28 mmol) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (68 mg, 0.34 mmol) in DMF (5.0 mL) was added HATU (160 mg, 0.42 mmol) and DIPEA (145 mg, 1.12 mmol). The mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was purified by reverse-phase HPLC (MeCN / HO / NHHO) to give the title compound (58 mg). MS obsd. (ESI+) 527.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ ppm:8.80(1H),8.02(2H),7.69(1H),7.58(1H),7.42(1H),6.37-6.08(1H),5.32(1H),5.21(1H), 3.22(1H), 2.56(2H), 2.44(3H), 2.12(3H), 2.05(2H), 1.85-1.77(2H), 1.44(3H), 1.34-1.26(6H).

[0379] Example 51: (R)—N-(1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a solution of 1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (100 mg, 0.29 mmol) in DMF (4.95 mL) was added HATU (222.7 mg, 0.56 mmol) and DIPEA (76 mg, 0.59 mmol). The mixture was stirred at room temperature for 15–20 min. Then, (R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethan-1-amine (71.4 mg, 0.35 mmol, prepared according to the procedure described in WO / 2019 / 122129) was added, and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (100 mL), and the organic mixture was washed with water (100 mL × 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (MeOH / DCM, 0-25%) followed by preparative HPLC (MeCN / 0.1% HCOOH-water = 20-40%) to give the title compound (63.9 mg, 41% yield, 0.6 equiv. of formic acid). MS obsd. (ESI+) 527.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:8.81(1H),8.18(1H),8.02(2H),7.57(1H),7.47(1H),7.30(1H),6.23(1H),5.36-5.26(1H ), 5.24 (1H), 3.42 (1H), 3.26 (2H), 2.60 (2H), 2.17 (3H), 2.15 (2H), 2.02 (3H), 1.84 (2H), 1.48 (3H), 1.44-1.32 (4H).

[0380] Example 52: (R)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a mixture of 1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (49.0 mg, 0.14 mmol) in DMF (4 mL) was added HATU (81.9 mg, 0.22 mmol), DIPEA (55.7 mg, 0.43 mmol), and (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (35 mg, 0.14 mmol, prepared according to the procedure described in WO / 2019 / 122129) sequentially. The mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc (10 mL), and the organic mixture was washed with HO (8 mL × 3) and brine (8 mL × 3). The organic layer was dried (NaSO), filtered, and concentrated. The residue was purified by preparative TLC (DCM:MeOH = 10:1) followed by preparative HPLC (acetonitrile:0.1% FA in water = 10% to 95%) to give the title compound (33.9 mg, 44% yield, 0.54 equivalents of formic acid). MS obsd. (ESI+) 531.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.85(1H),8.18(1H),8.05(1H),7.99(1H),7.76(1H),7.68(1H),7.42(1H),6.24(1H),5.31(1H ), 5.23 (1H), 3.28-3.21 (1H), 2.57 (2H), 2.16 (3H), 2.13 (1H), 1.83 (2H), 1.50 (3H), 1.36 (6H).

[0381] Example 53: (R)—N-(1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] Prepared according to a procedure similar to Example 52 using (R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethan-1-amine hydrochloride (prepared according to the procedure described in WO / 2019 / 122129). MS obsd. (ESI+) 523.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:8.76(1H),8.01(2H),7.53-7.48(2H),7.14(1H),6.37(1H),5.22(1H),5.22(1H) ,4.89-4.80(2H),3.29-3.19(3H),2.60-2.50(2H),2.14-2.08(5H),1.82(2H),1.47(3H),1.47-1.24(4H).

[0382] Example 54: (R)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(3-fluorobenzofuran-7-yl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] Prepared according to a procedure similar to Example 52 using (R)-1-(3-fluorobenzofuran-7-yl)ethan-1-amine hydrochloride (prepared according to the procedure described in WO / 2019 / 122129). MS obsd. (ESI+) 503.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ:8.89(1H),8.30(1H),8.03(2H),7.59(1H),7.38-7.32(2H),6.37(1H),5.55-5.48(1H) ,5.22(1H),3.25-3.18(1H),2.59-2.53(2H),2.12(3H),2.11-2.02(2H),1.85(2H),1.57(3H),1.40-1.24(6H).

[0383] Example 55: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] Step A: tert-Butyl (1R,5S,6s)-6-((1-(1-(difluoromethyl)cyclopropyl)-5-(methoxycarbonyl)-2-oxo-1,2-dihydropyridin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of methyl 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate (1.5 g, 3.83 mmol) in DMSO (8 mL) was added tert-butyl (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.52 g, 7.67 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered to give the title compound (1.3 g, 77% yield). MS obsd. (ESI+) 440.3 [M+H] + .

[0384] Step B: Lithium 4-(((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate To a solution of tert-butyl (1R,5S,6s)-6-((1-(1-(difluoromethyl)cyclopropyl)-5-(methoxycarbonyl)-2-oxo-1,2-dihydropyridin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.46 mmol) in water (3 mL) and MeOH (12 mL) was added LiOH (22 mg, 0.92 mmol) at room temperature. The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated directly to give the title compound (200 mg, crude) as a white solid, which was used without further purification. MS obsd. for the free acid: 426.2 (ESI+) [M+H] +

[0385] Step C: tert-Butyl (1R,5S,6s)-6-((5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-1-(1-(difluoromethyl)cyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate To a solution of lithium 4-(((1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (1.3 g, crude) in DMF (2.55 mL) were added HATU (1.38 g, 3.62 mmol), DIPEA (1.17 g, 9.04 mmol), and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (684 mg, 3.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 0-4% MeOH in DCM to give the title compound (1.50 g). MS obsd. (ESI+) 597.4 [M+H] + .

[0386] Step D: 4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride To a solution of tert-butyl (1R,5S,6s)-6-((5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-1-(1-(difluoromethyl)cyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.50 g, 2.51 mmol) in 1,4-dioxane (10 mL) was added HCl (4 M in 1,4-dioxane, 30 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to the title compound (1.50 g, crude), which was used without further purification. MS obsd. (ESI+) 497.2 [M+H] + .

[0387] Step E: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide To a solution of 4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride (120 mg, assumed crude, 0.23 mmol) in MeOH (5 mL) was added paraformaldehyde (102.2 mg) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. To the mixture was added sodium cyanoborohydride (71 mg, 1.13 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative TLC (MeOH:DCM=1:10) followed by preparative HPLC to give (14.7 mg, 13% yield). MS obsd.(ESI+)511.8[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.81(1H),8.06(1H),7.98(1H),7.59(1H),7.52(1H),7.35(1H),7.21(1H),6.24(1H),5.35(1H), 5.27(1H), 3.00(2H), 2.48(1H), 2.27(2H), 2.20(3H), 1.54-1.49(2H), 1.47(3H), 1.29-1.23(4H).

[0388] Example 56: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] Example 56 was synthesized following a similar procedure as described in Example 55, using tert-butyl (1R,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate in Step A. (ESI+) 511.2 [M+H] + .

[0389] Example 57: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-(methyl-d3)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a solution of 4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride (50 mg, crude, assumed 0.09 mmol) in acetonitrile (10 mL), potassium carbonate (38.9 mg, 0.28 mmol) was added at room temperature. The reaction mixture was stirred for 20 minutes. To the reaction mixture, trideuteriomethyl 4-methylbenzenesulfonate (19.53 mg, 0.1 mmol) was added at room temperature. The reaction mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (5 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was combined with the crude product from a reaction performed on the same scale and purified by silica gel chromatography (0-50% MeOH in DCM) followed by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (16.6 mg) as a white solid. MS obsd. (ESI+) 514.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.82(1H),8.06(s,1H),7.98(1H),7.60(1H),7.52(1H),7.35(1H),7.21(1H),6.24(1H) ,5.36(1H),5.30-5.23(1H),3.00(2H),2.47(1H),2.27(2H),1.49(5H),1.39-1.19(4H).

[0390] Example 58: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-ethyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a solution of 4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride (50 mg, assumed crude, 0.09 mmol) in MeOH (5 mL) was added acetaldehyde (83 mg, 1.88 mmol) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. Sodium cyanoborohydride (59 mg, 0.9 mmol) was then added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (5 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. This crude product was combined with crude material from a reaction carried out under identical conditions and purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (34.2 mg). MS obsd. (ESI+) 525.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.81(1H),8.06(1H),7.99(1H),7.59(1H),7.52(1H),7.35(1H),7.21(1H),6.24(1H),5.36(1H),5. 26(1H), 3.06(2H), 2.45(1H), 2.38(2H), 2.26(2H), 1.52(2H), 1.47(3H), 1.35-1.30(4H), 0.97(3H).

[0391] Example 59: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-isopropyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] Example 59 was prepared according to a similar procedure described in Example 58, using acetone instead of acetaldehyde. MS obsd. (ESI+) 539.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.80(1H),8.06(1H),7.99(1H),7.60(1H),7.52(1H),7.34(1H),7.21(1H),6.24(1H),5.36(1H), 5.26(1H),3.05(2H),2.42(1H),2.39-2.32(3H),1.51(2H),1.47(3H),1.35-1.30(4H),0.96(6H).

[0392] Example 60: 4-(((1R,5S,6s)-3-cyclopropyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a solution of 4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride (50 mg, assumed crude, 0.09 mmol) in MeOH (5 mL) was added HOAc (23 mg, 0.38 mmol), (1-ethoxycyclopropoxy)trimethylsilane (98 mg, 0.56 mmol), and sodium cyanohydride (29.5 mg, 0.47 mmol) at room temperature. The reaction mixture was stirred at 65 °C for 3 h. After cooling to room temperature, the reaction mixture was poured into water (5 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. This crude product was combined with crude material from a reaction carried out under identical conditions and purified by preparative HPLC (ACN / water / 0.1% NH4HCO3) to give the title compound (40.6 mg). MS obsd. (ESI+) 537.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.80(1H),8.05(1H),7.97(1H),7.59(1H),7.52(1H),7.34(1H),7.20(1H),6.23(1H),5.33(1H),5.26(1H) ),3.02(2H),2.56(2H),2.34(1H),1.61(1H),1.51(2H),1.47(3H),1.35-1.30(4H),0.34(2H),0.24(2H).

[0393] Example 61: (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((2-(dimethylamino)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] Step A: Methyl 1-(1-(difluoromethyl)cyclopropyl)-4-((2-(dimethylamino)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylate To a solution of N',N'-dimethylethane-1,2-diamine (379 mg, 4.29 mmol) in DMSO (8.0 mL) was added methyl 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate (525 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (eluted with 3% MeOH in DCM) to give the title compound (244 mg, 69% yield). MS obsd. (ESI+) 330.2 [M+H] + .

[0394] Step B: 1-(1-(difluoromethyl)cyclopropyl)-4-((2-(dimethylamino)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid To a solution of methyl 1-(1-(difluoromethyl)cyclopropyl)-4-((2-(dimethylamino)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylate (244 mg, 0.74 mmol) in THF (3.0 mL) and HO (1.0 mL) was added lithium hydroxide (36 mg, 1.5 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was then directly concentrated in vacuo. The residue was dissolved in HO, adjusted to pH 1 with 1 M aqueous HCl, and concentrated in vacuo to give the title compound (340 mg, crude). This crude material was used in the following step without further purification. MS obsd. (ESI+) 316.1 [M+H] + .

[0395] Step C: (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((2-(dimethylamino)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] A solution of ((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (164 mg, 0.87 mmol), 1-(1-(difluoromethyl)cyclopropyl)-4-((2-(dimethylamino)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (330 mg, crude from the previous step), HATU (412 mg, 1.08 mmol), and DIPEA (280 mg, 2.17 mmol) in DMF (5.0 mL) was stirred at room temperature for 2 h. The mixture was then diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (eluted with 10% MeOH in DCM) followed by preparative HPLC (MeCN / HO / 10% NHCO) to give the title compound (39 mg) as a white solid. MS obsd.(ESI+)487.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:8.86(1H),8.14(1H),8.06(1H),7.63(1H),7.54(1H),7.36-7.08(2H ), 6.36 (1H), 5.39 (1H), 5.29 (1H), 3.42 (2H), 3.13 (2H), 2.74 (6H), 1.49 (3H), 1.37-1.14 (4H).

[0396] Example 62: (R)-4-((1-cyclopropylpiperidin-4-yl)amino)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] Step A: Methyl 4-((1-cyclopropylpiperidin-4-yl)amino)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate To a solution of methyl 1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridine-3-carboxylate (80 mg, 0.20 mmol) in DMSO (2 mL) was added 1-cyclopropylpiperidin-4-amine (86 mg, 0.61 mmol). The mixture was stirred at 80° C. for 2 hours. The mixture was then diluted with DCM (5 mL) and washed with water (5 mL×3). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (eluted with 0-10% MeOH in DCM) to give the title compound (46 mg, 59% yield). MS obsd. (ESI+) 382.7 [M+H] + .

[0397] Step B: Lithium 4-((1-cyclopropylpiperidin-4-yl)amino)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate To a solution of methyl 4-((1-cyclopropylpiperidin-4-yl)amino)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (46 mg, 0.12 mmol) in methanol (5 mL) was added LiOH (6 mg, 0.24 mmol) dissolved in water (1 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to give the crude title compound (45 mg, crude), which was used in the next step reaction without further purification. MS obsd. (ESI+) 368.4 [M+H] for the free acid. + .

[0398] Step C: (R)-4-((1-cyclopropylpiperidin-4-yl)amino)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (Example 62) [ka] To a solution of lithium 4-((1-cyclopropylpiperidin-4-yl)amino)-1-(1-(difluoromethyl)-cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (45 mg, crude from the previous step) in DMF (2 mL) was added triethylamine (36 mg, 0.36 mmol), HATU (91 mg, 0.24 mmol), and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (25 mg, 0.13 mmol). The mixture was stirred at room temperature for 16 h. The mixture was then diluted with DCM (6 mL) and washed with water (4 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (ACN / water / 0.1% NHHCO) to give the title compound (27 mg, 42% yield). MS obsd.(ESI+)539.4[M+H] + . 1 H NMR(400MHz,DMSO)δ 8.80(1H),8.04(2H),7.61(1H),7.52(1H),7.35(1H),7.21(1H),6.24(1H),5.30(1H),5.22(1H),3.29-3.17( 1H), 2.73(2H), 2.34(2H), 1.80(2H), 1.56(1H), 1.48(3H), 1.38-1.20(6H), 0.42-0.35(2H), 0.30-0.22(2H).

[0399] Examples 63 and 64: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide (diastereomer not assigned) [ka] Step A: Methyl 4-(((cis)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)amino)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate To a mixture of methyl 1-[1-(difluoromethyl)cyclopropyl]-6-oxo-4-(trifluoromethylsulfonyloxy)pyridine-3-carboxylate (150 mg, 0.38 mmol) in DMSO (3 mL) was added cis-tert-butyl 4-amino-3-fluoro-piperidine-1-carboxylate (251 mg, 1.15 mmol). The mixture was stirred in a sealed tube at 90 °C for 6 hours. The mixture was cooled to room temperature and diluted with EtOAc (10 mL). The mixture was washed with water (10 mL × 3) and brine (10 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography column (DCM:MeOH = 30:1) to give the impure title compound (150 mg, approximately 88% purity), which was used without further purification. MS obsd. (ESI+) 460.4 [M+H] + .

[0400] Step B: 4-(((cis)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)amino)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid To a mixture of methyl 4-(((cis)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)amino)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (130 mg, approximately 88% pure, approximately 0.25 mmol) in MeOH (2 mL) at 0° C. was added a solution of lithium hydroxide monohydrate (23 mg, 0.56 mmol) in water (0.4 mL). The mixture was stirred at room temperature for 16 hours. The mixture was cooled to 0° C., adjusted to pH=5 with 1N HCl, and extracted with EtOAc (3 mL×3). The combined organic layers were washed with water (4 mL×3) and brine (4 mL×3), then dried over sodium sulfate, filtered, and concentrated to give the crude title compound (126 mg, crude). This material is used in the subsequent step without further purification. MS obsd.(ESI+)446.4[M+H] + .

[0401] Step C: tert-butyl (3S,4R)-4-((5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-1-(1-(difluoromethyl)cyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)amino)-3-fluoropiperidine-1-carboxylate and tert-butyl (3R,4S)-4-((5(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-1-(1-(difluoromethyl)cyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)amino)-3-fluoropiperidine-1-carboxylate To a mixture of 4-(((cis)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)amino)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (126 mg, crude) in DMF (5 mL) was added HATU (161 mg, 0.42 mmol), triethylamine (86 mg, 0.85 mmol), and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (76 mg, 0.34 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc (20 mL) and washed with HO (12 mL × 3) and brine (12 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (7% MeOH in DCM) to give a diastereomeric mixture of the title compounds (151 mg, 86% yield). MS obsd. (ESI+) 617.6 [M+H] + .

[0402] Step D: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-((difluoromethyl)cyclopropyl)-4-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((34,4S)-3-fluoropiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide hydrochloride To a mixture of tert-butyl (3S,4R)-4-((5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)carbamoyl)-1-(1-(difluoromethyl)cyc...

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: R １ But C １ -C ６ alkyl, 4- to 10-membered heterocyclyl, or C ３ -C １０ cycloalkyl, wherein each alkyl, heterocyclyl, and cycloalkyl is selected from one or more R ａ and optionally substituted with R ａ However, each independently, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C ３ -C ６ Cycloalkyl, halogen, —C(O)C １ -C ３ Alkyl, or —C(O)—C ３ -C ６ cycloalkyl, each cycloalkyl optionally substituted with one or more halogens; R ２ But C ６ aryl or 5- to 10-membered heteroaryl, each of which is selected from the group consisting of one or more R ｂ and optionally substituted with R ｂ each independently represents a halogen, C １ -C ３ Haloalkyl, C １ -C ３ Alkyl, or C ３ is cycloalkyl, R ３ is —H, 4- to 10-membered heterocyclyl, C １ -C ６ Alkyl, C １ -C ６ Alkylene-O-NH-C(NH)(NH ２ ), C ３ -C １０ Cycloalkyl, C １ -C ６ alkylene-5 to 10 membered heteroaryl, C １ -C ６ alkylene-4 to 10-membered heterocyclyl, C １ -C ６ Alkylene-(C ３ -C １０ cycloalkyl), or C ３ -C １０ cycloalkyl, and each alkylheterocyclyl, cycloalkyl, and heteroaryl is selected from one or more R ｃ and optionally substituted with R ｃ However, each independently, C １ -C ６ Alkyl, —OH, —O—(C １ -C ６ alkyl), C １ -C ６ Alkylene -O-CH ３ , halogen, C １ -C ６ alkylene-5 to 10-membered heterocyclyl, —N(CH ３ ) (CH ３ ), C ３ -C １０ Cycloalkyl, C １ -C ６ haloalkyl, wherein each heterocyclyl, cycloalkyl, and alkyl is selected from the group consisting of one or more deuterium, C １ -C ６ Alkyl, —OH, halogen, CN, or C １ -C ６ optionally substituted with haloalkyl; R ４ is H, -CH ３ , —CN, —OMe, or halogen; R ５ But C １ -C ３ Alkyl or C １ -C ３ is haloalkyl, A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is NH or S.

2. R ４ is H, or a pharmaceutically acceptable salt thereof.

3. R ２ However, one or more R ｂ C optionally substituted with ６ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

4. R ２ But two R ｂ 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, substituted with:

5. R ２ but, 【Chemistry 2】 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, selected from:

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is NH.

7. R ５ But C １ -C ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

8. R ３ However, one or more R ｃ 2. The compound of claim 1, wherein R is 4 to 10-membered heterocyclyl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

9. R ３ But one R ｃ 9. The compound of claim 8, wherein the heterocyclyl is 4- to 6-membered and substituted with:

10. R ｃ But -CH ３ or -CD ３ 10. The compound of claim 9, wherein:

11. R ３ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein is piperidinyl.

12. R １ However, one or more R ａ 2. The compound of claim 1, wherein R is 4 to 10-membered heterocyclyl optionally substituted with R, or a pharmaceutically acceptable salt thereof.

13. Each R ａ But independently, C １ -C ３ Alkyl, halogen, C １ -C ３ Haloalkyl, and —C(O)C １ -C ３ 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein:

14. In formula (I), 【Transformation 3】 but, 【Chemistry 4】 2. The compound of claim 1, wherein:

15. R １ However, one or more R ａ C optionally substituted with ３ The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is -C6 cycloalkyl.

16. R １ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexyl, or bicyclo[1.1.1]pentyl, each of which is optionally substituted with one R a .

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R a is F or methyl.

18. below: (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-4-((2-(dimethylamino)ethyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((R)-1-methylpyrrolidin-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((S)-1-methylpyrrolidin-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((R)-1-methylpiperidin-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((S)-1-methylpiperidin-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, 4-(((1r,3R)-3-(dimethylamino)cyclobutyl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1-methylazetidin-3-yl)methyl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-4-((3-(dimethylamino)propyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-4-(((1-methyl-1H-imidazol-5-yl)methyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-4-(((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methyl)amino)-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(methylamino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, 4-(((1S,3S)-3-hydroxycyclopentyl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, 4-(((1R,3R)-3-hydroxycyclopentyl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)-1,6-dihydropyridine-3-carboxamide, (R)-4-((1-(2-fluoroethyl)piperidin-4-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-5-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-5-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-5-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-5-cyano-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-4-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, 4-(((3R,4R)-3-methoxy-1-methylpiperidin-4-yl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, 4-(((3S,4S)-3-methoxy-1-methylpiperidin-4-yl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, 4-(((1s,3S)-3-(dimethylamino)cyclobutyl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylazetidin-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-4-(((3-methoxy-1-methylazetidin-3-yl)methyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-4-(((3-fluoro-1-methylazetidin-3-yl)methyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((S)-1-methylazepan-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((R)-1-methylazepan-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((S)-1-methylazepan-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((R)-1-methylazepan-3-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,2R,4S)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1S,2S,4R)-7-methyl-7-azabicyclo[2.2.1]heptan-2-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((S)-4-methyl-4-azaspiro[2.5]octan-7-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((R)-4-methyl-4-azaspiro[2.5]octan-7-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1,6-dihydropyridine-3-carboxamide, (R)-4-(azetidin-3-ylamino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-4-(pyrrolidin-3-ylamino)-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-4-((1,4-dimethylpiperidin-4-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-4-((2-(guanidinooxy)ethyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(3-fluorobenzofuran-7-yl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-(methyl-d3)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-ethyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-isopropyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 4-(((1R,5S,6s)-3-cyclopropyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((2-(dimethylamino)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-4-((1-cyclopropylpiperidin-4-yl)amino)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3S,4R)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3R,4S)-3-fluoro-1-(methyl-d3)piperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3R,4S)-3-fluoropiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1S,2R)-[1,1′-bi(cyclopropan)]-2-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1S,2R)-[1,1′-bi(cyclopropan)]-2-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(1-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclobutyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(fluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(1-(cyclopropanecarbonyl)-3-methylazetidin-3-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((2-morpholinoethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-(2-fluoroethyl)piperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(((R)-quinuclidin-3-yl)amino)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(((S)-quinuclidin-3-yl)amino)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-((((S)-quinuclidin-2-yl)methyl)amino)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-((((R)-quinuclidin-2-yl)methyl)amino)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((S)-1-(1-methyl-1H-imidazol-5-yl)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((R)-1-(1-methyl-1H-imidazol-5-yl)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-(methyl-d3)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-2,2-difluorocyclopropyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-2,2-difluorocyclopropyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((R)-2,2-dimethylcyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((S)-2,2-dimethylcyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((1s,3S)-3-fluorocyclobutyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((1r,3R)-3-fluorocyclobutyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-(3-methylbicyclo[1.1.1]pentan-1-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-isopropyl-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(3,3-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-cyclopropyl-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-(spiro[2.3]hexan-5-yl)-1,6-dihydropyridine-3-carboxamide, 1-(2-cyclopropylpropan-2-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1R,3R)-2,2-difluoro-3-methylcyclopropyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1S,3S)-2,2-difluoro-3-methylcyclopropyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((1S,2S)-2-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((1R,2R)-2-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((S)-spiro[2.2]pentan-1-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((R)-spiro[2.2]pentan-1-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((S)-spiro[2.3]hexan-1-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((R)-spiro[2.3]hexan-1-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-(1-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-(1-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(4,4-difluorocyclohexyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(6,6-difluorospiro[3.3]heptan-2-yl)-4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(6,6-difluorospiro[3.3]heptan-2-yl)-4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(1-(difluoromethyl)cyclopropyl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclobutyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[2.2.1]heptan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1s,3S)-3-(dimethylamino)cyclobutyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1-(1-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1-(1-(trifluoromethyl)cyclopropyl)-1,6-dihydropyridine-3-carboxamide, 1-cyclopropyl-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-cyclopropyl-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-1-(3-fluorobicyclo[1.1.1]pentan-1-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-2,2-difluorocyclobutyl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-2,2-difluorocyclobutyl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-2,2-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((3-fluoro-1-methylazetidin-3-yl)methyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-2,2-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((3-fluoro-1-methylazetidin-3-yl)methyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-2,2-difluorocyclobutyl)-N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-2,2-difluorocyclobutyl)-N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-cyclobutyl-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-((S)-3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-((R)-3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3S,4R)-3-methoxy-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3R,4S)-3-methoxy-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-oxo-4-(((R)-quinuclidin-3-yl)amino)-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-oxo-4-(((S)-quinuclidin-3-yl)amino)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-4-(piperidin-4-ylthio)-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2,2-difluoroethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)-2,2-difluoroethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-N-((R)-1-(3-(pentafluoro-16-sulfanayl)phenyl)ethyl)-1,6-dihydropyridine-3-carboxamide 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(2-fluoro-3-(pentafluoro-16-sulfanayl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-cyclobutyl-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-N-((R)-1-(3-(pentafluoro-16-sulfanayl)phenyl)ethyl)-1,6-dihydropyridine-3-carboxamide, (R)-1-cyclobutyl-4-((1-methylpiperidin-4-yl)amino)-6-oxo-N-(1-(3-(pentafluoro-16-sulfanayl)phenyl)ethyl)-1,6-dihydropyridine-3-carboxamide, (R)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-fluoro-4-methoxy-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (S)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-fluoro-4-methoxy-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (S)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(4-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-(1-(4-cyclopropyl-3-(trifluoromethyl)phenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-(1-(2-chloro-3-(trifluoromethyl)phenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (S)-1-(1-(difluoromethyl)cyclopropyl)-N-(1-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(1-(difluoromethyl)cyclopropyl)-N-(1-(4-methoxy-3-(trifluoromethyl)phenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoro(pyridin-4-yl)methyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((S)-1-(3-(difluoro(pyridin-4-yl)methyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-(1-(3-(difluoro(oxazol-4-yl)methyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(2-chloro-3-cyanophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((S)-1-(2-chloro-3-cyanophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-cyano-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(2-chloro-3-(difluoromethoxy)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-cyano-2-methylphenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3-hydroxybicyclo[1.1.1]pentan-1-yl)methyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(((S)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)amino)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-4-(((R)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)amino)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((3-fluoro-1-methylazetidin-3-yl)methyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((S)-4-fluoroquinuclidin-3-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((R)-4-fluoroquinuclidin-3-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-4-((3-aminobicyclo[1.1.1]pentan-1-yl)amino)-1-(bicyclo[1.1.1]pentan-1-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-4-amino-1-(bicyclo[1.1.1]pentan-1-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-(1-(hydroxymethyl)cyclopropyl)ethyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(2-oxabicyclo[2.1.1]hexan-4-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-cyano-2-methylphenyl)ethyl)-1-((1R,3R)-2,2-difluoro-3-methylcyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-cyano-2-methylphenyl)ethyl)-1-((1S,3S)-2,2-difluoro-3-methylcyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1R,3R)-2,2-difluoro-3-methylcyclopropyl)-N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1S,3S)-2,2-difluoro-3-methylcyclopropyl)-N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1R,3R)-2,2-difluoro-3-methylcyclopropyl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1S,3S)-2,2-difluoro-3-methylcyclopropyl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-2,2-difluorocyclopropyl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-2,2-difluorocyclopropyl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-2,2-difluorocyclopropyl)-N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-2,2-difluorocyclopropyl)-N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(2,2-difluorospiro[2.2]pentan-1-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-cyclobutyl-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-2,2-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-2,2-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-2,2-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-2,2-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-cyclobutyl-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-cyclobutyl-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(bicyclo[1.1.1]pentan-1-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((R)-spiro[2.2]pentan-1-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((S)-spiro[2.2]pentan-1-yl)-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((((R)-1-methylpyrrolidin-2-yl)methyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(3,3-difluoro-1-methylcyclobutyl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(1-(trifluoromethyl)cyclopentyl)-1,6-dihydropyridine-3-carboxamide, 1-(3,3-difluoro-1-methylcyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-(1-(trifluoromethyl)cyclobutyl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)methyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1s,3S)-3-(dimethylamino)cyclobutyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(1-(1,1-difluoroethyl)cyclopropyl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(6,6-difluorospiro[3.3]heptan-2-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-((S)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1-((R)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((S)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((R)-3-(trifluoromethyl)tetrahydrofuran-3-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,4R,5S)-2-methyl-2-azabicyclo[2.2.1]heptan-5-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1S,4S,5S)-2-methyl-2-azabicyclo[2.2.1]heptan-5-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1S,4S,5R)-2-methyl-2-azabicyclo[2.2.1]heptan-5-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,4R,5R)-2-methyl-2-azabicyclo[2.2.1]heptan-5-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((4-methyl-4-azaspiro[2.5]octan-7-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(1-cyclobutylcyclopropyl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(6,6-difluorospiro[2.5]octan-1-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(3-cyclopropyltetrahydrofuran-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1s,3S)-3-cyclopropylcyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1r,3R)-3-cyclopropylcyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclobutyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclobutyl)-4-(((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((R)-spiro[2.2]pentan-1-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1-((S)-spiro[2.2]pentan-1-yl)-1,6-dihydropyridine-3-carboxamide, 1-((R)-2,2-difluorocyclobutyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-1,6-dihydropyridine-3-carboxamide, 1-((S)-2,2-difluorocyclobutyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-1,6-dihydropyridine-3-carboxamide, 1-(3,3-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(3,3-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(fluoromethyl)cyclopropyl)-4-(((1R,5S,8r)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(fluoromethyl)cyclopropyl)-4-(((1R,5S,8s)-3-methyl-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-1-(bicyclo[1.1.1]pentan-1-yl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((3-methoxybicyclo[1.1.1]pentan-1-yl)methyl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(1-acetyl-3-methylpyrrolidin-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-1-acetyl-3-methylpyrrolidin-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-1-acetyl-3-methylpyrrolidin-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(1-fluorocyclopropane-1-carbonyl)-3-methylpyrrolidin-3-yl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((S)-1-(1-fluorocyclopropane-1-carbonyl)-3-methylpyrrolidin-3-yl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((R)-1-(1-fluorocyclopropane-1-carbonyl)-3-methylpyrrolidin-3-yl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-(1-(cyclopropanecarbonyl)-3-methylazetidin-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-((1S,2S)-2-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-((1R,2R)-2-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-((1S,2R)-2-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-((1R,2S)-2-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((S)-1-(3-(difluoromethyl)-2-fluorophenyl)-2,2,2-trifluoroethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)-2,2,2-trifluoroethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 4-(((S)-4-azaspiro[2.5]octan-7-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, 4-(((R)-4-azaspiro[2.5]octan-7-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, 4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, 4-(((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, 4-(((1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-yl)amino)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-4-(piperidin-4-ylamino)-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, 4-((3,3-difluoro-1-methylpiperidin-4-yl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, (R)-4-((1-cyclopropylpiperidin-4-yl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, 1-((1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-(methyl-d3)piperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-((1-(1-methylcyclopropyl)piperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl)-N-((R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((R)-3-cyclopropyltetrahydrofuran-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, 1-((S)-3-cyclopropyltetrahydrofuran-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,8r)-3-(methyl-d3)-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((1R,5S,8s)-3-(methyl-d3)-3-azabicyclo[3.2.1]octan-8-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, (R)-4-(((1-(2-methoxyethyl)azetidin-3-yl)methyl)amino)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1S,4R)-6-methyl-6-azaspiro[3.5]nonan-1-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,4S)-6-methyl-6-azaspiro[3.5]nonan-1-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1S,4S)-6-methyl-6-azaspiro[3.5]nonan-1-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-(((1R,4R)-6-methyl-6-azaspiro[3.5]nonan-1-yl)amino)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-4-((5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)amino)-1,6-dihydropyridine-3-carboxamide, 4-((((1r,4R)-4-(dimethylamino)cyclohexyl)methyl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, 4-((((1s,4S)-4-(dimethylamino)cyclohexyl)methyl)amino)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((7R,8aS)-octahydroindolizin-7-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((7S,8aR)-octahydroindolizin-7-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((7S,8aS)-octahydroindolizin-7-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((7R,8aR)-octahydroindolizin-7-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-((1-methylpiperidin-4-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((S)-4-methyl-4-azaspiro[2.5]octan-7-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(1-(difluoromethyl)cyclopropyl)-4-(((R)-4-methyl-4-azaspiro[2.5]octan-7-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide, and N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-1-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

19. A compound, comprising: 【Transformation 5】 N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-1-((S)-3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof.

20. A compound, comprising: 【Transformation 6】 N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-((1-methylpiperidin-4-yl)amino)-1-((R)-3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof.

21. A compound, comprising: 【Transformation 7】 4-(((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)amino)-1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof.

22. A compound, comprising: 【Transformation 8】 1-(bicyclo[1.1.1]pentan-1-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof.

23. A compound, comprising: 【Chemistry 9】 1-((R)-2,2-difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof.

24. A compound, comprising: 【Chemistry 10】 1-((S)-2,2-Difluorocyclobutyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-(((1R,5S,6s)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl)amino)-6-oxo-1,6-dihydropyridine-3-carboxamide or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

26. 25. A composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for treating cancer in a subject in need thereof.

27. 27. The composition of claim 26, wherein the cancer is a Ras pathway-associated cancer.

28. A composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for treating neurofibromatosis type 1 (NF1) in a subject in need thereof.

29. The composition of claim 28, wherein the composition is administered in combination with one or more additional therapies or therapeutic agents.

30. The composition of claim 29, wherein the one or more additional therapies include a MEK inhibitor.

31. The composition of claim 30, wherein the MEK inhibitor is selumetinib.

32. The composition of claim 30, wherein the MEK inhibitor is mirdametinib.

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