Ras inhibitors and methods of use thereof

Abstract

The disclosure provides compounds, e.g., compounds of Formula I, and their use in treating medical diseases or disorders, such as cancer. The compounds are contemplated to be modulators of Ras (e.g., K-Ras).

Description

RAS INHIBITORS AND METHODS OF USE THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 631,608 filed on April 9, 2024, the entire contents of which is hereby incorporated by reference herein.BACKGROUND

[0002] Ras proteins (e.g., K-Ras, H-Ras and N-Ras) play an important role in various human cancers and represent attractive targets for anticancer therapy. Dysregulation of Ras proteins by activating mutations, overexpression or upstream activation is commonly observed in human tumor cells, and activating mutations in Ras are often observed in human cancers. For example, activating mutations at codon 12 in Ras proteins function by inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly altering the population of Ras mutant proteins to the "on" (GTP -bound) state (Ras(ON)), leading to oncogenic MAPK signaling. Ras proteins show a strong affinity for GTP, thereby allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) of Ras are also responsible for oncogenic activity in some cancers.

[0003] For example, oncogenic K-Ras mutations that stabilize GTP binding and lead to constitutive activation of K-Ras and downstream signaling have been reported in various types of cancers. K-Ras mutations at codons 12, 13, 61 and other positions of the K-Ras primary amino acid sequence have been observed in patient with pancreatic, colorectal, nonsmall cell lung, and small cell lung adenocarcinomas.

[0004] Despite extensive research and discovery efforts by the pharmaceutical industry to develop inhibitors of Ras (e.g., K-Ras) for treating cancer, no such inhibitor has yet demonstrated sufficient safety and / or efficacy to obtain regulatory approval. Thus, an unmet need exists to develop new pan-Ras inhibitors, for example inhibitors of activating Ras mutants, that show safety and efficacy profiles necessary for treating Ras-mediated cancers and other conditions that are affected by, associated with, or would benefit from inhibition of Ras.SUMMARY

[0005] The disclosure is directed, in part, to compounds that inhibit Ras, for example, multiple mutated forms of Ras, for example, K-Ras. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a method of treating a disease or disorder characterized by aberrant Ras activity due to a Ras mutation (e.g., aberrant K-Ras activity due to a K-Ras mutation). In some embodiments, the disease or disorder is a cancer.

[0006] Disclosed herein are compounds represented by Formula I:and pharmaceutically acceptable salts and / or stereoisomers thereof, wherein:X is N or C-Rx;Y is selected from the group consisting of O, S, and NRY;Ring A is selected from the group consisting of 8-10 membered bicyclic heteroaryl, naphthyl, phenyl, and 5-6 membered monocyclic heteroaryl;Rxis selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, - CN, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy; wherein Ci-Cealkyl and Ci-Cealkoxy may optionally be substituted with one or more halogens;RYis selected from the group consisting of hydrogen and Ci-C3alkyl; wherein Ci- C3alkyl may optionally be substituted with one or more halogens;RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cealkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, - NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci- C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(0)2NRaRb, and -NRaS(0)2Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, - NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Ring B is a bond, a 4-10 membered heterocyclyl containing at least one ring nitrogen, or Cs-Cecycloalkyl;RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, -CH2NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R1is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Cs-Cecycloalkyl, -S(O)2NRaRb, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5- 6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R11;R2is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R22; orR1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 4-8 membered heterocyclyl which may optionally be substituted with one or more R5;R11and R22are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, Ci-Cealkyl, -Cealkoxy, C3- C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, - O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl;R3is selected from the group consisting of hydrogen, deuterium, halogen, and Ci- Csalkyl;R4is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, - CN, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R5is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, oxo, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Ci-Cealkoxy, Cs-Cecycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci- Cealkyl, -S(0)2NRaRb, and -NRaS(O)2Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;RaandRbare each independently selected from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci- Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Rcand Rdare each independently selected from the group consisting of hydrogen and Ci-Csalkyl; wherein Ci-Csalkyl may optionally be substituted with one or more halogens;Reand Rfare each independently selected from the group consisting of hydrogen and Ci-Csalkyl; wherein Ci-Csalkyl may optionally be substituted with one or more halogens; n is 0 or 1; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0007] Also disclosed herein are compounds represented by Formula II:and pharmaceutically acceptable salts and / or stereoisomers thereof, wherein:Ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl;RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, - NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci- C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, - S(0)2NRaRb, and -NRaS(O)2Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, - NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Ring B is a bond, a 4-10 membered heterocyclyl containing at least one ring nitrogen, or Cs-Cecycloalkyl;RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, -CH2NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R1is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Cs-Cecycloalkyl, -SO2NRaRb, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R11;R2is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R22; orR1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 5-7 membered heterocyclyl which may optionally be substituted with one or more R4;R11and R22are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, Ci-Cealkyl, Ci-Cealkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, - O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl;R3is selected from the group consisting of hydrogen, deuterium, halogen, and Ci- Csalkyl;R4is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, oxo, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Ci-Cealkoxy, Cs-Cecycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci- Cealkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;RaandRbare each independently selected from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci- Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Rcand Rdare each independently selected from the group consisting of hydrogen and Ci-Cealkyl; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0008] Further disclosed herein are compounds of Formula III:and pharmaceutically acceptable salts and / or stereoisomers thereof, wherein:Ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NH2, Ci-C4alkyl, C2-C4alkynyl, and C3-C4cycloalkyl, wherein Ci-C4alkyl and C3-C4cycloalkyl may optionally be substituted with one, two or three halogens;R1is selected from the group consisting of hydrogen, Ci-C4alkyl, and -S(O)2NH2, wherein Ci-C4alkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, and -S(O)2NH2;R2is selected from the group consisting of Ci-C4alkyl and -CRcRd-(5-6 membered heteroaryl); wherein alkyl or heteroaryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, - NH2, -S(O)2NH2, and -C(=O)NH2; orR1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 6-7 membered heterocyclyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -C(O)NH2, -SO2NH2, -CH2OH, -CHF2, Ci-C4alkyl, and Ci-C4alkoxy;R3is halogen or hydrogen;RBis halogen; and q is 2 or 3.

[0009] In addition, disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent.

[0010] Also disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from inhibition of Ras (e.g., K-Ras), comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0011] For example, disclosed herein are methods of treating a Ras protein-related (e.g., a K-Ras protein-related) disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. For example, in some embodiments, the compounds and compositions disclosed herein may be used to treat a cancer having one or more Ras mutations (e.g., a K-Ras mutation). In some embodiments, the methods described herein may be useful to treat cancers including, but not limited to, pancreatic cancer, colorectal cancer, multiple myeloma, lung adenocarcinoma, melanoma, endometrial cancer, uterine cancer, thyroid, acute myelocytic leukemia, bladder carcinoma, gastric cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0012] Also disclosed herein are methods of inhibiting a Ras protein (e.g., a K-Ras protein) in a cell or tissue, comprising contacting the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.DETAILED DESCRIPTION

[0013] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions

[0014] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0015] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci-ealkyl, Ci-4alkyl, andCi-3 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2 -m ethyl- 1 -butyl, 3-methyl-2-butyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0016] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as Ci-Csalkenyl, C2-Cealkenyl, and C3-C4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0017] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-ealkynyl, and Cs-ealkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0018] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Ci-Csalkoxy, Ci-Cealkoxy, and C2-Cealkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0019] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g, bicyclic or tricyclic) 4n+2 aromatic ring system (e.g, having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms inthe aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61are each independently hydrogen, Ci-Cs alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, substituted Ce-Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0020] The term “carbonyl” as used herein refers to the radical -C(O)-.

[0021] The term “cyano” as used herein refers to the radical -CN.

[0022] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3-C10cycloalkyl, C3-6cycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0023] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[0024] The terms “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are notlimited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br and I), referred to herein as Ci-ehaloalkyl, Ci-4 haloalkyl, and Ci-shaloalkyl, respectively.

[0025] The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0026] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

[0027] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 3-12 membered ring structures, for example, 4- 10 membered ring structures, for example, 4-8 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur, wherein the sulfur atom may be oxidized to SO or SO2.. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. Further examples include Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl,imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyi, piperidonyl, 4-piperidinonyl, quinudidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro- 1 H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro- 1 'H,3'H- spiro [cyclopropane- 1 ,2'-pyrrolizine] , hexahy dro- 1 H-pyrroliziny 1, hexahy dro- 1 H-pyrrolo [2,1- c][l]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyI 1 -oxide and tetrahydro-2H-thiopyranyl 1,1 -dioxide. In some embodiments, the heterocycle is a spiro heterocycle (e.g., 2,8- diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-lH-4,7-methanoisoindole). "Spiro heterocyclyl," or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is an integer of 0 to 2) as ring atoms.

[0028] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH.

[0029] The term “oxo” as used herein refers to the radical =0.

[0030] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0031] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0032] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0033] “ Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and / or partial agonism.

[0034] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0035] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, -toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2 -hydroxy-3 -naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moietymay also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0036] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. Stereoisomers of the compounds may include optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),”depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0037] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol — denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0038] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents arounda carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans,” where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0039] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley -VCH: Weinheim, 2009.

[0040] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0041] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0042] Certain isotopically labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0043] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-s)alkyl, (C2-i2)alkylcarbonyloxymethyl, 1- (alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkylcarbonyloxy)- ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3 -phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci- 2)alkylamino(C2-3)alkyl (such as P-dimethylaminoethyl), carbarn oyl-(Ci-2)alkyl, N,N-di(Ci- 2)alkylcarbamoyl-(Ci-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl.

[0044] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-e)alkyl carbonyloxymethyl, l-((Ci-6)alkylcarbonyloxy)ethyl, l-methyl-l-((Ci-6)alkylcarbonyloxy)ethyl (Ci-e)alkoxy carbonyloxymethyl, N-(Ci- 6)alkoxycarbonylaminom ethyl, succinoyl, (Ci-6)alkylcarbonyl, a-amino(Ci-4)alkylcarbonyl, aryl alkyl carbonyl and a-aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a- aminoalkylcarbonyl, where each a -aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(Ci-6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0045] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N- alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al., Molecules 2008, 13, 519 and references therein.I. Compounds

[0046] The disclosure is directed, in part, to compounds that inhibit Ras, for example, multiple mutated forms of Ras, for example, K-Ras. In some embodiments, the present disclosure provides a method of treating a disease or disorder characterized by aberrant Ras activity due to a Ras mutant (e.g., aberrant K-Ras activity due to a K-Ras mutant). In some embodiments, the disease or disorder is a cancer.

[0047] For example, disclosed herein are compounds represented by Formula I:and pharmaceutically acceptable salts and / or stereoisomers thereof, wherein:X is N or C-Rx;Y is selected from the group consisting of O, S, and NRY;Ring A is selected from the group consisting of 8-10 membered bicyclic heteroaryl; naphthyl, phenyl, and 5-6 membered monocyclic heteroaryl;Rxis selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, - CN, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy; wherein Ci-Cealkyl and Ci-Cealkoxy may optionally be substituted with one or more halogens;RYis selected from the group consisting of hydrogen and Ci-C3alkyl; wherein Ci- C3alkyl may optionally be substituted with one or more halogens;RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cealkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, - NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci- C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, - S(O)2NRaRb, and -NRaS(O)2Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, - NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Ring B is a bond, a 4-10 membered heterocyclyl containing at least one ring nitrogen, or Cs-Cecycloalkyl;RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, -CH2NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R1is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, C3-Cecycloalkyl, -S(O)2NRaRb, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5- 6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R11;R2is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, C3-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl mayoptionally be substituted with one or more substituents each independently selected from R22; orR1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 4-8 membered heterocyclyl which may optionally be substituted with one or more R5;R11and R22are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, Ci-Cealkyl, -Cealkoxy, C3- C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, - O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl;R3is selected from the group consisting of hydrogen, deuterium, halogen, and Ci- Csalkyl;R4is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, - CN, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R5is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, oxo, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Ci-Cealkoxy, Cs-Cecycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci- Cealkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;RaandRbare each independently selected from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci- Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Rcand Rdare each independently selected from the group consisting of hydrogen and Ci-Csalkyl; wherein Ci-Csalkyl may optionally be substituted with one or more halogens;Reand Rfare each independently selected from the group consisting of hydrogen and Ci-Csalkyl; wherein Ci-Csalkyl may optionally be substituted with one or more halogens; n is 0 or 1; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0048] For example, in some embodiments X is N. In other embodiments, X is, for example, selected from the group consisting of C-H, C-Cl, C-F, C-CH3, C-CFfcF, C-CHF2, and C-CF3.

[0049] In some embodiments, ring A is a 8-10 membered bicyclic heteroaryl containing at least one ring nitrogen. In other embodiments, ring A is selected from the group consisting of, for example, phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl, wherein ring A is optionally substituted with one or more groups selected from RA. In still other embodiments, RAis independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, cyano, -NH2, Ci-C4alkyl, C2-C4alkynyl, and C3-C4cycloalkyl, wherein Ci- C4alkyl and C3-C4cycloalkyl may optionally be substituted with one, two or three halogens. In further embodiments, q is 2, 3, or 4. For example, in certain embodiments ring A is selected from the group consisting of, e.g.,

[0050] In further embodiments, ring A is selected from the group consisting of:

[0051] In some embodiments, R1is hydrogen or Ci-Cealkyl optionally substituted by R11. In other embodiments, R1is hydrogen or Ci-Cealkyl optionally substituted by hydroxyl, - S(O)2NH2, or cyano. In further embodiments, R1is selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH(OH)CH3, -CH2C(CH3)2OH, -S(O)2NH2, -CH2-S(O)2NH2, and -CH2CH2CN. For example, in certain embodiments R1is selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, -S(O)2NH2, and -CH2-S(O)2NH2. In still other embodiments, R1hydrogen.

[0052] In some embodiments, R2is Ci-Cealkyl optionally substituted by one or more R22. In other embodiments, R2is Ci-Cealkyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of, for example, halogen, hydroxyl, - SO2NH2, and -C(=O)NH2. For example, in certain embodiments, R2is selected from the group consisting of -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH(OH)CH3, -CH2C(CH3)2OH, -CH(CH3)SO2NH2, and -CH(CH3)C(=O)NH2.

[0053] In other embodiments, R2is -CRcRd-(5-6 membered heteroaryl) optionally substituted by -NRaRbor Ci-Cealkyl. For example, in further embodiments R2is

[0054] In some embodiments, for example, R1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 5-7 membered heterocyclyl optionally substituted with one or more R5. In other embodiments, R5is selected from the group consisting of, for example halogen, hydroxyl, oxo, -C(O)NH2, -SO2NH2, -CH2OH, -CHF2, Ci-C4alkyl, and Ci-C4alkoxy.

[0055] In some embodiments, p is 1. In other embodiments, RBis halogen. In still other embodiments, R3is selected from the group consisting of, for example, hydrogen, halogen, and -CH3. In further embodiments, R3is hydrogen or fluoro. In certain embodiments, R4is, for example, hydrogen. In certain other embodiments, n is 1.

[0056] In some embodiments, for example, compounds of the present disclosure are represented by Formula IA:

[0057] Also disclosed herein are compounds represented by Formula II:and pharmaceutically acceptable salts and / or stereoisomers thereof, wherein:Ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl;RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, - NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci- C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, - S(O)2NRaRb, and -NRaS(O)2Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, - NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Ring B is a bond, a 4-10 membered heterocyclyl containing at least one ring nitrogen, or Cs-Cecycloalkyl;RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, -CH2NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R1is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Cs-Cecycloalkyl, -SO2NRaRb, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R11;R2is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R22; orR1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 5-7 membered heterocyclyl which may optionally be substituted with one or more R4;R11and R22are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, Ci-Cealkyl, Ci-Cealkoxy, C3- C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, - O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl;R3is selected from the group consisting of hydrogen, deuterium, halogen, and Ci- Csalkyl;R4is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, oxo, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Ci-Cealkoxy, Cs-Cecycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci- Cealkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituentseach independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;RaandRbare each independently selected from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci- Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Rcand Rdare each independently selected from the group consisting of hydrogen and Ci-Cealkyl; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

[0058] For example, in some embodiments, RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NH2, Ci-C4alkyl, C2-C4alkynyl, and C3- C4cycloalkyl, wherein Ci-C4alkyl and C3-C4cycloalkyl may optionally be substituted with one, two or three halogens. In other embodiments, q is 2 or 3. For example, in certain embodiments ring A is selected from the group consisting of:

[0059] In some embodiments, R1is selected from the group consisting of, for example, hydrogen, -CH3, -CH2CH2OH, -S(O)2NH2, and -CH2-S(O)2NH2. In other embodiments, R2isselected from the group consisting of -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -

[0060] In further embodiments, R1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 6-7 membered heterocyclyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -C(O)NH2, -SO2NH2, -CH2OH, -CHF2, Ci-C4alkyl, and Ci- C4alkoxy.

[0061] In other embodiments, R3is halogen or hydrogen. In still other embodiments, p is 1 and RBis halogen. For example, in some embodiments a compound of the present disclosure is represented by Formula IIA:

[0062] Further disclosed herein are compounds represented by Formula III:are pharmaceutically acceptable salts and / or stereoisomers thereof, wherein:Ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NH2, Ci-C4alkyl, C2-C4alkynyl, and C3-C4cycloalkyl, wherein Ci-C4alkyl and C3-C4cycloalkyl may optionally be substituted with one, two or three halogens;R1is selected from the group consisting of hydrogen, Ci-C4alkyl, and -S(O)2NH2, wherein Ci-C4alkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, and -S(O)2NH2;R2is selected from the group consisting of Ci-C4alkyl and -CRcRd-(5-6 membered heteroaryl); wherein alkyl or heteroaryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, - NH2, -S(O)2NH2, and -C(=O)NH2; orR1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 6-7 membered heterocyclyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -C(O)NH2, -SO2NH2, -CH2OH, -CHF2, Ci-C4alkyl, and Ci-C4alkoxy;R3is halogen or hydrogen;RBis halogen; and q is 2 or 3.

[0063] For example, in some embodiments, ring A is selected from the group consisting of:

[0064] In other embodiments, R1is selected from the group consisting of, for example, hydrogen, -CH3, -CH2CH2OH, -S(O)2NH2, and -CH2-S(O)2NH2. In still other embodiments, R2is selected from the group consisting of -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -

[0065] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.Table 1. Exemplary compounds.

[0066] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein. Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0067] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify disclosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups.

[0068] Where it is desired to obtain a particular enantiomer of a disclosed compound, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a disclosed compound (such a racemate) and an appropriate chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0069] In another resolution process a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.

[0070] In an alternative embodiment, disclosed compounds may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.II. Methods

[0071] Further disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from inhibition of Ras (e.g., K-Ras), comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. For example, disclosed herein are methods of treating a Ras protein-related (e.g., a K-Ras protein-related) disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0072] In some embodiments, the present disclosure provides a method of treating a disease or disorder characterized by aberrant Ras activity due to a Ras mutant (e.g., aberrant K-Ras activity due to a K-Ras mutation). In some embodiments, for example, the compounds and compositions disclosed herein may be used to treat a cancer having one or more Ras mutations (e.g., a K-Ras mutation).

[0073] For example, the methods described herein may be useful to treat cancers including, but not limited to, lung, prostate, breast, brain, skin, cervical carcinomas, and testicular carcinomas. For example, in some embodiments, the cancers that may be treated by the compounds, compositions and methods disclosed herein are, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.

[0074] In certain embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, related to the cardiovascular system. Nonlimiting examples contemplated herein include, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma.

[0075] In further embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the lung. Non-limiting examples contemplated herein include, e.g., bronchogenic carcinoma (for example, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (for example, bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, and mesothelioma.

[0076] In some embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the gastrointestinal system. Non-limiting examples contemplated herein include, e.g., esophageal cancer (for example, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach cancer (for example, carcinoma, lymphoma, and leiomyosarcoma), pancreatic cancer (for example, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel cancer (for example, adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), and large bowel cancer (for example, adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma).

[0077] In other embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the genitourinary tract. Non-limiting examples contemplated herein include, e.g., kidney cancer (for example, adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (for example, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (for example, adenocarcinoma, sarcoma), and testicular cancer (for example, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0078] In still other embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the liver. Non-limiting examples contemplated herein include, e.g., hepatoma (for example, hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma.

[0079] In further embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the biliary tract. Non-limiting examples contemplated herein include, e.g., gall bladder carcinoma, ampullary carcinoma, and cholangiocarcinoma.

[0080] In certain embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the bone. Non-limiting examples contemplated herein include, e.g., osteogenic sarcoma (for example, osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (for example, reticulum cell sarcoma), multiple myeloma, malignant giant celltumor chordoma, osteochronfroma (for example, osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.

[0081] In some embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the nervous system. Non-limiting examples contemplated herein include, e.g., cancer and / or tumors of the skull (for example, osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), cancer and / or tumors of the meninges (for example, meningioma, meningiosarcoma, gliomatosis), brain cancer (for example, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and cancer and / or tumors of the spinal cord (for example, neurofibroma, meningioma, glioma, sarcoma).

[0082] In other embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the gynecological system. Non -limiting examples contemplated herein include, e.g., cancers and / or tumors of the uterus (for example, endometrial carcinoma), cancers and / or tumors of the cervix (for example, cervical carcinoma, pre-tumor cervical dysplasia), cancers and / or tumors of the ovaries (for example, ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), cancers and / or tumors of the vulva (for example, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), cancers and / or tumors of the vagina (for example, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and cancers and / or tumors of the fallopian tubes (carcinoma).

[0083] In further embodiments, the compounds, compositions and methods disclosed herein can be used to treat hematologic cancers, including tumors. Non-limiting examples contemplated herein include, e.g., cancers and / or tumors of the blood (for example, myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, and non-Hodgkin's lymphoma (malignant lymphoma).

[0084] In certain embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the skin. Non-limiting examplescontemplated herein include, e.g., malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and psoriasis. In some embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the adrenal glands, e.g., neuroblastoma.

[0085] In some embodiments, the methods described herein may be useful to treat cancers including, but not limited to, pancreatic cancer, colorectal cancer, multiple myeloma, lung adenocarcinoma, melanoma, endometrial cancer, uterine cancer, thyroid, acute myelocytic leukemia, bladder carcinoma, gastric cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0086] In particular, in certain embodiments, the disclosure provides a method of treating the medical indications contemplated herein comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.

[0087] In some embodiments, the Ras protein is wild-type (Ras"1). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Ras"1(e.g., I<-Ras"\ H-Ras"1or N-Ras"1). In some embodiments, the Ras protein is Ras amplification (e.g., K-Rasamp). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Rasamp(K-Rasamp, H-Rasampor N-Rasamp).

[0088] In some embodiments, the cancer comprises a Ras mutation, such as a Ras mutation described herein. In some embodiments, the mutation is selected from a K-Ras mutation (for example, G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof); a H-Ras mutation (for example, Q61 R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof); and a N-Ras mutation (for example, Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof); or a combination of any thereof.

[0089] In some embodiments, the cancer comprises a K-Ras mutation selected from the group consisting of, for example, G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K and Q61L. In other embodiments, the cancer comprises an N-Ras mutation selected from the group consisting of, for example, G12C, Q61H, Q61K, Q61L, Q61P and Q61R. In still other embodiments, the cancer comprises an H-Ras mutation selected from the group consisting of, for example, Q61H and Q61L. In further embodiments, the cancer comprises a Ras mutation selected from the group consisting of, for example, G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In certain embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of, for example, G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V.

[0090] In some embodiments, a compound disclosed herein may inhibit more than one Ras mutant. For example, in some embodiments a disclosed compound may inhibit both K-Ras G12C and K-Ras G13C. In other embodiments, disclosed compound may inhibit both N-Ras G12C and K-Ras G12C. In still other embodiments, a disclosed compound may inhibit both N-Ras G12C and K-Ras G12C. In further embodiments, a disclosed compound may inhibit both K-Ras G12C and K-Ras G12D. In certain embodiments, a disclosed compound may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, a disclosed compound may inhibit both K-Ras G12V and K-Ras G12S.

[0091] In some embodiments, a compound disclosed herein inhibits Ras"1in addition to one or more additional Ras mutations (e.g., K, H or N-Ras"1and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61 K, L 19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K, H, or N-Ras"1and H- Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, KI 17N, A59T, G12V, G13C, Q61 H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Ras"1and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0092] In some embodiments, a compound disclosed herein inhibits Rasampin addition to one or more additional Ras mutations (e.g., K-, H- or N-Rasampand K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K-, H- or N-Rasampand H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D,G12C, KI 17N, A59T,G12V, G13C, Q61H ,G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K-, H- or N-Rasampand N-Ras Q61R, Q61K, G12D, Q61L, Q61H, GBR, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0093] In some embodiments, a cancer comprises a Ras mutation and an STK11LOF, a KEAP1, an EPHA5 or an NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation. In other embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and an STK11LOFmutation. In other embodiments, the cancer is non-small cell lung cancer and comprises a K- Ras G12C mutation and an STK11LOFmutation. In further embodiments, a cancer comprises a K-Ras G13C Ras mutation and an STK11LOF, a KEAP1, an EPHA5 or an NF1 mutation. In certain embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K- Ras G12V mutation. In further embodiments, the cancer is colorectal cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12D mutation. In other embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12V mutation. In still other embodiments, the cancer is endometrial cancer and comprises a K-Ras G12C mutation. In certain embodiments, the cancer is lung cancer, colorectal cancer, or pancreatic cancer and comprises a K-Ras G12D mutation. In further embodiments, the cancer is lung cancer or pancreatic cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is colorectal cancer and comprises a K- Ras G12D mutation. In some embodiments, the cancer is gastric cancer and comprises a K- Ras G12C mutation. In addition, a disclosed compound may inhibit Ras"1(e.g., K-, H- or N- Ras"1) or Rasamp(e.g., K-, H- or N-Rasamp).

[0094] Also disclosed herein are methods of inhibiting a Ras protein (e.g., a K-Ras protein) in a cell or tissue, comprising contacting the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the Ras protein is a mutated Ras protein. Further disclosed herein are methods of inhibiting a Ras protein (e.g., a K-Ras protein) in a patient, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0095] The compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a disclosed compound and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a disclosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a disclosed compound and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

[0096] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y- Y, etc.

[0097] In some embodiments, the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence or severity of side effects of treatment). For example, in some embodiments, the compounds of the present invention can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0098] In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies includes a therapeutic agent (e.g., a compound or biologic that is an anti- angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In other embodiments, the one or more additional therapies includes two therapeutic agents. In still other embodiments, the one or more additional therapies includes three therapeutic agents. In some embodiments, the one or more additional therapies includes four or more therapeutic agents.

[0099] Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T cell adoptive transfer (ACT) therapy. In some embodiments, the compounds of the invention may be used as an adjuvant therapy after surgery. In some embodiments, the compounds of the invention may be used as a neo-adjuvant therapy prior to surgery.

[0100] A therapeutic agent may be a compound used in the treatment of cancer or symptoms associated with cancer. For example, a therapeutic agent may be a steroid. Non -limiting examples contemplated herein include, but are not limited to, 21 -acetoxy pregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluoromethoIone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate,mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0101] In further embodiments, a therapeutic agent contemplated herein may be a biologic (e.g., cytokine (e.g., interferon or an interleukin such as IL-2)) used in treatment of cancer or symptoms associated therewith. In some embodiments, the biologic is an immunoglobulin- based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fe fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti -cancer response or antagonizes an antigen important for cancer. Also contemplated herein are antibody-drug conjugates.

[0102] In other embodiments, a therapeutic agent contemplated herein may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fe-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti- CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L 1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fe fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2 / lg fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160, CGEN- 15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab,ipilimumab, tremelimumab, or lirilumab. In other embodiments, a therapeutic agent may be an anti-TIGIT antibody, such as etigilimab.

[0103] In some embodiments, a therapeutic agent contemplated herein may be an anticancer agent. Non-limiting examples contemplated herein include, but are not limited to, mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Further anti-cancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, the one or more additional therapies includes two or more anti-cancer agents, for example, to be administered in combination or administered separately.

[0104] Other non-limiting examples of anti-cancer agents include, e.g., imatinib mesylate, carfilzornib, bortezornib, bicalutarnide, gefitinib, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, and meturedopa; uredopaethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); camptothecin and synthetic analogues (e.g., topotecan); bryostatin; cally statin; adozelesin; carzelesin; bizelesin; cryptophy cins (e.g., cryptophy cin 1 and cryptophycin 8); dolastatin; duocarmycin and synthetic analogues; eleutherobin; pancrati statin; sarcodictyin A; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, such as calicheamicin gammall and calicheamicin omegall; dynemicin such as dynemicin A; bisphosphonates such as clodronate; an esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores,aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogues such as denopterin, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti -adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes such as T-2 toxin, verracurin A, roridin A and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside; cyclophosphamide; thiotepa; toxoids (e.g., paclitaxel and doxetaxel; chloranbucil; tamoxifen; raloxifene; aromatase inhibiting 4(5)-irnidazoles; 4-tiydroxytamoxifen; trioxifene; keoxifene; onapristone; torernifene; flutamide, nilutamide, bicalutarnide, leuprnlide, goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan; topoisomerase inhibitors; difluoromethylornithine; retinoids such as retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts of any of the aforementioned agents.

[0105] Additional non-limiting examples of anti-cancer agents include trastuzumab, bevacizumab, cetuximab, rituximab, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3- aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastics (e.g., cell-cycle nonspecific antineoplastic agents, and other antineoplastics described herein), antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, biricodar, brostallicin, bryostatin, buthionine sulfoximine, calyculin, di chloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2- chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, and zosuquidar.

[0106] Further non-limiting examples of anti -cancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., abemaciclib, ribociclib, palbociclib; seliciclib, dinaciclib), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine and analogs, and streptozocin), trazenes-dacarbazinine, antiproliferative / antimitotic antimetabolites such as folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2- chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, romidepsin, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors, DNA binding agents, P13K delta and gamma inhibitors, copanlisib, alpelisib and idelalisib; multi-kinase inhibitors (e.g., sorafenib),hormones (e.g., estrogen), goserelin, leuprolide, triptorelin, IKK inhibitors, p38MAPK inhibitors, anti-IL-6, telomerase inhibitors, aurora kinase inhibitors, cell surface monoclonal antibodies, elotuzumab, HSP90 inhibitors, P13K / Akt inhibitors, Akt inhibitors, PKC inhibitors (e.g., enzastaurin), Torcl / 2 specific kinase inhibitors, ER / UPR targeting agents, cFMS inhibitors, JAK1 / 2 inhibitors, PARP inhibitors (e.g., olaparib and veliparib), and BCL- 2 antagonists. In some embodiments, a contemplated anti-cancer agent is selected from, for example, mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, sorafenib, or any analog or derivative variant of the foregoing.

[0107] In some embodiments, the anti-cancer agent is a HER2 inhibitor, for example, monoclonal antibody such as trastuzumab and pertuzumab; or a small molecule tyrosine kinase inhibitor such as gefitinib, erlotinib, pilitinib, canertinib, or lapatinib. In other embodiments, a contemplated anti-cancer agent is an ALK inhibitor, for example, ceritinib, crizotinib, alectinib, brigatinib, entrectinib, ensartinib, or lorlatinib. In other embodiments, a contemplated anti -cancer agent is a SHP2 inhibitor an S0S1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a P13K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., mTORCl inhibitor or mT0RC2 inhibitor).

[0108] In some embodiments, a contemplated anti-cancer agent is an additional Ras inhibitor or a Ras vaccine, or another therapeutic modality designed to directly or indirectly decrease the oncogenic activity of Ras. For example, in some embodiments a contemplated anti-cancer agent is an additional Ras inhibitor. In some embodiments, the Ras inhibitor targets Ras in its active, or GTP -bound state (Ras(ON)). In some embodiments, the Ras inhibitor targets Ras in its inactive, or GDP -bound state. In some embodiments, the Ras inhibitor is an inhibitor of K-Ras G12C. In other embodiments, the Ras inhibitor is an inhibitor of K-Ras G12C. In other embodiments, the Ras inhibitor is a K-Ras G12V inhibitor.

[0109] In certain embodiments, the methods described herein further comprises administering to the patient one or more additional therapeutic agents that treats a disease or disorder that is affected by, associated with, or would benefit from inhibition of Ras protein (e.g., K-Ras).

[0110] The methods described herein include administering to the patient a therapeutically effective amount of at least one compound as described herein, which is optionallyformulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the patient an additional therapeutic agent that treats a cancer, or that treats a disease or disorder that is affected by, associated with, or would benefit from inhibition of Ras, e.g., K-Ras.[OHl] In some embodiments, administering the compound(s) described herein to the patient allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, and / or preventing cancer, or in treating, ameliorating, and / or preventing a disease or disorder that is affected by, associated with, or would benefit from inhibition of Ras (e.g., K-Ras) in the patient. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.

[0112] In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications comprising administering a subject in need thereof a therapeutically effective amount of a compound described herein.III. Pharmaceutical Compositions and Kits

[0113] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral or subcutaneous administration.

[0114] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0115] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, di calcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a nontoxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0116] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0117] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0118] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0119] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0120] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0121] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0122] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0123] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0124] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.Aerosols generally are prepared from isotonic solutions.

[0125] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, soluteswhich render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0126] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0127] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D,Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

[0128] The disclosure also provides kits for use by a e.g., a consumer in need of treatment of a disease or disorder described herein. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0129] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . etc”. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of onetablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.EXAMPLES

[0130] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.General Procedures

[0131] HPLC conditions: Method A: Column: Xselect C18 Column, 19*250 mm, 5pm;Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: 0-100% MeCN; Flow rate: 15 mL / min.Synthesis of Intermediates:Synthesis of l-benzyl-5,7-dichloro-8-fluoro-4-hydroxy-l,6-naphthyridin-2(lH)-one(Intermediate 1)Step 1: Synthesis of 4-bromo-2,6-dichloro-5-jluoronicotinic acid

[0132] To a solution of 2,6-dichloro-5-fluoronicotinic acid (3 g, 14.29 mmol) in THF (30 mL) was added methyllithium (1.6 M, 17.86 mL, 28.6 mmol) at -78 °C and the mixture was stirred for 2 h at -20 °C. The reaction mixture was cooled to -78 °C and to it was added a solution of l,2-dibromo-l,l,2,2-tetrachloroethane (4.65 g, 14.29 mmol) in THF (10 mL). The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The aqueous layer was then acidified with IN HC1 and extracted with 5% MeOH in DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.1 g, 65%) as an orange solid. LCMS m / z = 288 [M+H]+.Step 2: Synthesis of 4- benzylamino)-2, 6-dichloro-5-jluoronicotinic acid

[0133] To a solution of 4-bromo-2,6-dichloro-5-fhioronicotinic acid (3.5 g, 12.12 mmol) in DMF (20 mL) was added DIPEA (6.35 mL, 36.3 mmol) followed by phenylmethanamine (1.55 g, 14.54 mmol) at rt under N2. The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (3 x 50 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (2:23) to afford the title compound (2.2 g, 40%) as a yellow solid. LCMS m / z = 315 [M+H]+.Step 3: Synthesis of 4-(N-benzyl-3-ethoxy-3-oxopropanamido)-2,6-dichloro-5-fluoronicotinic acid

[0134] To a solution of 4-(benzylamino)-2,6-dichloro-5-fluoronicotinic acid (2.2 g, 6.98 mmol) in DMF (10 mL) was added CS2CO3 (0.22 g, 0.69 mmol) followed by dropwise addition of ethyl 3-chloro-3-oxopropanoate (1.57 g, 10.47 mmol) at rt under N2. The resulting mixture was stirred at 50 °C for 16 h. The cooled reaction mixture was diluted with water (20 mL), extracted with EtOAc (3 x 30 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (2:23) to afford the title compound (1.4 g, 43%) as an orange solid. LCMS m / z = 429 [M+H]+.Step 4: Synthesis of ethyl l-benzyl-5, 7-dichloro-8-fluoro-2,4-dioxo-l,2,3,4-tetrahydro-l,6- naphthyridine-3-carboxylate

[0135] To a solution of 4-(N-benzyl-3-ethoxy-3-oxopropanamido)-2,6-dichloro-5- fluoronicotinic acid (1.4 g, 3.26 mmol) in DCE (20 mL) was added TEA (1.37 mL, 9.79mmol) and thionyl chloride (0.47 mL, 6.52 mmol) at 0 °C under N2. The resulting mixture was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo. The crude residue was diluted with water, extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with sat. NaHCCh (10 mL) and brine (10 mL), dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc / hexanes (2:23) to afford the title compound (820 mg, 59.0%) as an orange solid. LCMS m / z = 409 [M+H]+.Step 5: Synthesis of 7-benzyl-5, 7-dichloro-8-fluoro-4-hydroxy-l ,6-naphthyridin-2( lH)-one

[0136] To a solution of ethyl l-benzyl-5,7-dichloro-8-fluoro-2,4-dioxo-l,2,3,4-tetrahydro- l,6-naphthyridine-3-carboxylate (820 mg, 1.99 mmol) in dioxane (5 mL) was added 6N HC1 in dioxane (2.49 mL, 29.9 mmol) at rt under N2. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water (10 mL). The precipitated solid was collected by filtration and dried to give the title compound (7.2 g, 25.1%) as a yellow solid. LCMS m / z = 339 [M+H]+.Synthesis of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(2-hydroxyethyl)carbamate (Intermediate 2a)Intermediate 2aStep 1: Synthesis of 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)ethan-l-ol

[0137] To a solution of (2-bromoethoxy)(tert-butyl)dimethylsilane (3 g, 12.54 mmol) in MeCN (40 mL) was added 2-aminoethan-l-ol (15.02 mL, 251 mmol) at rt under N2. The resulting mixture was stirred at 80 °C for 3 h. The reaction mixture was diluted with water (15 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with MeOH / DCM (1 :9) to afford the title compound (2 g, 50.9%) as a colorless liquid. LCMS m / z = 220 [M+H]+.Step 2: Synthesis of tert-butyl (2-((tert-butyldimethylsilyl)oxy)ethyl)(2- hydr oxy ethyl) carbamate

[0138] To a solution of 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)ethan-l-ol (2 g, 9.12 mmol) in DCM (20 mL) was added TEA (1.52 mL, 10.94 mmol) followed by di-tert-butyldicarbonate (3.05 mL, 13.67 mmol) at 0 °C under N2. The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with ammonium chloride solution (10 mL), extracted with DCM (3 x 20 mL), and the combined organic layers were dried over JSfeSCU, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / hexanes (1 : 1) to afford the title compound (1.9 g, 63.9%) as a colorless liquid. LCMS m / z = 320 [M+H]+.Synthesis of 3-benzyl-5-chloro-4-fluoro-8a,9,10,ll,12,13-hexahydro-8H- azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-2(3H)-one (Intermediate 2b)Step 1: Synthesis of tert-butyl 2-(((l-benzyl-7 -chlor o-8-fluoro-4-hydr oxy-2-oxo-l, 2-dihydro- l,6-naphthyridin-5-yl)oxy)methyl)azepane-l-carboxylate

[0139] To a solution of Intermediate 1 (1.6 g, 1.77 mmol) and tert-butyl 2- (hydroxymethyl)azepane-l -carboxylate (2.5 g, 2.12 mmol) in THF (10 mL) was added IM NaHMDS in THF (5.31 mL, 5.31 mmol) at 0 °C under N2. The resulting mixture was stirred at 25 °C for 3 h, then diluted with sat. NH4CI (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexanes / EtOAc (23:2) to afford the title compound (3.41 g, 35.1%) as a yellow solid. LCMS m / z = 530 [M+H]+Step 2: Synthesis of 5-(azepan-2-ylmethoxy)-l-benzyl-7 -chloro-8-fluor o-4-hydroxy- 1,6- naphthyridin-2( lH)-one trifluoroacetate

[0140] To a solution of the title compound from step 1 (3.21 g, 0.34 mmol) in DCM (5 mL) was added TFA (0.15 mL, 1.97 mmol) at 0°C under N2 and the reaction mixture was stirred at rt for 16 h. The reaction was concentrated in vacuo. The residue was triturated with n- pentane (3 x 10 mL) and dried to give the title compound (4.2 g, 72.6%) as a yellow solid. LCMS m / z = 432 [M+H]+Step 3: Synthesis of 3-benzyl-5-chloro-4-fluoro-8a,9,10,l l,12,13-hexahydro-8H- azepino[ 2 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0141] To a solution of the title compound from step 2 (4.17 g, 0.39 mmol) in DCM / THF (10 mL, v / v = 1 :1) was added DIEA (0.21 mL, 1.18 mmol) and PyBOP (512 mg, 0.98 mmol) at rt under N2. The reaction mixture was stirred at rt for 16 h and then at 60 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexanes, 3:7) to afford the title compound, Intermediate 2b, (80 mg, 47.6%) as a yellow solid. LCMS m / z = 414 [M+H]+.Synthesis of 6-methyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)-lH-indazole (Intermediate 3)Step 1: Synthesis of l-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene

[0142] To a solution of l-bromo-5-fluoro-2-iodo-3-methylbenzene (14 g, 44.5 mmol) in DMF (140 mL) was added Cui (72.0 g, 377.9 mmol) and methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (72.6 g, 377.9 mmol) and the reaction mixture was stirred at 70 °C for 12 h under N2. The reaction mixture was filtered, the filtrate was diluted with H2O (200 mL) and extracted with PE (200 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over ISfeSCU, filtered and evaporated under reduced pressure to give the title compound (9 g, 78.8%) as a yellow oil. 1H NMR (400 MHz, CDCI3) 5: 7.33 - 7.31 (m, 1H), 6.95 (dd, 1H), 2.56 - 2.53 (m, 3H).Step 2: Synthesis of 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde

[0143] To a solution of the compound from step 1 (5 g, 19.5 mmol) in THF (85 mL) was added LDA (2 M in THF, 19.45 mL) under N2 at -65 °C and the mixture was stirred for 0.5 h. DMF (4.27 g, 58.4 mmol) was added dropwise at -65 °C and the reaction mixture was stirred for 1 h. The reaction was quenched with NH4CI (50 mL) at 0 °C and then extracted withEtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0 to 50% EtOAc / PE gradient, to give the title compound (3.3 g, 59.5%) as a yellow oil. 1H NMR (400 MHz, CDC13) 8: 10.35 (s, 1H), 7.08 (d, 1H), 2.64 - 2.60 (m, 3H).Step 3: Synthesis of 4-bromo-6-methyl-5-(trijluoromethyl)-lH-indazole

[0144] To a solution of the compound from step 2 (5 g, 17.5 mmol) in DMSO (50 mL) was added NH2NH2.H2O (17.56 g, 17.0 mL) and the reaction mixture was stirred at 60 °C for 2 h. The pH of the reaction mixture was adjusted to 7 using IM HC1, the mixture diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (4.6 g, crude) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 10.99 (br s, 1H), 8.19 (s, 1H), 7.31 (s, 1H), 2.66 - 2.63 (m, 3H).Step 4: Synthesis of 4-bromo-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-lH- indazole

[0145] To a solution of the compound from step 3 (4.6 g, 16.48 mmol) in DCM (100 mL) was added TsOH (567.7 mg, 3.30 mmol), followed by DEEP (5.55 g, 65.94 mmol) in MeCN (20 mL) and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0 to 50% EtOAc / PE gradient to give the title compound (5 g, 83.5%) as a yellow oil. 1H NMR (400 MHz, CDCI3) 6: 8.11 (s, 1H), 7.43 (s, 1H), 5.69 (dd, 1H), 4.03 - 3.99 (m, 1H), 3.79 - 3.72 (m, 1H), 2.71 - 2.65 (m, 3H), 2.56 - 2.47 (m, 1H), 2.19 - 2.07 (m, 2H), 1.81 - 1.67 (m, 3H).Step 5: Synthesis of 6-methyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)-lH-indazole

[0146] To a solution of the compound from step 4 (4.5 g, 12.4 mmol) and bis(pinacolato)diboron (18.88 g, 74.3 mmol) in dioxane (45 mL) was added Pd(dppf)C12.DCM (1.01 g, 1.24 mmol) and KO Ac (4.86 g, 49.6 mmol) and the reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0-60% EtOAc / PE gradient to give the title compound (1.9 g, 36.7%) as a white solid. 1H NMR (400 MHz, CDCI3) 6: 8.06 (s, 1H), 7.49 (s, 1H), 5.72 (dd, 1H), 3.98 (d, 1H), 3.77 - 3.71 (m, 1H), 2.62 (s, 3H), 2.57 -2.48 (m, 1H), 2.18 - 2.15 (m, 1H), 2.08 - 2.04 (m, 1H), 1.80 - 1.66 (m, 3H), 1.45 (s, 12H), 1.27 (s, 1H).Synthesis of 6-chloro-5-cyclopropyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole (Intermediate 4)Step 1: Synthesis of 4-bromo-6-chloro-5-cyclopropyl-l-(oxan-2-yl)indazole

[0147] A mixture of 4-bromo-6-chloro-5-iodo-l-(oxan-2-yl)indazole (2 g, 4.53 mmol), cyclopropylboronic acid (467 mg, 5.44 mmol), K3PO4 (2.88 g, 13.59 mmol) and Pd(dppf)C12.CH2C12 (739.9 mg, 0.91 mmol) in dioxane (15 mL) and water (5 mL) was stirred at 100°C for 2 h under N2. The mixture was cooled to rt and diluted with water. The resulting mixture was extracted with EtOAc (3 x 50mL), the combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous ISfeSCU, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PEZEtOAc (1 :5) to afford the title compound (0.52 g, 32.3%) as a white solid. LCMS m / z = 357 [M+H]+Step 2: Synthesis of 6-chloro-5-cyclopropyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-lH-indazole

[0148] A mixture of the title compound from step 1 (0.38 g, 1.068 mmol), bis(pinacolato)diboron (325.6 mg, 1.28 mmol), KOAc (314.6 mg, 3.20 mmol) and Pd(dppf)C12.DCM (87.25 mg, 0.107 mmol) in dioxane (5 mL) was stirred at 100°C for 2h under N2. The cooled reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc:hexanes (1 :5) to afford the title compound (0.1 g, 23.24%) as a colorless oil. LCMS m / z = 403 [M+H]+Synthesis of (5aS)-14-benzyl-8-((tert-butyldiphenylsilyl)oxy)-2-chloro-l-fluoro- 5a,6,7,8,9,10-hexahydro-5H-azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin- 13(14H)-one (Intermediate 5) and(8aS)-3-benzyl-ll-((tert-butyldiphenylsilyl)oxy)-5-chloro-4-fluoro-8a,9,10,ll,12,13- hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-2(3H)-oneStep 1: Synthesis of 1 -(tert-butyl) 2-methyl (2S)-5-((tert-butyldiphenylsilyl)oxy)azepane-l,2- dicarboxylate

[0149] Imidazole (3.19 g, 46.8 mmol) and TBDPS-C1 (6.68 mL, 25.8 mmol) were added to a solution of 1 -(tert-butyl) 2-methyl (2S)-5-hydroxyazepane-l,2-dicarboxylate (Compound S9, US2018179186) (6.4 g, 23.42 mmol) in DMF (60 mL) and the reaction mixture was stirred for 16 h at rt. The reaction mixture was concentrated in vacuo and the crude was purified by reverse-phase chromatography [column: Redisep Rf Gold ® reversed-phase C18-teledyne ISCO 150 g) using a gradient of 0-100% MeCN to afford the title compound (8 g, 66.6 %) as a pale-yellow liquid. LCMS m / z = 412 [M+H]+Step 2: Synthesis of tert-butyl (2S)-5-((tert-butyldiphenylsilyl)oxy)-2- (hydroxymethyl)azepane-l -carboxylate

[0150] LiAllH (IM in THF, 23.45 ml, 46.9 mmol) was added drop wise over 5 min to a solution of the title compound from step 1 (8 g, 15.63 mmol) in THF (160 mL) at 0 °C and the reaction mixture was stirred at 0°C for 1 h. The reaction was quenched with MeOH (10 mL) at 0 °C, the resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 50 mL). The filtrate was concentrated in vacuo and the crude was purified by reverse-phase chromatography [column: Redisep Rf Gold ® reversed-phase C18-teledyne ISCO 150 g)using a gradient of 0-100% MeCN to afford the title compound (6 g, 79 %) as a pale yellow liquid. LCMS m / z = 384 [M+H]+Step 3: Synthesis of tert-butyl (2S)-2-(((l-benzyl-7-chloro-8-fluoro-4-hydroxy-2-oxo-l,2- dihydro-1, 6-naphthyridin-5-yl)oxy)methyl)-5-( tert-butyldiphenylsilyl)oxy)azepane-l- carboxylate

[0151] NaH (0.75 g, 18.61 mmol) was added to a solution of the title compound from step 2 (3 g, 6.20 mmol) in THF (60 mL) at 0 °C and the mixture stirred for 30 min. Intermediate 1 (2.31 g, 6.82 mmol) was added at 0 °C and the reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with NH4CI (2 mL) and extracted into EtOAc (3 x 100 mL). The combined organic layer was dried over Na2SC>4, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexane to afford the title compound (2.6 g, 45.6 %) as a light yellow solid. LCMS m / z = 788 [M+H]+Step 4: Synthesis of l-benzyl-5-(((2S)-5-((tert-butyldiphenylsilyl)oxy)azepan-2-yl)methoxy)-7- chloro-8-fluoro-4-hydroxy-l , 6-naphthyridin-2( lH)-one

[0152] TFA (2.53 mL, 33.1 mmol) was added to a solution of the title compound from step 3 (2.6 g, 3.31 mmol) in DCM (30 mL) at 0 °C and the reaction mixture was stirred at 60 °C for 2 h. The mixture was concentrated in vacuo. The crude was triturated with n-pentane twice and used without further purification. LCMS m / z = 686 [M+H]+Step 5: Synthesis of (5aS)-14-benzyl-8-((tert-butyldiphenylsilyl)oxy)-2-chloro-l-fluoro- 5a, 6, 7, 8, 9, 10-hexahydro-5H-azepino [ 2',1':3,4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 naphthyridin- 13(14H)-one

[0153] DIEA (3.30 mL 18.94 mmol) was added to a solution of the title compound from step 4 (2.6 g, 3.79 mmol) in DCM (25 mL) at rt. PyBOP (2.96 g, 5.68 mmol) was added slowly at 0 °C and the reaction mixture was stirred at rt for 3 h and at 50 °C for 16 h. The residue was purified by reverse-phase flash chromatography [column, Cl 8 silica gel: mobile phase, MeCN in water, 80% to 100% gradient in 20 min] to afford the title compound (1.4 g, 47.9 %) as pale yellow solid. LCMS m / z = 669 [M+H]+Synthesis of (8aS,llS)-3-benzyl-ll-((tert-butyldiphenylsilyl)oxy)-4-fluoro-5-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-8a,9,10,ll,12,13-hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-2(3H)-one(Intermediate 6) and (8aS,l lR)-3-benzyl-ll-((tert-butyldiphenylsilyl)oxy)-4-fluoro-5-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-8a,9,10,ll,12,13- hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-2(3H)-oneIntermediate 6 Intermediate 7

[0154] A mixture of Intermediate 5 (700 mg, 1.05 mmol), ((2-fluoro-6-(methoxymethoxy)- 8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (1.074 g, 2.1 mmol) and K3PO4 (667 mg, 3.14 mmol) in dioxane (8 mL) and water (2 mL) was degassed with N2 gas for 5 min. CataCXium® A Pd G3 (76 mg, 0.11 mmol) was added and the reaction mixture was stirred at 120 °C for 2 h under microwave irradiation. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography, using a gradient of 0-100% EtOAc in hexanes, to afford Peak 1, Intermediate 6 (330 mg, 0.272 mmol) and Peak 2, Intermediate 7 (450 mg, 0.39 mmol) as a pale yellow solid.Peak 1, Intermediate 6: LCMS m / z = 1019 [M+H]+Peak 2, Intermediate 7: LCMS m / z = 1019 [M+H]+Example la: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,10,ll,12,13-hexahydro-8H- azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-5-yl)naphthalen-2-ol (Compound 101)Step 1: Synthesis of tert-butyl 2-(((l-benzyl-7 -chlor o-8-fluoro-4-hydr oxy-2-oxo-l, 2-dihydro- l,6-naphthyridin-5-yl)oxy)methyl)azepane-l-carboxylate

[0155] To a solution of Intermediate 1 (1.6 g, 1.77 mmol) and tert-butyl 2- (hydroxymethyl)azepane-l -carboxylate (2.5 g, 2.12 mmol) in THF (10 mL) was added IM NaHMDS in THF (5.31 mL, 5.31 mmol) at 0 °C under N2. The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with sat. NH4CI (20 mL) and was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous ISfeSCU, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexanes / EtOAc (23:2) to afford the title compound (3.41 g, 35.1%) as a yellow solid. LCMS m / z = 530 [M+H]+.

[0156] To a solution of tert-butyl 2-(((l-benzyl-7-chloro-8-fluoro-4-hydroxy-2-oxo-l,2- dihydro-l,6-naphthyridin-5-yl)oxy)methyl)azepane-l-carboxylate (3.21 g, 0.34 mmol) in DCM (5 mL) was added TFA (0.15 mL, 1.97 mmol) at 0 °C under N2. The reaction mixture was stirred at rt for 16 h. The reaction was concentrated in vacuo. The residue was triturated with n-pentane (3 x 10 mL) and dried to give the title compound (4.2 g, 72.6%) as a yellow solid. LCMS m / z = 432 [M+H]+.Step 3: Synthesis of 3-benzyl-5-chloro-4-i\uovo-8a,9, 1 , 1 l,12,13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0157] To a solution of 5-(azepan-2-ylmethoxy)-l-benzyl-7-chloro-8-fluoro-4-hydroxy-l,6- naphthyridin-2(lH)-one (4.17 g, 0.39 mmol) in DCM / THF (10 mL, v / v = 1 : 1) was added DIPEA (0.21 mL, 1.18 mmol) and PyBOP (512 mg, 0.98 mmol) at rt under N2. The reaction mixture was stirred at rt for 16 h and then 60 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexanes, 3:7) to afford the title compound (80 mg, 47.6%) as a yellow solid. LCMS m / z = 414 [M+H]+.Step 4: Synthesis of 3-benzyl-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-8a,9, 10,11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0158] A mixture of 3-benzyl-5-chloro-4-fluoro-8a,9,10,l l,12,13-hexahydro-8H- azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-2(3H)-one (80 mg, 0.19 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen- l-yl)ethynyl)triisopropylsilane (198 mg, 0.39 mmol), K3PO4 (123 mg, 0.58 mmol), and cataCXium-A-Pd-G3 (14.1 mg, 0.02 mmol) in dioxane / H2O (3 mL, v / v = 4: 1) was stirred at 100°C under N2 for 2 h. The cooled reaction mixture was extracted with EtOAc (20 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexanes, 1 : 1) to give the title compound (100 mg, 60.8%) as a yellow solid. LCMS m / z = 764 [M+H]+.Step 5: Synthesis of 4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-8a,9, 10,11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0159] A solution of 3-benzyl-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen- 1 -yl)-8a,9, 10, 11 , 12, 13 -hexahydro-8H- azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-2(3H)-one (100 mg, 0.13 mmol) in MeOH (5 mL) was sparged with N2 for 2 min and 10% Pd(OH)2 (55.1 mg, 0.04 mmol)was added under N2. The reaction mixture was stirred under H2 at rt for 3 h. The mixture was filtered, and the filter cake was washed with MeOH / DCM (2 x 10 mL, v / v = 1 :9). The filtrate was concentrated in vacuo to afford the title compound (75 mg, 48.5%) as a brown solid. LCMS m / z = 674 [M+H]+.Step 6: Synthesis of 4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-8a, 9, 10,11, 12, 13-hexahydro-8H-azepino[2', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7- de ][ 1, 6 ] naphthyr idine

[0160] To a solution of 4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen- 1 -yl)-8a,9, 10, 11 , 12, 13 -hexahydro-8H- azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-2(3H)-one (75 mg, 0.11 mmol) in toluene (5 mL) was added ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (35.4 mg, 0.22 mmol) followed by cyanomethylenetributylphosphorane (81 mg, 0.33 mmol) at rt under N2. The resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 x 15 mL), and the combined organic layers were dried over anhydrous ISfeSCU, filtered and concentrated in vacuo to give the title compound (100 mg, 49.6%) as an orange oil. LCMS m / z = 815 [M+H]+Step 7: Synthesis of 6-fluoro-4-(4-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-8a, 9, 10,11, 12, 13-hexahydro-8H-azepino[2', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7- de] [ 1 ,6]naphthyridin-5-yl)-5-((\.mso^m^y\s \y\)ethynyl)naphthalen-2-ol

[0161] To a solution of 4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen- 1 -yl)-2-(((2R,7aS)-2-fluorotetrahydro- IH-pyrrolizin- 7a(5H)-yl)methoxy)-8a,9,10,l l,12,13-hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7- de][l,6]naphthyridine (100 mg, 0.12 mmol) in dioxane (3 mL) was added 1.25 N HC1 in MeOH (1.96 mL, 2.45 mmol) at rt under N2. The reaction mixture was stirred at rt for 6 h. To the mixture was added TEA (0.5 mL) and the resulting mixture was concentrated in vacuo to afford the title compound (100 mg, 51.6%) as an orange solid. LCMS m / z = 771 [M+H]+.Step 8: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-8a, 9,10, 11, 12, 13-hexahydro-8H- az epino [ 2 ', 1 3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ] naphthyr idin-5-yl)naphthalen-2-ol

[0162] To a solution of 6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-8a,9,10,l l,12,13-hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7- de][l,6]naphthyridin-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (100 mg, 0.13 mmol) in DMF (5 mL) was added CsF (394 mg, 2.59 mmol) at rt under N2. The reaction mixturewas stirred at 80 °C for 16 h. The cooled reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Method A, 0% to 100% B in 12.5 min) to afford the title compound (7.6 mg, 9.07%) as a white solid. LCMS m / z = 615 [M+H]+. ‘HNMR (400 MHz, DMSO-t / e): 8 10.13 - 10.11 (m, 1H), 7.97 - 7.93 (m, 1H), 7.47 - 7.42 (m, 1H), 7.36 (d, J = 2.40 Hz, 1H), 7.20 - 7.14 (m, 1H), 6.11 - 5.96 (m, 1H), 5.35 - 5.30 (m, 1H), 4.43 - 4.38 (m, 2H), 4.19 - 3.75 (m, 4H), 3.21 - 2.99 (m, 5H), 2.84 - 2.75 (m, 2H), 2.15 - 1.89 (m, 2H), 1.99 - 1.65 (m, 8H), 1.53 - 1.19 (m, 3H). Note: an N-linked set of diastereomers were also formed along with the title Compound 101 in Step 6 and separated in Step 8.Example lb: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,10,ll,12,13-hexahydro-8H- azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-5-yl)naphthalen-2-ol (Compound 101)

[0163] Step-1: Synthesis of 3-benzyl-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-8a,9, 10,11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0164] To a solution of Intermediate 2 (200 mg, 0.48 mmol) in dioxane (8 mL) and water (2 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (619 mg, 1.21 mmol), K3PO4 (308 mg, 1.45 mmol), the mixture was degassed with N2 for 2 min, then cataCXium® A Pd G3 (35.2 mg, 0.05 mmol) was added at rt. The reaction mixture was irradiated in the microwave at 100 °C for 2 h. The reaction was quenched with water (5 mL), extracted into EtOAc (2 x 20 mL), the organic layer dried over Na2SC>4, filtered and concentrated in vacuo. The crude was purified by silica-gel column chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (260 mg, 69.3 %) as a pale yellow solid. LCMS m / z = 764 [M+H]+

[0165] Step-2: Synthesis of 4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-8a,9, 10,11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0166] N2 was bubbled through a solution of the title compound from step 1 (260 mg, 0.34 mmol) in MeOH (10 mL) for 2 min, then Pd(OH)2 / C (20% loading, 143 mg, 1.02 mmol) was added. The reaction mixture was stirred under H2 (balloon) at rt for 2 h. The reaction mixture was filtered through a Celite® pad, washed with 10% MeOH / DCM (3 x 10 mL) and the filtrate was evaporated under reduced pressure to afford the title compound, crude 220 mg, as a pale yellow solid. LCMS m / z = 674 [M+H]+

[0167] Step 3: Synthesis of 4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-8a, 9, 10,11, 12, 13-hexahydro-8H-azepino[2', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7- de ][ 1, 6 ] naphthyr idine

[0168] To a solution of the title compound from step 2 (200 mg, 0.30 mmol) in toluene (5 mL) was added ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (142 mg, 0.89 mmol) followed by (tributylphosphoranylidene)acetonitrile (358 mg, 1.48 mmol) at rt under N2. The resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was quenched with water (5 mL), extracted into EtOAc (3 x 15 mL), the combined organic layerdried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound, crude, 240 mg. LCMS m / z = 815 [M+H]+

[0169] Step 4: Synthesis of 6-jluoro-4-(4-jluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-8a, 9,10, 11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ]naphthyridin-5-yl)-5-( ( triisopropylsilyl) ethynyl)naphthalen-2-ol

[0170] To a solution of the title compound from step 3 (250 mg, 0.31 mmol) in dioxane (3 mL) was added 1.25 M HC1 in MeOH (2.45 mL, 3.07 mmol) under N2 and the reaction mixture was stirred at 25 °C for 6 h. The reaction mixture was quenched with TEA (0.5 mL) and the mixture concentrated in vacuo to give the title compound, crude, 250 mg. LCMS m / z = 771 [M+H]+

[0171] Step 5: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-8a, 9,10, 11, 12, 13-hexahydro-8H- az epino [ 2 ', 1 3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ] naphthyr idin-5-yl)naphthalen-2-ol

[0172] To a solution of the title compound from step 4 (250 mg, 0.34 mmol) in DMF (5 mL) was added CsF (493 mg, 3.24 mmol) under N2 and the reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude compound was purified by prep-HPLC (Method A) to give Peak 1, the title compound (Compound 101), 18.5 mg, 9.2% as an off-white solid. LCMS m / z = 615 [M+H]+1H-NMR (400 MHz, DMSO-de): 8 10.09 (br s, 1H), 7.96 (dd, 1H), 7.45 (td, 1H), 7.36 (d, 1H), 7.19- 7.14 (m, 1H), 6.10 (d, 1H), 5.36-5.13 (m, 1H), 4.49-4.36 (m, 2H), 4.18-3.85 (m, 4H), 3.66- 3.49 (m, 1H), 3.12-2.99 (m, 4H), 2.87-2.76 (m, 1H), 2.15-1.98 (m, 5H), 1.89-1.63 (m, 9H).

[0173] Further elution provided Peak 2, 5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-4- fhioro-3-(((2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methyl)-8a, 9, 10,11,12,13- hexahydro-8H-azepino[2',r:3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-2(3H)-one 14 mg, 6.6 %) as an off white solid.Example 2: Synthesis of 5-ethynyl-6-fluoro-4-(7-fluoro-9-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-l-(2-hydroxyethyl)-2,3-dihydro-lH- [l,4]oxazepino[5,6,7-de] [l,6]naphthyridin-6-yl)naphthalen-2-ol (Compound 103)Step 1: Synthesis of l-benzyl-5-[2-({2-[(tert-butyldiphenylsilyl)oxy]ethyl}amino)ethoxy]-7- chloro-8-fluoro-4-hydroxy-l , 2-dihydro-l, 6-naphthyridin-2-one

[0174] To a solution ofNaH (60%, 106.14 mg, 2.655 mmol) in THF (5 mL) was added 2- ({2-[(tert-butyldiphenylsilyl)oxy]ethyl}amino)ethanol (303.89 mg, 0.885 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. To the mixture was added Intermediate 1 (300 mg, 0.885 mmol) in portions at 0 °C. The resulting mixture was stirred at rt for 4 h. The reaction was diluted with water and ice at 0 °C. The mixture was acidified to pH 2 with cone. HC1. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2CI2 / MeOH (21 :4) to afford the title compound (442 mg, 95%) as a brown solid. LCMS m / z = 646 [M+H]+.Step 2: Synthesis 8-benzyl-l-(2-(( t-butyldiphenylsilyl)oxy)ethyl)-6-chloro-7-jluoro-2,3- dihydro-lH-[ 1, 4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ] naphthyr idin-9(8H)-one

[0175] To a solution of l-benzyl-5-[2-({2-[(tert- butyldiphenylsilyl)oxy]ethyl}amino)ethoxy]-7-chloro-8-fluoro-4-hydroxy-l,6-naphthyridin- 2-one (440 mg, 0.681 mmol in THF (3 mL) was added TEA (206.70 mg, 2.043 mmol) at 0 °C followed by the addition of PyBOP (531.49 mg, 1.022 mmol) in portions at 0 °C. The resulting mixture was stirred at 80°C for 16 h. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (11 :9) to afford the title compound (112 mg, 13.09%) as a yellow oil. LCMS m / z = 628 [M+H]+.Step 3: Synthesis 8-benzyl-l-(2-((.Qd-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-6-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-l-yl)-2,3-dihydro-lH-[1.4 ]oxazepino[5, 6, 7 -de ][ 1 ,6]naphthyridin-9(8H)-one

[0176] To a solution of 8-benzyl-l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloro-7-fluoro- 2,3-dihydro-lH-[l,4]oxazepino[5,6,7-de][l,6]naphthyridin-9(8H)-one (479 mg, 0.762 mmol) in dioxane (5 mL) was treated with ((6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (952.82 mg, 1.524 mmol) and CataCXium-A-Pd-G3 (55.53 mg, 0.076 mmol) at rt followed by the addition of K2CO3 (316.13 mg, 2.286 mmol) and H2O (0.5 mL) in portions at rt. The resulting mixture was stirred at 100 °C for 8 h under N2. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3 : 1) to afford the title compound (110 mg, 10.58%) as a yellow solid. LCMS m / z = 1090 [M+H]+.Step 4: Synthesis of l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-jluoro-6-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-l-yl)-2,3-dihydro-lH-[1.4 ]oxazepino[5, 6, 7 -de ][ 1, 6 / naphthyridin-9-o /

[0177] To a solution of 8-benzyl-l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fhioro-6-(7- fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-l-yl)-2,3-dihydro- lH-[l,4]oxazepino[5,6,7-de][l,6]naphthyridin-9(8H)-one (100 mg, 0.092 mmol) in MeOH (10 mL) was added trifluoroacetic acid (0.5 mL, 0.004 mmol) and palladium hydroxide on carbon powder, anhydrous (5%, 128.76 mg, 0.920 mmol) at rt. The resulting mixture was stirred at rt for 2 h under H2 (5 Pa). The resulting mixture was filtered and the filter cake was washed with MeOH (4 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with EtOAc to afford the title compound (37 mg, 8.47%) as a yellow solid. LCMS m / z = 1002 [M+H]+.Step 5: l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-6-(7-jluoro-8- ((triisopropylsilyl)ethynyl)-3-((\.msci^m^y\s \y\)oxy)naphthalen-l-yl)-9-(((2R, 7aS)-2- jluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7- de ][ 1, 6 ] naphthyr idine

[0178] To a solution of l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-6-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-l-yl)-2,3-dihydro-lH-[1.4]oxazepino[5,6,7-de][l,6]naphthyridin-9-ol (30 mg, 0.030 mmol) in toluene (1 mL) was added with [(2R,7aS)-2-fluoro-hexahydro-lH-pyrrolizin-7a-yl]methanol (14.32 mg, 0.090 mmol) at rt followed by the addition of 2-(tributyl-lA[5]-phosphanylidene)acetonitrile (14.47mg, 0.060 mmol) dropwise at rt. The resulting mixture was stirred at 100°C for 16 h under N2. The cooled reaction mixture was diluted with EtOAc (10 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (EtOAc) to afford the title compound (20 mg, 11.68%) as a yellow solid. LCMS m / z = 1142 [M+H]+.Step 6: Synthesis of 5-ethynyl-6-jluoro-4-(7-fluoro-9-(((2R, 7aS)-2 -fluor otetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-l-(2-hydroxyethyl)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7- de ][ 1, 6 ]naphthyridin-6-yl)naphthalen-2-ol

[0179] To a solution of l-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-6-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-l-yl)-9-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-lH-[l,4]oxazepino[5,6,7- de][l,6]naphthyridine (10 mg, 0.009 mmol) in DMF (1 mL) was added CsF (26.61 mg, 0.180 mmol) at rt. The resulting mixture was stirred at 60°C for 30 min. The crude mixture was purified by Prep-HPLC (Method B, 12% to 100% B in 8 min) to afford the title compound (0.4 mg, 7.7%) as a white solid. LCMS m / z = 591 [M+H]+. 'H NMR (400 MHz, DMSO-t / 6) 5 10.12 (s, 1H), 8.21 (s, 1H), 8.03 - 7.82 (m, 1H), 7.47 - 7.44 (m, 1H), 7.34 (m, 1H), 7.14, (s, 1H), 7.11 (s, 1H), 6.80 - 6.67 (m, 1H), 6.12 (m, 1H), 5.75 (m, 1H), 5.33 - 5.21 (m, 2H), 4.97 (m, 1H), 4.48 (m, 2H), 4.11 (m, 2H), 4.09 (m, 2H),4.07 (m, 1H), 3.95 (m, 2H), 3.86 (m, 5H), 3.74 (m, 4H), 3.36 (m, 2H), 3.11 (m, 3H), 3.08 (m, 2H), 2.82 (m, 2H), 2.10 (m, 2H), 2.02 - 1.99 (m, 5H), 1.77 (m, 3H), 1.45 (m, 2H), 1.35 (m, 1H), 1.23 (m, 18H), 0.85 - 0.83 (m, 4H).Example 3: Synthesis of 5-ethyl-6-fluoro-4-(7-fluoro-9-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-l-(2-hydroxyethyl)-2,3-dihydro-lH-[l,4]oxazepino[5,6,7-de] [l,6]naphthyridin-6-yl)naphthalen-2-ol (Compound 106)Step 1: Synthesis of tert-butyl (2-((l-benzyl-7-chloro-8-fluoro-4-hydroxy-2-oxo-l,2-dihydro- l,6-naphthyridin-5-yl)oxy)ethyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate

[0180] To a solution of Intermediate 1 (500 mg, 1.47 mmol) in THF (10 mL) and DMF (2 mL) was added Intermediate 2 (707 mg, 2.21 mmol) followed by sodium bis(trimethylsilyl)amide (4.42 mL, 4.42 mmol) at 0°C under N2. The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with ice-cold water (5 mL), extracted with EtOAc (2 x 20 mL), and the organic layer was dried over JSfeSCU, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / hexanes (1 :4) to afford the title compound (300 mg, 24.20%) as a yellow oil. LCMS m / z = 622 [M+H]+.Step 2: Synthesis of l-\)Qnzy\-7-chloro-8-fhioro-4-hydroxy-5-(2-((2- hydroxyethyl)amino)ethoxy)-l, 6-naphthyridin-2( lH)-one

[0181] To a solution of tert-butyl (2-((l-benzyl-7-chloro-8-fluoro-4-hydroxy-2-oxo-l,2- dihydro-l,6-naphthyridin-5-yl)oxy)ethyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (400 mg, 0.64 mmol) in dioxane (15 mL) was added HC1 in MeOH (1.25 M, 5.14 mL, 6.43 mmol) at 0°C under N2. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure and co-distilled with toluene (10 mL) to afford the title compound (300 mg, 82%) as a brown oil. LCMS m / z = 408 [M+H]+.Step 3: Synthesis of l-benzyl-5-(2-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)ethoxy)-7- chloro-8-fluoro-4-hydroxy-l , 6-naphthyridin-2( lH)-one

[0182] To a solution of 1 -benzyl -7-chloro-8-fluoro-4-hydroxy-5-(2-((2- hydroxyethyl)amino)ethoxy)-l,6-naphthyridin-2(lH)-one (300 mg, 0.73 mmol) in DCM (5 mL) was added TBDMS-C1 (333 mg, 2.20 mmol) and imidazole (150 mg, 2.20 mmol) at 0°C. The resulting reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with MeOH / DCM (3: 17) to afford the title compound (190 mg, 45.4%) as a yellow liquid. LCMS m / z = 522 [M+H]+.Step 4: Synthesis of 8-benzyl-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloro-7-fluoro-2,3- dihydro-lH-[ 1, 4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ] naphthyr idin-9(8H)-one

[0183] To a solution of l-benzyl-5-(2-((2-((tert- butyldimethylsilyl)oxy)ethyl)amino)ethoxy)-7-chloro-8-fluoro-4-hydroxy-l,6-naphthyridin- 2(lH)-one (190 mg, 0.36 mmol) in THF (5 mL) was added TEA (0.25 mL, 1.82 mmol) and PyBOP (379 mg, 0.72 mmol) at rt. The resulting mixture was stirred at rt for 16 h then 60°C for 2 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with EtOAc / hexanes (7:3) to afford the title compound (40 mg, 18.47%) as a yellow oil. LCMS m / z = 504.2 [M+H]+.Step 5: Synthesis of 8-benzyl-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-7-fluoro-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7- de ][ 1, 6 ]naphthyridin-9(8H)-one

[0184] To a solution of 8-benzyl-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloro-7-fluoro- 2,3-dihydro-lH-[l,4]oxazepino[5,6,7-de][l,6]naphthyridin-9(8H)-one (30 mg, 0.06 mmol) in dioxane (1.5 mL) and H2O (0.4 mL) was added 2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (42.9 mg, 0.11 mmol) and K3PO4 (37.9 mg, 0.17 mmol). The reaction mixture was sparged with N2 for 2 min and CataCXium-A-Pd-G3 (4.33 mg, 5.95 pmol) was added at rt. The resulting reaction mixture was sparged with N2 for 2 min and irradiated in the microwave at 100 °C for 2 h. The cooled reaction mixture was diluted with EtOAc (10 mL), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / hexanes (7:3) to afford the title compound (30 mg, 0.03 mmol, 65.1%) as a yellow oil.LCMS m / z = 702 [M+H]+.Step 6: Synthesis of l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-7-jluoro-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7- de ][ 1, 6 ]naphthyridin-9(8H)-one

[0185] To a solution of 8-benzyl-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-l-yl)-7-fluoro-2,3-dihydro-lH-[l,4]oxazepino[5,6,7- de][l,6]naphthyridin-9(8H)-one (30 mg, 0.04 mmol) in MeOH (3 mL) was added palladium hydroxide on carbon (20%, 30 mg, 0.04 mmol) under N2. The reaction mixture was stirred under H2 at rt for 1 h. The reaction mixture was filtered through a celite bed and concentrated under reduced pressure to provide the title compound (30 mg, 115%) as a brown oil that was used directly in the next step. LCMS m / z = 612 [M+H]+.Step 7: Synthesis of l-(2-((X.Qd-butyldimethylsilyl)oxy)ethyl)-6-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-7-fluoro-9-( ( (2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7 -de ][ 1 f] naphthyr idine

[0186] To a solution of l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-7-fluoro-2,3-dihydro-lH-[l,4]oxazepino[5,6,7- de][l,6]naphthyridin-9(8H)-one (30 mg, 0.05 mmol) in toluene (1 mL) was added ((2A,7a5 - 2-fluorotetrahydro- IT / -pyrrolizin-7a(57 / )-yl)m ethanol (19.52 mg, 0.12 mmol) and cyanomethylenetributylphosphorane (36 mg, 0.15 mmol) at rt under N2. The reaction mixture was stirred at 100 °C for 16 h. The cooled reaction mixture was diluted with H2O (1 mL), extracted with EtOAc (3 x 5 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (30 mg) as a brown solid that was used directly in the next step. LCMS m / z = 753 [M+H]+.Step 8: Synthesis of 5-ethyl-6-fluoro-4-(7-fluoro-9-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-l-(2-hydroxyethyl)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7- de ][ 1, 6 ]naphthyridin-6-yl)naphthalen-2-ol

[0187] To a solution of l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-7-fluoro-9-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-2,3-dihydro-lH-[l,4]oxazepino[5,6,7-de][l,6]naphthyridine (30 mg, 0.04 mmol) in dioxane (2 mL) was added HC1 in MeOH (1.25 M, 0.3 mL, 0.39 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with TEA (4 mL) and concentrated under reduced pressure. The residue was purified by prep- HPLC (Method C, 0% to 63.5% B in 10.8 min) to afford the title compound (1.36 mg, 5.7%) as a white solid. LCMS m / z = 595 [M+H]+.1H-NMR (400 MHz, DMSO-< b 9.92 (Brs, 1H), 7.74 (dd, J= 6.00, 8.80 Hz, 1H), 7.36-7.29 (m, 2H), 7.02 (d, J= 2.40 Hz, 1H), 6.23 (s, 1H), 5.34-5.22 (m, 1H), 4.97 (brs, 1H), 4.50 (t, J= 4.40 Hz, 2H), 4.18-4.13 (m, 1H), 4.08-4.03 (m, 1H), 3.90-3.87 (m, 2H), 3.75-3.74 (m, 2H), 3.65 (d, J= 5.60 Hz, 2H), 3.12-3.02 (m, 3H), 2.83-2.82 (m, 1H), 2.41-2.37 (m, 1H), 2.30-2.02 (m, 4H), 1.85-1.76 (m, 2H), 1.60-1.42 (m, 1H), 0.79 (t, J= 7.60 Hz, 3H) ppm.Example 4: Synthesis of 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,10,ll,12,13-hexahydro-8H- azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-5-yl)naphthalen-2-ol (Compound 179)

[0188] Step 1: Synthesis of 3-benzyl-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l- yl)-4-jluoro-8a,9, 10,11, 12, 13-hexahydro-8H-azepino[2', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7- de] [1,6 ] naphthyr idin-2 ( 3H)-one

[0189] The title compound was obtained as an off-white solid, 290 mg, 94%, from Intermediate 2 and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane, following a similar procedure to that described in Example 1, step 1. LCMS m / z = 612 [M+H]+

[0190] Step 2: Synthesis of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4- fluoro-8a, 9,10, 11, 12, 13-hexahydro-8H-azepino[2', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7- de] [1,6 ] naphthyr idin-2 ( 3H)-one

[0191] The title compound was obtained as an off-white solid, 160 mg, 59%, from the title compound from step 1, following a similar procedure to that described in Example 1, step 2. LCMS m / z = 522 [M+H]+

[0192] Step 3: Synthesis of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4- fluoro-2-( (2R, 7aS)-2-fhiorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-8a, 9,10, 11, 12, 13- hexahydro-8H-azepino [ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 naphthyridine

[0193] The title compound was obtained as a brown gum, 170 mg, crude, from the title compound from step 2 and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)m ethanol, following a similar procedure to that described in Example 1, step 3. LCMS m / z = 663 [M+H]+

[0194] Step 4: Synthesis of 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R, 7aS)-2-f!uorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-8a, 9,10, 11, 12, 13-hexahydro-8H- az epino [ 2 ', 1 3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ] naphthyr idin-5-yl)naphthalen-2-ol

[0195] 1.25 M HC1 in MeOH (1.2 mL, 1.50 mmol) was added to a solution of the title compound from step 3 (0.2 g, 0.30 mmol) in dioxane (5 mL) at 0 °C and the reaction mixture was allowed to stir at rt for 16 h. The reaction was basified to pH 8-9, using trimethylamine and the mixture concentrated in vacuo. The crude compound was purified by prep-HPLC reverse phase purification [Column: X-select C18(150*19*5u), Mobile Phase-A: 0.1% formic acid in water, Mobile Phase-B: MeCN, using gradient 0 to 100 % MeCN, Flow rate: 16 mL / min) and the combined pure fraction was lyophilized to afford the title compound (3.7 mg, 1.9 %) as an off-white solid. LCMS m / z = 619 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): 8 9.87 (d, 1H), 7.76-7.73 (m, 1H), 7.37-7.29 (m, 2H), 7.07-6.99 (m, 1H), 6.15 (s, 1H), 5.39-5.26 (m, 1H), 4.50-4.41 (m, 2H), 4.38-3.95 (m, 4H), 3.29-2.79 (m, 5H), 2.31-1.99 (m, 5H), 1.95-1.45 (m, 10H), 1.35-1.15 (m, 1H), 0.95-0.65 (m, 3H) ppm.Example 5: Active KRAS G12D / CRAF RBD TR-FRET Binding Assay

[0196] The ability of compounds to inhibit activation of KRAS G12D (GMPPNP loaded) and its interaction with effector protein, CRAF, was measured using a TR-FRET assay. In a 10-pl final assay volume, 2.5 pL of biotinylated KRAS G12D and 2.5 pL FLAG-tagged CRAF-RBD were added to pre-dispensed compounds. The assay buffer consisted of 25 mM HEPES, pH 7.4, 0.002% Tween20, 0.1% BSA, 100 mM NaCl and 5 mM MgCh. Then, 1 nM Tb-anti-FLAG and 5 nM SA-XL665 were added to detect the interaction. After a 60-minuteincubation at room temperature, the reaction was measured in a plate reader using excitation and emission wavelengths of 340 nm and 620 / 665 nm, respectively. IC50 values were established using a four-parameter fit model. The results are shown in Table 2, where A is < 10 nM; B is > 10 nm and < 100 nM; C is > 100 nM and < 1000 nM; D is > 1000 nM and < 3000 nM; and E is > 3000 nM.Example 6: Synthesis of 4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-(6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl)-8a, 9, 10, 11,12,13- hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridine (Compound 180)

[0197] Step 1: Synthesis of 3-benzyl-4-fluoro-5-(6-methyl-l-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-lH-indazol-4-yl)-8a, 9,10, 11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0198] The title compound was obtained as a pale yellow solid, 170 mg, 68%, fromIntermediate 2 and Intermediate 3, following a similar procedure to that described in Example1, step 1. LCMS m / z = 662 [M+H]+

[0199] Step 2: Synthesis of 4-fluoro-5-(6-methyl-l-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-lH-indazol-4-yl)-8a, 9,10, 11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0200] The title compound was obtained as a pale yellow solid, 180 mg, 93%, from the title compound from step 1, following a similar procedure to that described in Example 1, step 2. LCMS m / z = 572 [M+H]+.

[0201] Step 3: Synthesis of 4-jluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)~ yl)methoxy)-5-( 6-methyl-l-( tetrahydro-2H-pyran-2-yl)-5-( trifluor omethyl)- lH-indazol-4-yl)- 8a, 9,10, 11, 12, 13-hexahydro-8H-azepino [2', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7- de ][ 1, 6 ] naphthyr idine

[0202] To a solution of the title compound from step 2 (160 mg, 0.28 mmol) in toluene (5 mL) were added ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (134 mg, 0.84 mmol) followed by (tributylphosphoranylidene)acetonitrile (338 mg, 1.40 mmol) under N2 and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with water (5 mL), extracted into EtOAc (3 x 20 ml), the combined organic layer was dried over Na2SO4 filtered and concentrated in vacuo. The crude was purified by silica- gel column chromatography using a gradient of 0-20% MeOH in DCM to afford the title compound (180 mg, 85 %) as an orange liquid. LCMS m / z = 714 [M+H]+

[0203] Step 4: Synthesis of 4-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-( 6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl)-8a, 9,10, 11, 12, 13-hexahydro- 8H-azepino[ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 naphthyridine

[0204] To a solution of the title compound from step 3 (180 mg, 0.25 mmol) in dioxane (3 mL) was added 1.25 M HC1 in MeOH (2.02 ml, 2.53 mmol) under N2 and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo and the crude compound was purified by prep-HPLC (Column: shimpack cl8(20*250)5um, using a gradient 0-100% 10 mM NH4HCO3: 100% MeCN Flow rate: 18 mL / min) to give Peak 1, 4- fluoro-3-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methyl)-5-(6-methyl-5- (trifhroromethyl)-lH-indazol-4-yl)-8a,9, 10,11, 12, 13-hexahydro-8H- azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-2(3H)-one (12 mg, 7.4 %) as an off-white solid. Further elution provided Peak 2, the title compound, 30 mg, 18.9 %, as an off-white solid. LCMS m / z = 629 [M+H]+1H-NMR (400 MHz, DMSO-d6): 8 13.45 (s, 1H), 7.75-7.64 (m, 2H), 6.13 (d, 1H), 5.35-5.21 (m, 1H), 4.46-4.40 (m, 2H), 4.18-3.88 (m, 4H), 3.65-3.52 (m, 1H), 3.14-2.97 (m, 3H), 2.87-2.78 (m, 1H), 2.65 (s, 3H), 2.16-1.92 (m, 4H), 1.88-1.62 (m, 8H), 1.56-1.43 (m, 1H), 1.35-1.26 (m, 1H).Example 7 and Example 8: (8aR)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-(6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl)- 8a,9,10,ll,12,13-hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7- de][l,6]naphthyridine (Compound 181); and (8aS)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-(6-methyl-5-(trifluoromethyl)- lH-indazol-4-yl)-8a,9,10,ll,12,13-hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7- de][l,6]naphthyridine (Compound 182)Compound 181 Compound 182

[0205] The title compound from Example 5 (22 mg, 0.035 mmol) was purified by SFC chiral purification (Column: LUX IA3 [250*30) mm, 5pm, Mobile Phase CO2: 0.5% isopropyl amine in MeCN:2-propanol [50:50], Gradient [CO2:Co-solvent]:[65:35], Total Flow: 100 mL / min) to give Peak 1, Example 6, Compound 181 (11.5 mg, 52.0 %) as an off- white solid. LCMS m / z = 629 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): 8 13.45 (br s, 1H), 7.70 (m, 2H), 6.14 (s, 1H), 5.29 (d, 1H), 4.51-4.40 (m, 2H), 4.19-3.88 (m, 4H), 3.65-3.52 (m, 1H), 3.18-2.97 (m, 3H), 2.87-2.78 (m, 1H), 2.65 (s, 3H), 2.16-1.95 (m, 4H), 1.92-1.62 (m, 8H), 1.56-1.43 (m, 1H), 1.35-1.28 (m, 1H).

[0206] And Peak 2, Example 7, Compound 182 (9 mg, 40.9 %) as an off-white solid. LCMS m / z = 629 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): 6 13.45 (br s, 1H), 7.76-7.64 (m, 2H), 6.14 (s, 1H), 5.35-5.21 (m, 1H), 4.51-4.40 (m, 2H), 4.19-3.88 (m, 4H), 3.65-3.52 (m, 1H), 3.18-2.97 (m, 3H), 2.87-2.78 (m, 1H), 2.65 (s, 3H), 2.16-1.95 (m, 4H), 1.92-1.62 (m, 8H), 1.56-1.43 (m, 1H), 1.35-1.28 (m, 1H).Example 9: Synthesis of 5-(6-chloro-5-cyclopropyl-lH-indazol-4-yl)-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,10,ll,12,13- hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridine (Compound 183)

[0207] Step 1: Synthesis of 3-benzyl-5-(6-chloro-5-cyclopropyl-l-(tetrahydro-2H-pyran-2- yl)-lH-indazol-4-yl)-4-f1uoro-8a,9, 10,11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0208] To a solution of Intermediate 2 (150 mg, 0.36 mmol) in dioxane (1.5 mL) and water (0.5 mL) were added Intermediate 4 (292 mg, 0.73 mmol) and K3PO4 (231 mg, 1.09 mmol) and the mixture was degassed with N2 for 5 min. CataCXium® A Pd G3 (26.4 mg, 0.04 mmol) was added and the reaction mixture was stirred at 110 °C for 1 h in a microwave. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (5 mL), dried over ISfeSCL, filtered and concentrated in vacuo. The crude was purified by reverse phase column chromatography [column: RediSep Gold, C18, 30 g column, mobile phase-A: 10 mM NH4HCO3 in water, mobile phase-B: MeCN, using a gradient 0 to 100 % MeCN, flow rate: 15 mL / min). The product containing fractions were lyophilized to afford the title compound (140 mg, 57.0 %) as an off-white solid. LCMS m / z = 654 [M+H]+.

[0209] Step 2: Synthesis of 5-(6-chloro-5-cyclopropyl-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-4-yl)-4-fluoro-8a,9, 10,11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0210] To a solution of the title compound from step 1 (140 mg, 0.214 mmol) in MeOH (5 mL) was added Pd(OH)2 / C (50% wet, 140 mg, 0.5 mmol) at 25 °C under N2. The resulting mixture was stirred under H2 balloon for 2 h. The reaction mixture was diluted with MeOH(10 mL), filtered through a pad of Celite® washing through with MeOH (3 x 5 mL). The filtrate was evaporated under reduced pressure to give the title compound (120 mg, 74.6 %) as an off-white solid. LCMS m / z = 564 [M+H]+

[0211] Step 3: Synthesis of 5-(6-chloro-5-cyclopropyl-l-(tetrahydro-2H-pyran-2-yl)-lH- indazol-4-yl)-4-jluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 8a, 9,10, 11, 12, 13-hexahydro-8H-azepino [2', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7- de ][ 1, 6 ] naphthyr idine

[0212] To a solution of the title compound from step 2 (120 mg, 0.23 mmol) in toluene (5 mL) were added ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (180 mg, 1.13 mmol) and (tributylphosphoranylidene)acetonitrile (547 mg, 2.27 mmol) at rt under N2. The reaction mixture was heated at 120 °C for 6 h. The reaction mixture was cooled to rt and poured into water (5 mL). The aqueous layer was extracted with EtOAc (2x 5 mL), the combined organic layer was dried over anhydrous ISfeSCU and filtered. The filtrate was concentrated in vacuo and the crude was purified by reverse phase column chromatography (Column: RediSep Gold, C18 60 g column, mobile phase A: 10 mM NH4HCO3 in water, mobile phase-B: MeCN, using a gradient 0 to 100 % MeCN, flow rate: 15 mL / min) and the pure fractions were lyophilized to afford the title compound (75 mg, 34.5 %) as an off white solid. LCMS m / z = 706 [M+H]+

[0213] Step 4: Synthesis of 5-(6-chloro-5-cyclopropyl-lH-indazol-4-yl)-4-fluoro-2- ( ((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-8a, 9,10,11, 12, 13- hexahydro-8H-azepino [ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 naphthyridine

[0214] To a solution of the title compound from step 3 (75 mg, 0.11 mmol) in DCM (2.5 mL) was added trifluoromethanesulfonic acid (160 mg, 1.06 mmol) at 0 °C and the reaction mixture was stirred for 30 min at rt. The reaction mixture was basified (pH ~8-9) using saturated NaHCCL solution (5 mL) and extracted with 10% MeOH in DCM (3 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over ISfeSCU and filtered. The filtrate was concentrated in vacuo and the crude was purified by preparative HPLC (Method A). The pure fractions were lyophilized to afford the title compound (14 mg, 20.9 %) as an off white solid. LCMS m / z = 621 [M+H]+1H-NMR (400 MHz, DMSO-d6): 8 13.22 (s, 1H), 7.84-7.75 (m, 2H), 6.13 (s, 1H), 5.35-5.21 (m, 1H), 4.46-4.42 (m, 2H), 4.17-3.91 (m, 4H),3.59-3.54 (m, 1H), 3.11-3.01 (m, 3H), 2.83-2.81 (m, 1H), 2.10-1.66 (m, 13H), 1.55-1.42 (m, 1H), 1.36-1.18 (m, 1H), 0.90-0.71 (m, 1H), 0.66-0.51 (m, 1H), 0.13-0.11 (m, 2H).Example 10 and Example 11: (8aR)-5-(6-chloro-5-cyclopropyl-lH-indazol-4-yl)-4- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 8a,9,10,ll,12,13-hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7- de][l,6]naphthyridine (Compound 184), and (8aS)-5-(6-chloro-5-cyclopropyl-lH- indazol-4-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-8a,9,10,ll,12,13-hexahydro-8H-azepino[2',l':3,4][l,4]oxazepino[5,6,7- de][l,6]naphthyridine (Compound 185)Compound 184 Compound 185

[0215] Example 8, Compound 183, (8 mg, 0.013 mmol) was separated using chiral SFC (column: I-Amylose-A [250*30) mm, 5pm; mobile phase: CO2 : 0.5% Isopropyl amine in IPA: MeCN Gradient [CO2: Co-solvent]: (70:30), co-solvent: MeOH at Flow rate: 120 mL / min, to give Peak 1 (Compound 184) 2.85 mg, 35.4 % as an off white solid. LCMS m / z = 621 [M+H]+1H-NMR (400 MHz, DMSO-d6): 8 13.20 (s, 1H), 7.84-7.75 (m, 2H), 6.14 (s, 1H), 5.35-5.21 (m, 1H), 4.47-4.42 (m, 2H), 4.18-3.92 (m, 4H), 3.59-3.57 (m, 1H), 3.11-3.01 (m, 3H), 2.83-2.81 (m, 1H), 2.10-1.50 (m, 13H), 1.57-1.42 (m, 1H), 1.36-1.18 (m, 1H), 0.91- 0.70 (m, 1H), 0.61-0.50 (m, 1H), 0.13-0.11 (m, 2H). And Peak 2 (Compound 185) 2.72 mg, 33.6 %) as an off white solid. LCMS m / z = 621 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): 6 13.21 (s, 1H), 7.84-7.75 (m, 2H), 6.14 (s, 1H), 5.36-5.22 (m, 1H), 4.52-4.39 (m, 2H), 4.20- 3.92 (m, 4H), 3.65-3.51 (m, 1H), 3.12-3.02 (m, 3H), 2.84-2.82 (m, 1H), 2.11-1.60 (m, 13H), 1.49-1.47 (m, 1H), 1.36-1.19 (m, 1H), 0.91-0.70 (m, 1H), 0.68-0.50 (m, 1H), 0.24-0.01 (m, 2H).Example 12: Synthesis of (5aS)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-l-yl)-l-fluoro- 13-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10- hexahydro-5H-azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-8-ol (Compound 186)

[0216] Step 1: Synthesis of (8aS)-3-benzyl-l 1 -((tert-butyldiphenylsilyl)oxy)-5-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4-fluoro-8a, 9,10, 11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0217] The title compound was obtained as an orange gum, 110 mg, 54.5%, from Intermediate 5 and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane, following a similar procedure to that described in Example 4, step 1. LCMS m / z = 866 [M+H]+

[0218] Step 2: Synthesis of (8aS)-ll-((tert-butyldiphenylsilyl)oxy)-5-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-4-fluoro-8a,9, 10, 11, 12, 13-hexahydro-8H- azepino[ 2 ', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0219] 20% Pd(OH)2 on carbon (32.4 mg, 0.23 mmol) was added to a solution of the title compound from step 1 (100 mg, 0.12 mmol) in MeOH (3 mL) and THF (2 mL) under N2. The reaction was stirred at rt under H2 balloon pressure for 6 h. The reaction mixture was filtered and washed with 10% MeOH in DCM (5 x 10 mL). The filtrate was evaporated under reduced pressure to afford the title compound (90 mg, 53.6 % yield) as a brown gum. LCMS m / z = 776 [M+H]+

[0220] Step 3: Synthesis of (8aS)-l l-((tert-butyldiphenylsilyl)oxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4-fluoro-2-( ( (2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8a, 9, 10,11, 12, 13-hexahydro-8H-azepino[2', 1 ':3, 4] [1,4 ]oxazepino[5, 6, 7- de ][ 1, 6 ] naphthyr idine

[0221] Into a 20 ml pressure vial containing a well-stirred solution of the title compound from step 2 (90 mg, 0.11 mmol) in toluene (3 mL) was added ((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methanol (5, 55.4 mg, 0.35 mmol) followed by (tributylphosphoranylidene)acetonitrile (140 mg, 0.580 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with water (5 mL) extracted into ethyl acetate (3 x 10 mL), organic layer dried over Na2SO4, filtered and concentrated under reduced pressure to get crude, which was purified by silica gel column chromatography (230-400 mesh) using a gradient of 0-20% methanol in DCM desired product was eluted at 7-8% methanol in DCM to afford the title compound (110 mg, 66.3 %) as an orange liquid. LCMS m / z = 917 [M+H]+.

[0222] Step 4: Synthesis of (5aS)-2-(8-ethyl-7-jluoro-3-hydroxynaphthalen-l-yl)-l-jluoro- 13-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5a,6, 7,8,9,10- hexahydro-5H-azepino [ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ]naphthyridin-8-ol

[0223] Into a 25 mL single neck RBF containing a well-stirred solution of the title compound from step 3 (100 mg, 0.11 mmol) in dioxane (3 mL) was added 1.25 M HC1 in MeOH (0.87 ml, 1.09 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure to get a crude compound. The crude compound was purified by prep-HPLC (Method: X-SELECTC18(150*19MM)5um, Mobile phase-A: 10 mm ammonium bicarbonate in water, Mobile phase-B: 100 % acetonitrile, using a gradient of 0 to 100 % acetonitrile, Flow rate: 16 ml / min, RT-14.5 min. The combined pure fraction was lyophilized to afford the title compound (2 mg, 2.8 %) as an off-white solid. LCMS m / z = 635 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): 8 9.94 (br s, 1H), 7.76-7.72 (m, 1H), 7.38- 7.26 (m, 2H), 7.02 (dd, 1H), 6.15 (d, 1H), 5.19-2.35 (m, 1H), 4.76 (t, 1H), 4.48-4.31 (m, 2H), 4.20-4.11 (m, 1H), 4.08-3.95 (m, 2H), 3.85-3.71 (m, 2H), 3.54-3.48 (m, 2H), 3.13-2.96 (m, 4H), 2.88-2.74 (m, 1H), 2.28-1.94 (m, 6H), 1.88-1.67 (m, 6H), 0.84-0.68 (m, 3H).Example 13: Synthesis of (5aS,8R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-l- fluoro-13-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-8-0I (Compound 187)

[0224] Step 1: Synthesis of (8aS,llR)-ll-((tert-butyldiphenylsilyl)oxy)-4-fluoro-5-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-8a,9, 10, 11 , 12, 13- hexahydro-8H-azepino [ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0225] A solution of Intermediate 7 (450 mg, 0.44 mmol) in a mixture of THF (4.5 mL) and MeOH (4.5 mL) was degassed with N2 gas for 2 min. Pd(OH)2 / C (20% dry basis, 310 mg, 0.44 mmol) was added and the reaction mixture was stirred at 25 °C for 9 h under H2 balloon. The reaction mixture was filtered through Celite® and washed with 10% MeOH / DCM (3 x 20 mL). The filtrate was concentrated in vacuo and the crude was purified by column chromatography on silica gel eluting with 0-100% EtOAc in hexane to afford the title compound (150 mg, 29 %) as pale yellow solid. LCMS m / z = 928 [M+H]+.

[0226] Step 2: Synthesis of (8aS, 11R)-1 l-((tert-butyldiphenylsilyl)oxy)-4-fluoro-5-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8a, 9,10, 11, 12, 13-hexahydro-8H- az epino [ 2 ', 1 3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ] naphthyr idine

[0227] The title compound was obtained as a brown oil, 220 mg, 92%, from the title compound from step 1 and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)m ethanol, following a similar procedure to that described in Example 5, step 3. LCMS m / z = 1070 [M+H]+

[0228] Step 3: Synthesis of 4-((8aS,l 1R)-1 l-((tert-butyldiphenylsilyl)oxy)-4-fluoro-2- ( ((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-8a, 9,10,11, 12, 13- hexahydro-8H-azepino [ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ] naphthyr idin-5-yl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0229] The title compound was obtained, 110 mg, crude from the title compound from step 2, following a similar procedure to that described in Example 1, step 4. LCMS m / z = 1029 [M+H]+

[0230] Step 4: Synthesis of (5aS,8R)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-l- fluoro-13-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5a, 6, 7,8,9, 10- hexahydro-5H-azepino [ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ]naphthyridin-8-ol

[0231] To a solution of the title compound from step 3 (110 mg, 0.140 mmol) in DMF (5 mL) was added CsF (425 mg, 2.80 mmol) and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was dissolved in MeCN (5 mL) and 4M HCl / dioxane (1 mL) was added at 0 °C. The resulting reaction mixture was stirred for 1 h at 25 °C. The pH of the reaction mixture was adjusted to ~7 with TEA, diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude compound was purified by prep-HPLC (Method A), to give Peak 1, (5aS,8R)-2-(8-ethynyl-7- fluoro-3 -hydroxynaphthalen- 1 -y 1)- 1 -fluoro- 14-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methyl)-8-hydroxy-5a,6,7,8,9,10-hexahydro-5H- azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-13(14H)-one (2.7 mg, 3.0 %) as off white solid and Peak 2, the title compound (8.8 mg, 9.7 %) as an off-white solid. LCMS m / z = 632 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): 8 10.09-10.05 (m, 1H), 7.96 (q, 1H), 7.48-7.43 (m, 1H), 7.36 (d, 1H), 7.19-7.15 (m, 1H), 6.16-6.01 (m, 1H), 5.39-5.18 (m, 1H), 4.71-4.68 (m, 1H), 4.39-4.31 (m, 2H), 4.20-3.92 (m, 3H), 3.73-3.61 (m, 4H), 3.33-3.03 (m, 3H), 2.87-2.79 (m, 2H), 2.13-2.02 (m, 3H), 1.83-1.60 (m, 8H).Example 14: Synthesis of (5aS,8S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-l- fluoro-13-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-azepino[2',l':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-8-ol formate (Compound 188)

[0232] Step 1: Synthesis of (8aS,llS)-ll-((tert-butyldiphenylsilyl)oxy)-4-fluoro-5-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-8a,9, 10, 11 , 12, 13- hexahydro-8H-azepino [ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ]naphthyridin-2(3H)-one

[0233] The title compound was obtained as a pale yellow solid, 120 mg, 33.6%, from Intermediate 6, following a similar procedure to that described in Example 12, step 1. LCMS m / z = 929 [M+H]+

[0234] Step 2: Synthesis of (8aS, 11S)-1 l-((tert-butyldiphenylsilyl)oxy)-4-fluoro-5-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8a, 9,10, 11, 12, 13-hexahydro-8H- az epino [ 2 ', 1 3, 4] [1,4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ] naphthyr idine

[0235] The title compound was obtained as an oil, 180 mg, 86%, from the title compound from step 1 and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol, following a similar procedure to that described in Example 12, step 2. LCMS m / z = 1070 [M+H]+

[0236] Step 3: Synthesis of 4-((8aS,l 1S)-1 l-((tert-butyldiphenylsilyl)oxy)-4-fluoro-2-( ((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-8a, 9,10,11, 12, 13- hexahydro-8H-azepino [ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ] naphthyr idin-5-yl)-6-fluor o-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0237] 4 M HC1 in dioxane (0.56 mL, 2.24 mmol) was added to a solution of the title compound from step 2 (160 mg, 0.150 mmol) in MeCN (3.2 mL) at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. The pH of the mixture was adjusted to 7 with TEA and the solution was evaporated under reduced pressure to afford the title compound (110 mg, 54.1 %) as pale brown solid. LCMS m / z = 1026 [M+H]+.

[0238] Step 4: Synthesis of (5aS,8S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-l- fluoro-13-(((2R, 7aS)-2-jluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5a, 6, 7,8,9, 10- hexahydro-5H-azepino [ 2 ', 1 3, 4] [1,4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ]naphthyridin-8-ol formate

[0239] To a solution of the title compound from step 3 (110 mg, 0.107 mmol) in DMF (5 mL) was added CsF (326 mg, 2.15 mmol) and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude compound was purified by prep- HPLC [column: XTIMATE C18(250*22)5UM, Mobile Phase-A: 10 mM in NH4HCO3 in water, Mobile Phase-B: MeCN using gradient 0 to 100 % MeCN, Flow rate: 16 mL / min, to give Peak 1, ((5aS,8S)-2-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-l-fluoro-14- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methyl)-8-hydroxy-5a,6,7,8,9,10- hexahydro-5H-azepino[2',r:3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridin-13(14H)-one, 1.9 mg, 2.8 % as off white solid and Peak 2. The combined pure fractions of Peak 2 were lyophilized and re-purified by prep-HPLC [column: X-SELECT C18 Phenyl hexyl(19*250 mm) 5um, Mobile Phase-A: 0.1% FA in H2O, Mobile Phase-B: MeCN, using gradient 0 to 100 % MeCN, Flow rate: 16 mL / min, to give the title compound, 3.94 mg, 5.3 % as off-white solid. LCMS m / z = 632 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): 8 10.10 (s, 1H), 7.98-7.93 (m, 1H), 7.48-0.43 (m, 1H), 7.36 (d, 1H), 7.18-7.16 (m, 1H), 6.15 (d, 1H), 5.36-5.22 (m, 1H), 4.62-4.59 (m, 1H), 4.42-4.37 (m, 2H), 4.17-3.96 (m, 6H), 3.13-3.08 (m, 3H), 2.84-2.83 (m, 2H), 2.14-1.88 (m, 4H), 1.82-1.63 (m, 8H).Example 15: Synthesis of 4-(l-((R)-l-(2-aminopyridin-3-yl)ethyl)-7-fluoro-9-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-lH- [l,4]oxazepino[5,6,7-de][l,6]naphthyridin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compounds 189A) and 4-(l-((S)-l-(2-aminopyridin-3-yl)ethyl)-7-fluoro-9-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-lH-[l,4]oxazepino[5,6,7-de][l,6]naphthyridin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol(Compound 189B)

[0240] Step 1: Synthesis of l-benzyl-7-chloro-8-jluoro-4-hydroxy-5-(2-((4- methoxybenzyl)amino)ethoxy)-l,6-naphthyridin-2(lH)-one

[0241] To a solution of 2-((4-methoxybenzyl)amino)ethan-l-ol (2.0 g, 11.0 mmol) in THF (50 mL) was added NaH (1.32 g, 33.1 mmol, 60.0% purity) at 0 °C under N2 and the mixture was stirred at 0 °C for 15 min. Intermediate 1 (4.12 g, 12.1 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h. The mixture was quenched with saturated NH4CI (50 mL)and diluted with H2O (50 mL). The mixture was filtered and the filter cake was dried to give the title compound (4.50 g, 83.0%) as a yellow solid. 1H NMR (400 MHz, DMSO-de) 8 =7.46 (d, 2H), 7.32 - 7.23 (m, 2H), 7.22 - 7.15 (m, 1H), 7.06 (d, 2H), 6.92 (d, 2H), 5.36 (s, 2H), 5.19 (s, 1H), 4.50 (t, 2H), 4.07 (s, 2H), 3.73 (s, 3H), 3.10 (t, 2H).

[0242] Step 2: Synthesis of 8-benzyl-6-chloro-7-fluoro-l-(4-methoxybenzyl)-2,3-dihydro-lH- [1,4 ]oxazepino[5, 6, 7 -de ][ 1 ,6]naphthyridin-9(8H)-one

[0243] To a solution of the title compound from step 1 (4.50 g, 9.30 mmol) in DCE (100 mL) was added BOP-CI (4.73 g, 18.6 mmol) and DIEA (6.01 g, 46.5 mmol) and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with sat. aq.NaHCCE (50 mL), diluted with H2O (50 mL) and extracted with DCM (20 mL x 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 0-100% EtOAc / PE, to give the title compound (3.50 g, 76.7%) as a yellow solid. 1H NMR (400 MHz, DMSO-de) 6 = 7.32 - 7.19 (m, 5H), 7.07 (d, 2H), 6.95 (d, 2H), 5.74 (d, 1H), 5.44 (s, 2H), 4.62 (s, 2H),4.47 (t, 2H), 3.75 (s, 3H), 3.68 (t, 2H).

[0244] Step 3: Synthesis of 6-chloro-7-fluoro-2,3-dihydro-lH-[l,4]oxazepino[5,6, 7- de ][ 1, 6 ]naphthyridin-9(8H)-one

[0245] A solution of the title compound from step 2 (3.50 g, 7.51 mmol) in TfOH (20 mL) was stirred at 60 °C for 12 h. The mixture was concentrated in vacuo and the residue was basified with saturated aqueous NaHCOs. The resulting mixture was filtered and the filter cake was dried to give the title compound (2.40 g, crude) as a green solid. 1H NMR (400 MHz, DMSO-de) 6 = 7.93 (d, 1H), 5.50 (s, 1H), 4.43 - 4.39 (m, 2H), 3.57 (d, 2H)

[0246] Step 4: Synthesis of 6, 9 -dichloro- 7-fluoro-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[ 5, 6, 7- de ][ 1, 6 ] naphthyr idine

[0247] A solution of the title compound from step 3 (1.70 g, 6.65 mmol) in POCI3 (27.9 g, 182 mmol) was stirred at 80 °C for 2 h under N2. The reaction mixture was concentrated in vacuo, the residue was diluted with MeCN (20 mL), poured into water (50 mL), solid NaHCOs was added to adjust pH to 8 and the mixture extracted with EtOAc (50 mL). The organic extract was dried over Na2SO4, filtered and concentrated in vacuo. The residue wastriturated with EtOAc / PE =3: 1 (30 mL), filtered and the resulting solid dried, to give the title compound (0.63 g, 31.7%) as a yellow solid. LCMS: m / z = 274 [M+H]+

[0248] Step 5: Synthesis of 3-(l -(6, 9 -dichloro- 7-jluoro-2, 3-dihydro-lH-[1,4 ]oxazepino[5, 6, 7 -de ][ l,6]naphthyridin-l-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2- amine

[0249] 4 reactions were conducted in parallel.

[0250] To a solution of the title compound from step 4 (0.10 g, 364 pmol) in hexane (2 mL) and DCM (2 mL) was added TBAB (23.5 mg, 72.9 pmol), NaOH (262 mg, 3.28 mmol, 0.5 mL, 50.0% purity in H2O) and the title compound from step 14 (362 mg, 912 pmol) at 0 °C. The reaction mixture was stirred at 20 °C for 12 h. The 4 reaction batches were combined, quenched with saturated NH4CI (10 mL), and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (5 mL x 2), dried over ISfeSCU, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 0-100% EtOAc / PE and further purified by reverse-phase HPLC (0.1% FA condition), to give the title compound (220 mg, 23.7%) as a yellow solid. 1H NMR (400 MHz, CDCI3) 8 = 8.60 (dd, 1H), 7.61 (dd, 1H), 7.19 (dd, 1H), 6.83 - 6.81 (m, 4H), 6.74 (s, 1H), 6.63 (d, 4H), 5.48 - 5.26 (m, 1H), 4.19 - 4.06 (m, 3H), 4.04 - 3.96 (m, 2H), 3.92 - 3.84 (m, 1H), 3.76 (s, 6H), 3.32 - 3.36 (m, 1H), 3.09 - 3.03 (m, 1H), 1.24 (d, 3H)

[0251] Step 6: Synthesis of 3-( l-(6-chloro-7 -fluor o-9-(((2R, 7aS)-2-f!uorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7 -de ][ 1 ,6]naphthyridin- l-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0252] To a solution of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (238 mg, 1.50 mmol) in THF (4 mL) was added NaH (119 mg, 2.99 mmol, 60.0% purity) at 0 °C under N2 and the mixture was stirred at 0 °C for 15 min. The title compound from step 5 (190 mg, 299 pmol) was added at 0 °C and the reaction mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated NH4CI (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with 0-10% DCM: MeOH to give the title compound (180 mg, 79.4%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 = 8.48 (dd, 1H), 7.64 - 7.57 (m, 1H), 7.13 - 7.10 (m, 1H), 6.89 - 6.86 (m, 4H), 6.65 - 6.63 (m, 4H), 6.23 (d, 1H), 5.45 - 5.40 (m, 1H), 5.32 - 5.11 (m, 1H), 4.47 - 4.27 (m, 2H), 4.25 - 4.18 (m, 1H), 4.09 -3.95 (m, 5H), 3.76 (s, 6H), 3.43 - 3.14 (m, 5H), 3.05 - 2.95 (m, 1H), 2.29 - 2.06 (m, 3H), 2.00- 1.89 (m, 3H), 1.37 (d, 3H)

[0253] Step 7: Synthesis of 3-(l-(7-fluoro-6-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-l-yl)-9-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7 -de ][ 1 , 6] naphthyr idin-1 -yl)ethyl)~ N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0254] To a solution of the title compound from step 6 (145 mg, 191 pmol) and ((6-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (239 mg, 383 pmol) in dioxane (8 mL) was added K3PO4 (1.5 M, 382 pL) and SPhos Pd G3 (14.9 mg, 19.2 pmol) under N2 and the reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with 0-5% EtOAc / PE to give the title compound (230 mg, 98.5%) as a yellow solid. LCMS m / z = 1220 [M+H]+

[0255] Step 8: Synthesis of 4-(l-(l-(2-aminopyridin-3-yl)ethyl)-7-fluoro-9-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7- de] [ 1 ,6]naphthyridin-6-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0256] To a solution of the title compound from Step 7 (140 mg, 115 pmol) in EtOAc (5.6 mL) was added TfOH (475 mg, 3.16 mmol) at -40 °C and the reaction mixture was stirred at 20 °C for 12 h. The reaction was quenched with water, neutralized using saturated aq.NaHCOs and the mixture extracted with EtOAc (10 mL x 2). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (145 mg, crude) as a yellow oil. LCMS: m / z = 824 [M+H]+

[0257] Step 9: Synthesis of 4-(l-(l-(2-aminopyridin-3-yl)ethyl)-7-fluoro-9-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7- de ][ 1, 6 ] naphthyr idin-6-y I) -5 -ethynyl-6-fluoronaphthalen-2-ol

[0258] To a solution of the title compound from step 8 (145 mg, 176 pmol) in THF (2 mL) was added TBAF (1 M, 704 pL) and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (3 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters XbridgeC18 150*50mm*10 m; mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 36%- 66% B over 11.0 min) to give the title compound (43.0 mg, 36.6%) as a yellow solid. 1H NMR (400 MHz, CDCI3) 5 = 8.13 (d, 1H), 7.61 - 7.50 (m, 2H), 7.26 - 7.17 (m, 2H), 7.08 - 6.99 (m, 1H), 6.79 (dd, 1H), 6.40 - 6.34 (m, 1H), 5.40 - 5.18 (m, 1H), 4.99 (t, 1H), 4.49 - 4.17 (m, 3H), 4.12 - 3.89 (m, 1H), 3.39 - 3.23 (m, 4H), 3.02 - 2.99 (m, 1H), 2.81 - 2.68 (m, 1H), 2.22 (s, 1H), 2.17 - 2.04 (m, 2H), 2.00 - 1.85 (m, 3H), 1.73 - 1.65 (m, 3H), 1.53 (s, 3H).

[0259] Step 10: Synthesis of 4-(l-((S)-l-(2-aminopyridin-3-yl)ethyl)-7-fluoro-9-(((2R, 7aS)~ 2-jluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7- de] [l,6]naphthyridin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (Peak 1, Compound 189B) and 4-(l-((R)-l-(2-aminopyridin-3-yl)ethyl)-7-fluoro-9-(((2R, 7aS)-2-fluorotetrahydro- IH-pyrrolizin- 7a(5H)-yl)methoxy)-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7- de] [l,6]naphthyridin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol formate (Peak 2, Compound 189 A)

[0260] The title compound from step 9 (43.0 mg, 64.5 pmol) was separated by prep-SFC (column: DAICEL CHIRALCEL OD (250 mm* 30 mm, 10pm); mobile phase: [CCh-EtOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) and prep-HPLC (column : Phenomenex luna C18 150*25mm* 10 pm; mobile phase: [H2O (0.225% FA)-MeCN]; gradient: 11%-41% B over 10.0 min) to give Peak 1, (7.12 mg, 16.6%) as a yellow solid. LCMS: m / z = 667 [M+H]+; 1H NMR (4OO MHz, CDCI3) 5 = 8.10 (d, 1H), 7.67 - 7.57 (m, 1H), 7.55 - 7.47 (m, 1H), 7.26 - 7.04 (m, 3H), 6.80 - 6.73 (m, 1H), 6.35 - 6.22 (m, 1H), 5.44 - 5.21 (m, 1H), 4.84 -4.68 (m, 2H), 4.51 - 4.19 (m, 3H), 4.08 - 3.88 (m, 1H), 3.47 - 3.35 (m, 1H), 3.28 (d, J= 8.4 Hz, 3H), 3.12 - 3.00 (m, 1H), 2.84 - 2.76 (m, 1H), 2.27 - 2.08 (m, 3H), 2.03 - 1.95 (m, 3H),1.68 - 1.57 (m, 3H), 1.51 (d, 1H), 1.43 - 1.37 (m, 1H). And Peak 2, the title compound, 5.23 mg, 11.4% as a yellow solid. LCMS: m / z = 667 [M+H]+; 1H NMR (400 MHz, CDCI3) 8 = 8.47 (s, 1H), 8.06 (s, 1H), 7.67 - 7.57 (m, 1H), 7.55 - 7.42 (m, 1H), 7.35 - 7.28 (m, 1H), 7.22 - 7.05 (m, 2H), 6.75 - 6.72 (m, 1H), 6.37 - 6.26 (m, 1H), 5.46 - 5.20 (m, 1H), 5.00 - 4.67 (m, 2H), 4.52 - 4.23 (m, 3H), 4.22 - 4.10 (m, 1H), 3.99 - 3.87 (m, 1H), 3.59 - 3.42 (m, 2H), 3.34 - 3.19 (m, 3H), 3.14 - 3.04 (m, 1H), 2.89 - 2.72 (m, 1H), 2.37 - 1.96 (m, 6H), 1.58 (d, 2H), 1.49 - 1.41 (m, 1H).

[0261] Step 11: Synthesis of l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-l-one

[0262] A solution of l-(2-chl oro-3 -pyridyl)ethanone (5.0 g, 32.1 mmol) in bis(4- methoxybenzyl)amine (24.8 g, 96.4 mmol) was stirred at 110 °C for 3 h. The reaction mixture was diluted with H2O (50 mL), the aqueous phase was neutralized with aqueous IN HC1, then extracted with EtOAc (100 mL x 2). The combined organic layers were washed with IN HC1 (50 mL x 2) and brine (50 mL x 2), dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (9.70 g, 80.2%) as a yellow oil. 1H NMR (400 MHz, DMSO-de) 8 = 8.26 (dd, 1H), 7.83 (dd, 1H), 7.02 (d, 4H), 6.85 - 6.81 (m, 5H), 4.41 (s, 4H), 3.70 (s, 6H), 2.41 (s, 3H).

[0263] Step 12: Synthesis of l-(2-(bis(4-methoxybenzyl)amino)pyridin-3-yl)ethan-l-ol

[0264] To a solution of the title compound from step 11 (5.0 g, 13.2 mmol) in MeOH (50 mL) was added NaBH4 (1.0 g, 26.5 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated NH4CI (50 mL) at 0 °C, diluted with H2O (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (4.50 g, 89.5%) as a yellow oil. 1H NMR (400 MHz, DMSO-de) 6 = 8.13 (dd, 1H), 7.81 (dd, 1H), 7.16 (d, 4H), 7.04 (dd, 1H), 6.83 (d, 4H), 5.29 - 5.18 (m, 1H), 5.16 (d, 1H), 4.27 - 4.16 (m, 2H), 4.13 - 4.05 (m, 2H), 3.70 (s, 6H), 1.28 (d, 3H).

[0265] Step 13: Synthesis of 3-(l-chloroethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0266] To a solution of the title compound from step 12 (400 mg, 1.06 mmol) in DCM (4 mL) was added TEA (213 mg, 2.11 mmol) and ethanesulfonyl chloride (163 mg, 1.27 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was directly used in the next step without work up to give the title compound as a yellow oil. LCMS: m / z = 393 [M+H]+Example 16: Synthesis of (8aS)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-(6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl)-8a,9,12,13- tetrahydro-8H,llH-[l,4]oxazepino[3',4':3,4][l,4]oxazepino[5,6,7-de][l,6]naphthyridine (Compound 190)

[0267] Step 1: Synthesis of tert-butyl (S)-3-(((l-benzyl-7-chloro-8-fluoro-4-hydroxy-2-oxo- 1, 2-dihydro-l, 6-naphthyridin-5-yl)oxy)methyl)-l, 4-oxazepane-4-carboxylate

[0268] NaHMDS (1 M in THF, 44.5 mL, 44.5 mmol) was added drop wise to a solution of Intermediate 1 (5 g, 14.7 mmol) and tert-butyl (R)-3 -(hydroxymethyl)- l,4-oxazepane-4- carboxylate (Int 12, WO 2023046135, 4.1 g, 17.6 mmol) in dry THF (50 mL) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was re-cooled to 0 °C and slowly quenched with sat. NH4CI solution (20 mL). The mixture was extracted with EtOAc (2 x 50 mL), and the combined organic extracts washed with water (2 x 50 mL) and brine (50 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the title compound, 2.5 g, crude. LCMS m / z = 534 [M+H]+.

[0269] Step 2: Synthesis of (S)-5-((l,4-oxazepan-3-yl)methoxy)-l-benzyl-7-chloro-8-fluoro-4-hydroxy-l, 6-naphthyridin-2(lH)-one trifluoroacetate

[0270] The title compound was obtained as a pale yellow solid, 1.3 g, from the title compound from step 1, following a similar procedure to that described in Intermediate 2, step 2. LCMS m / z = 434 [M+H]+.

[0271] Step 3: Synthesis of (S)-3-benzyl-5-chloro-4-f!uoro-8a,9, 12, 13-tetrahydro-8H, 11H-[1,4 ]oxazepino[ 3',4': 3,4] [1,4 ]oxazepino[ 5, 6, 7 -de ] [1,6 ]naphthyridin-2 ( 3H) -one

[0272] To a stirred solution of the title compound from step 2 (1.3 g, 2.2 mmol) in DCM:THF (65 mL: 65 mL), were added DIEA (1.25 mL, 6.7 mmol) followed by PyBOP (2.92 g, 5.6 mmol) at rt under N2. The reaction mixture was stirred at rt for 16 h and then at 60 °C for 8 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography using a gradient of 5-10% MeOH / DCM to afford the title compound (750 mg, 80%) as a yellowish brown solid. LCMS m / z = 416 [M+H]+.

[0273] Step 4: Synthesis of (8aS)-3-benzyl-4-fluoro-5-(6-methyl-l-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-lH-indazol-4-yl)-8a, 9, 12, 13-tetrahydro-8H, 11H-[1,4 ]oxazepino[ 3',4': 3,4] [1,4 ]oxazepino[ 5, 6, 7 -de ] [1,6 ]naphthyridin-2 ( 3H) -one

[0274] The title compound was obtained as a pale yellow solid, 287 mg, 36%, from the title compound from step 3 and Intermediate 3, following a similar procedure to that described in Example 1, step 1. LCMS m / z = 664 [M+H]+.

[0275] Step 5: Synthesis of (8aS)-4-fluoro-5-(6-methyl-l-(tetrahydro-2H-pyran-2-yl)-5-( trifluoromethyl) -lH-indazol-4-yl) -8a, 9, 12, 13-tetrahydro-8H, 11H-[1,4 ]oxazepino[ 3',4': 3,4] [1,4 ]oxazepino[ 5, 6, 7 -de ] [1,6 ]naphthyridin-2 ( 3H) -one

[0276] The title compound was obtained as a white solid, 156 mg, 69%, from the title compound from step 4, following a similar procedure to that described in Example 8, step 2. LCMS m / z = 574 [M+H]+.

[0277] Step 6: Synthesis of (8aS)-4-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-(6-methyl-l-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-lH- indazol-4-yl)-8a,9, 12, 13-tetrahydro-8H, 1 lH-[ 1, 4 ]oxazepino[3',4':3, 4] [1,4 ]oxazepino[5, 6, 7- de ][ 1, 6 ] naphthyr idine

[0278] The title compound was obtained as an orange gum, 100 mg, crude, from the title compound from step 5 and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)m ethanol,following a similar procedure to that described in Example 1, step 3. LCMS m / z = 715 [M+H]+.

[0279] Step 7: Synthesis of (8aS)-4-jluoro-2-(((2R, 7aS)-2-jluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-(6-methyl-5-(trijluoromethyl)-lH-indazol-4-yl)-8a,9,12,13-tetrahydro- 8H, 11H~[ 1, 4 ]oxazepino[ 3',4': 3,4] [1,4 ]oxazepino[ 5, 6, 7 -de ] [1,6 ] naphthyr idine

[0280] 4 M HC1 in dioxane (0.1 mL) was added to a solution of the title compound from step 6 (100 mg, 0.16 mmol) in DCM (1 mL) at 0°C and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated NaHCCL solution (0.5 mL) and the mixture concentrated in vacuo. The residue was purified by prep. HPLC purification [Lux 5pm-Amylose-3, 250 x 21.2 mm; MeCN:MeOH (50:50%)] to afford the title compound (13 mg, 12 % over two steps)) as off-white solid. LCMS m / z = 631 [M+H]+ 1H NMR (500 MHz, DMSO- d6): 13.45 (br s, 1H), 7.8-7.6 (m, 2H), 6.3-6.1 (m, 1 H), 5.35-5.21 (m, 1 H), 4.52 (m, 1H), 4.42 (m, 1H), 4.18 (m, 1H), 4.1-3.95 (m, 2H), 3.87 (m, 1H), 3.77-3.6 (m, 2H), 3.46 (m, 1H), 3.19-2.92 (m, 3H), 2.8 (brs, 2 H), 2.62 (s, 3H), 2.18-1.72 (m, 6 H), 1.6 (m, 2 H), 1.41-1.31 (m, 2H).Example 17: Synthesis of 5-ethynyl-6-fluoro-4-((S)-7-fluoro-9-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2-(2-hydroxyethyl)-l-methyl-2,3- dihydro-lH-[l,4]oxazepino[5,6,7-de][l,6]naphthyridin-6-yl)naphthalen-2-ol (Compound 191)

[0281] Step 1: Synthesis of (R)-l-benzyl-5-(4-((tert-butyldiphenylsilyl)oxy)-2- (methylamino)butoxy)- 7-chloro-8-fluoro-4-hydroxy-l , 6-naphthyridin-2( lH)-one

[0282] A solution of NaH (247.7 mg, 6.19 mmol, 60%) in THF (5 mL) was treated with (S)- 4-((tert-butyldiphenylsilyl)oxy)-2-(methylamino)butan-l-ol (885.6 mg, 2.48 mmol) at 0°C and the mixture was stirred for Ih. Intermediate 1 (700 mg, 2.06 mmol) was added in portions at 0°C and the reaction mixture was stirred at rt overnight. The reaction was quenched with HC1 (aq.) at 0 °C and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous ISfeSCU, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (60%) to afford the title compound (833 mg, 42.8%) as a brown solid. LCMS m / z = 660 [M+H]+.

[0283] Step 2: Synthesis of (S)-8-benzyl-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloro-7- jluoro-l-methyl-2, 3-dihydro-lH-[ 1, 4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 ]naphthyridin-9(8H)-one

[0284] TEA (260.7 mg, 2.58 mmol) was added to a solution of the title compound from step 1 (567 mg, 0.86 mmol) in THF (5 mL) at 0°C. PyBOP (670.3 mg, 1.29 mmol) was added in portions at 0°C and the reaction mixture was stirred at 70°C overnight. The cooled mixture was quenched with water (lOmL) and then extracted with EtOAc (2 x 20mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (45%) to afford the title compound (370 mg, 60.4%) as a yellow oil. LCMS m / z = 642 [M+H]+.

[0285] Step 3: Synthesis of (S)-8-benzyl-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-6- (7-jluoro-8-( triisopropylsilyl)ethynyl)-3-( triisopropylsilyl)oxy)naphthalen-l-yl)-l-methyl- 2, 3-dihydro-lH-[ 1, 4 ]oxazepino[5, 6, 7 -de ][ 1, 6 ]naphthyridin-9(8H)-one

[0286] CataCXium® A Pd G3 (52.39 mg, 0.072 mmol) and K2CO3 (298.26 mg, 2.157 mmol) were added to a solution of the title compound from step 2 (899 mg, 1.44 mmol) in dioxane (10 mL). H2O (1 mL) was added dropwise and the reaction mixture was stirred at 100°C overnight under N2. The cooled reaction was diluted with water (lOmL) at rt and the mixture was extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with PE / EA (30%) to afford the title compound (520 mg, 62.0%) as a yellow solid. LCMS m / z = 1104 [M+H]+.

[0287] Step 4: Synthesis of (S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-6-(7-fluoro- 8-( f triisopropylsilyl)ethynyl)-3-( ( triisopropylsilyl)oxy)naphthalen-l -yl)-l -methyl-2, 3- dihydro-lH-[ 1, 4 ]oxazepino[ 5, 6, 7 -de ] [1,6 ] naphthyr idin-9-ol

[0288] A mixture of the title compound from step 3 (100 mg, 0.091 mmol) in THF (0.5 mL), MeOH (10 mL), trifluoroacetic acid (0.5 mL) and Pd(OH)2, Pd 5% on carbon (127.13 mg, 0.910 mmol) was stirred at rt overnight under H2 atmosphere (5 atm). The resulting mixture was filtered, the filter cake was washed with THF (3x5 mL) and MeOH (3x5 mL). The filtrate was concentrated in vacuo and the residue was purified by Prep-TLC (DCM / MeOH 20: 1) to afford the title compound (78 mg, 84.6%) as a yellow solid. LCMS m / z = 1014 [M+H]+.

[0289] Step 5: Synthesis of (S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7-fluoro-6-(7-fluoro- 8-( f triisopropylsilyl)ethynyl)-3-( ( triisopropylsilyl)oxy)naphthalen-l-yl)-9-( ( (2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-l-methyl-2,3-dihydro-lH-[1.4 ]oxazepino[ 5, 6, 7 -de ][ 1, 6 naphthyridine

[0290] To a solution of the title compound from step 4 (78 mg, 0.077 mmol) in toluene (2 mL) was added ((2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl)methanol (36.6 mg, 0.23 mmol) and (tributylphosphoranylidene)acetonitrile (37.0 mg, 0.154 mmol) and the reaction mixture was stirred at 100°C for 2h. The cooled reaction was quenched with sat. Na2S2O3(aq.) (5 mL) at rt and the mixture was extracted with EtOAc (3 x 8mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by Prep-TLC (DCM / MeOH 15: 1) to afford a mixture of the title compound and (S)-2-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-7-fluoro-6-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-l-yl)-8-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methyl)-l-methyl-2,3-dihydro-lH-[l,4]oxazepino[5,6,7-de][l,6]naphthyridin- 9(8H)-one (66 mg, 74.3%) as a yellow solid. LCMS m / z = 1157 [M+H]+.

[0291] Step 6: Synthesis of 5-ethynyl-6-fluoro-4-((S)-7-fluoro-9-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2-(2-hydroxyethyl)-l-methyl-2, 3- dihydro-lH-[ 1, 4 ]oxazepino[ 5, 6, 7 -de ] [1,6 ] naphthyr idin-6-yl)naphthalen-2-ol

[0292] A mixture of the products of step 5 (66 mg, 0.111 mmol) and CsF (336.5 mg, 2.22 mmol) in DMF (2 mL) was stirred at 60°C for 30 min. The mixture was allowed to cool to rt, then filtered and the filter cake was washed with DMF (3 mL). The filtrate was concentrated in vacuo. The crude product (150 mg) was purified by Prep-Achiral-SFC (Column: DAICEL DCpak P4VP 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH (20mM NH3); Flow rate: 60 mL / min; isocratic 50% B; Column Temperature(°C): 35; to give Peak 1, (S)-6- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-7-fluoro-8-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methyl)-2-(2-hydroxyethyl)-l-methyl-2,3-dihydro-lH-[1.4]oxazepino[5,6,7-de][l,6]naphthyridin-9(8H)-one (2.0 mg, 2.8%) as a white solid and Peak 2, the title compound (2.1 mg, 3.1%) as an off-white solid. LCMS m / z = 605 [M+H]+ 1H NMR (400 MHz, MeOD-d4) 8 7.86 -7.81 (m, 1H), 7.34 - 7.25 (m, 1H), 7.22 - 7.12 (m, 1H), 6.08 - 6.06 (m, 1H), 4.67 - 4.59 (m, 1H), 4.50 - 4.31 (m, 1H), 4.29 - 4.26 (m, 1H), 4.25- 4.21 (m, 1H), 4.07 - 4.05 (m, 1H), 3.79 - 3.67 (m, 2H), 3.64 (s, 1H), 3.06 - 2.96 (m, 1H), 2.39 - 2.22 (m, 1H), 2.18 - 2.17 (m, 2H), 2.05 - 1.92 (m, 5H), 1.28 (s, 8H).Example 18 to Example 39: Synthesis and Characterization of Compounds 192-213General synthetic scheme for the synthesis of Compounds 192-213:

[0293] Step 1: Synthesis of Boc-amines

[0294] To a solution of the appropriate amine (200 umol) in DCM (1 mL) was added (Boc)2O (43.6 mg, 200 umol) and TEA (60.6 mg, 600 umol). The mixture was stirred at 30 °C for 1 h, then concentrated with N2. The residue was diluted with H2O (3 mL) and extracted with DCM (3 mLx3). The combined organic layers were dried over ISfeSCL, filtered and concentrated with N2. The crude was used for next step without purification.

[0295] Step 2: Synthesis of Intermediates (when RI =H) or Synthesis of Examples (when R]fH)

[0296] To a solution of the product of step 1 (150 umol) and the title product of Example 4, Step 2 (100 umol) in toluene (1 mL) was added CMBP (72.3 mg, 300 umol). The reaction mixture was heated at 110 °C in a microwave, optionally in the presence of molecular sieve, until the reaction was complete, then concentrated with N2. The residue was diluted with H2O (3 mL) and extracted with EtOAc (3 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated with N2. For some products, the residue was purified by prep-TLC (Ri=Boc: EtOAc : PE = 2: 1, R Boc: MeOH : DCM = 1 : 10).

[0297] Step 3:

[0298] To a solution of the Intermediates from step 2 (100 umol) in DCM (1 mL) was added TFA (0.20 mL). The mixture was stirred at 30 °C. Upon completion (between 30 and 60 min), the reaction mixture was concentrated with N2. The residue was purified by prep- HPLC (Column: Phenomenex luna C18 150*25*10um, Mobile Phase: 0.01% TFA in water (solvent A) and MeCN (solvent B), Gradient: 8%-50% (solvent B) over 10 minutes at flow rate: 30 mL / min) or neutral conditions (Column: Waters XBridge BEH C18 150*25*10um, Mobile phase A: 0.1% NH4HCO3 in water, Mobile phase B: MeCN, Gradient: 20%-80% (solvent B) over 10 minutes at flow rate: 30 mL / min) to give the final compounds.Table 2. Characterization and Starting Materials (SM) for the Synthesis of Compounds 192-213IllTable 3. Characterization for the Synthesis of Compounds 214-219Biological ExamplesExample 46: KRAS G12D SOSl-mediated TR-FRET Assay

[0299] The ability of compounds to inhibit SOSl-mediated nucleotide exchange was measured using a TR-FRET assay. In a 10-pl final assay volume, 5 pL of GST-tagged KRAS G12D and 1 nM anti-GST-Tb were added to pre-dispensed compounds. The assay buffer consisted of 10 mM HEPES, pH 7.4, 150 mM NaCl, 0.05% BSA, 0.0025% Igepal and 5 mM MgCh. Then, 5 pL of S0S1 and 10 nM EDA-GTP-DY-647P1 were added to initiate the nucleotide exchange reaction. After a 60-minute incubation at room temperature, the reaction was measured in a plate reader using excitation and emission wavelengths of 337 nm and 615 / 665 nm, respectively. IC50 values were established using a four-parameter fit model. The results are shown in Table 2, where A is < 10 nM; B is > 10 nm and < 100 nM; C is > 100 nM and < 1000 nM; D is > 1000 nM and < 3000 nM; and E is > 3000 nM.Table 4. KRAS G12D SOSl-mediated TR-FRET IC50 dataExample 47: p-ERK HTRF Assay

[0300] The potency of test compounds in inhibiting phosphorylation of ERK was determined by p-ERK HTRF assay in human cancer cell lines expressing either mutant orwild-type KRAS. Cells (8000 cells per well) were plated in 384-well cell culture plates. After overnight incubation at 37 °C and 5% CO2, cells were treated with a 3-fold, 10 points dilution of indicated compounds or DMSO (0.1% DMSO final) for 3 hours. Cells were then lysed, and the lysates transferred to assay plates and incubated with phospho-ERK HTRF detection reagents according to the manufacturer’s protocol. The HTRF signal was measured using an EnVision multimode plate reader. Curves were fitted and IC50 values calculated using a four-parameter logistic model (XLFit; equation 201). The results are shown in Table 5, where IC50 values were established using a four-parameter fit model. The results are shown in Table 5, where A is < 10 nM; B is > 10 nm and < 100 nM; C is > 100 nM and < 1000 nM; D is > 1000 nM and < 3000 nM; and E is > 3000 nM.Table 5. p-ERK HTRF IC50 dataExample 48: CellTiter-Glo (CTG) IC50 Assay

[0301] The anti-proliferative activity of compounds was assessed by CellTiter-Glo® Luminescent Cell Viability Assay (CTG; Promega Corp.) in human cancer cell lines expressing either mutant or wild-type KRAS. Cells were seeded into 384-well plates at densities of 500-2000 cells per well in complete growth medium. After overnight incubation at 37 °C and 5% CO2, cells were treated with a 3-fold, 10-point dilution of indicated compounds or DMSO (0.1% DMSO final) and cell viability was assessed 3 days posttreatment according to the manufacturer’s protocol. The luminescent signal was measured using an EnVision multimode plate reader. Curves were fitted and IC50 values calculated using a four-parameter logistic model (XLFit; equation 201). The results are shown in Table 6 where A is < 10 nM; B is > 10 nm and < 100 nM; C is > 100 nM and < 1000 nM; D is > 1000 nM and < 3000 nM; and E is > 3000 nM.Table 6. 2D CTG IC50 dataINCORPORATION BY REFERENCE

[0302] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS AND SCOPE

[0303] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0304] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value orsubrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0305] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0306] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMS1. A compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is N or C-Rx;Y is selected from the group consisting of O, S, and NRY;Ring A is selected from the group consisting of 8-10 membered bicyclic heteroaryl; naphthyl, phenyl, and 5-6 membered monocyclic heteroaryl;Rxis selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, - CN, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy; wherein Ci-Cealkyl and Ci-Cealkoxy may optionally be substituted with one or more halogens;RYis selected from the group consisting of hydrogen and Ci-C3alkyl; wherein Ci- C3alkyl may optionally be substituted with one or more halogens;RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cealkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, - NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci- C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, - S(O)2NRaRb, and -NRaS(O)2Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, - NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Ring B is a bond, a 4-10 membered heterocyclyl containing at least one ring nitrogen, or Cs-Cecycloalkyl;RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, -CH2NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R1is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Cs-Cecycloalkyl, -S(0)2NRaRb, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5- 6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R11;R2is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R22; orR1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 4-8 membered heterocyclyl which may optionally be substituted with one or more R5;R11and R22are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, Ci-Cealkyl, -Cealkoxy, C3- C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, - O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl;R3is selected from the group consisting of hydrogen, deuterium, halogen, and Ci- Csalkyl;R4is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, - CN, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R5is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, oxo, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Ci-Cealkoxy, Cs-Cecycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci- Cealkyl, -S(0)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituentseach independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;RaandRbare each independently selected from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci- Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Rcand Rdare each independently selected from the group consisting of hydrogen and Ci-C3alkyl; wherein Ci-C3alkyl may optionally be substituted with one or more halogens;Reand Rfare each independently selected from the group consisting of hydrogen and Ci-C3alkyl; wherein Ci-C3alkyl may optionally be substituted with one or more halogens; n is 0 or 1; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.

2. The compound of claim 1, wherein X is N.

3. The compound of claim 1, wherein X is selected from the group consisting of C-H, C-Cl, C-F, C-CH3, C-CH2F, C-CHF2, and C-CF3.

4. The compound of any one of claims 1-3, wherein ring A is a 8-10 membered bicyclic heteroaryl containing at least one ring nitrogen.

5. The compound of any one of claims 1-4, wherein ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl, wherein ring A is optionally substituted with one or more groups selected from RA.

6. The compound of any one of claims 1-5, wherein RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, Ci-C4alkyl, C2- C4alkynyl, and C3-C4cycloalkyl, wherein Ci-C4alkyl and C3-C4cycloalkyl may optionally be substituted with one, two or three halogens.

7. The compound of any one of claims 1-6, wherein q is 2, 3, or 4.

8. The compound of any one of claims 1-7, wherein ring A is selected from the group consisting of:

9. The compound of any one of claims 1-8, wherein R1is hydrogen or Ci-Cealkyl optionally substituted by R11.

10. The compound of any one of claims 1-9, wherein R1is hydrogen or Ci-Cealkyl optionally substituted by hydroxyl, -S(O)2NH2, or cyano.

11. The compound of any one of claims 1-10, wherein R1is selected from the group consisting of hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2OH, - CH2CH2CH2OH, -CH2CH(OH)CH3, -CH2C(CH3)2OH, -S(O)2NH2, -CH2-S(O)2NH2, and - CH2CH2CN.

12. The compound of any one of claims 1-11, wherein R1is selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, -S(O)2NH2, and -CH2-S(O)2NH2.

13. The compound of any one of claims 1-10, wherein R1hydrogen.

14. The compound of any one of claims 1-13, wherein R2is Ci-Cealkyl optionally substituted by one or more R22.

15. The compound of any one of claims 1-14, wherein R2is Ci-Cealkyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -SO2NH2, and -C(=O)NH2.

16. The compound of any one of claims 1-15, wherein R2is selected from the group consisting of -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH3, -CH2C(CH3)2OH, -CH(CH3)SO2NH2, and -CH(CH3)C(=O)NH2.

17. The compound of any one of claims 1-13, wherein R2is -CRcRd-(5-6 membered heteroaryl) optionally substituted by -NRaRbor Ci-Cealkyl.

18. The compound of claim 17, wherein R2is19. The compound of any one of claims 1-8, wherein R1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 5-7 membered heterocyclyl optionally substituted with one or more R5.

20. The compound of claim 19, wherein R5is selected from the group consisting of halogen, hydroxyl, oxo, -C(O)NH2, -SO2NH2, -CH2OH, -CHF2, Ci-C4alkyl, and Ci-C4alkoxy.

21. The compound of any one of claims 1-20, wherein Y is O.

22. The compound of claim 21, wherein m is 2 or 3.

23. The compound of any one of claims 1-22, wherein p is 1.

24. The compound of any one of claims 1-23, wherein RBis halogen.

25. The compound of any one of claims 1-24, wherein R3is selected from the group consisting of hydrogen, halogen, and -CH3.

26. The compound of any one of claims 1-25, wherein R3is hydrogen or fluoro.

27. The compound of any one of claims 1-26, wherein R4is hydrogen.

28. The compound of any one of claims 1-27, wherein n is 1.

29. The compound of claim 1, wherein the compound is represented by Formula IA:

30. A compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:Ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl;RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, - NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci- C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, - S(0)2NRaRb, and -NRaS(O)2Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, - NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;Ring B is a bond, a 4-10 membered heterocyclyl containing at least one ring nitrogen, or Cs-Cecycloalkyl;RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, -CH2NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R1is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, C3-Cecycloalkyl, -SO2NRaRb, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R11;R2is selected from the group consisting of hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, C3-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and -CRcRd-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R22; orR1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 5-7 membered heterocyclyl which may optionally be substituted with one or more R4;R11and R22are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, Ci-Cealkyl, Ci-Cealkoxy, C3- C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, - O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl;R3is selected from the group consisting of hydrogen, deuterium, halogen, and Ci- Csalkyl;R4is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, oxo, -NRaRb, Ci-Cealkyl, C2-Cealkenyl, C2- Cealkynyl, Ci-Cealkoxy, Cs-Cecycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, - O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci- Cealkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-Cealkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, oxo, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;RaandRbare each independently selected from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci- Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Cl-C6alkyl, and Cl-C6alkoxy;Rc and Rd are each independently selected from the group consisting of hydrogen and Cl-C6alkyl; p is 0, 1, 2, 3, or 4; andq is 0, 1, 2, 3, or 4.

31. The compound of claim 30, wherein RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NH2, Ci-C4alkyl, C2-C4alkynyl, and C3- C4cycloalkyl, wherein Ci-C4alkyl and C3-C4cycloalkyl may optionally be substituted with one, two or three halogens.

32. The compound of claim 30 or 31, wherein q is 2 or 3.

33. The compound of any one of claims 30-32, wherein ring A is selected from the group consisting of:

34. The compound of any one of claims 30-33, wherein R1is selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, -S(O)2NH2, and -CH2-S(O)2NH2.

35. The compound of any one of claims 30-34, wherein R2is selected from the group consisting of -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH(CH3)SO2NH2, -36. The compound of any one of claims 30-33, wherein R1and R2, together with the adjacent atoms to which they are attached, are joined together to form a 6-7 membered heterocyclyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -C(O)NH2, -SO2NH2, -CH2OH, -CHF2, Ci- C4alkyl, and Ci-C4alkoxy.

37. The compound of any one of claims 30-36, wherein R3is halogen or hydrogen.

38. The compound of any one of claims 30-37, wherein p is 1 and RBis halogen.

39. The compound of claim 30, wherein the compound is represented by Formula IIA:

40. A compound represented by Formula III:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:Ring A is selected from the group consisting of phenyl, pyridyl, naphthyl, quinolinyl, and isoquinolinyl;RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NH2, Cl-C4alkyl, C2-C4alkynyl, and C3-C4cycloalkyl, wherein Cl- C4alkyl and C3-C4cycloalkyl may optionally be substituted with one, two or three halogens;R1 is selected from the group consisting of hydrogen, Cl-C4alkyl, and -S(O)2NH2, wherein Cl-C4alkyl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, and -S(O)2NH2;R2 is selected from the group consisting of Cl-C4alkyl and -CRcRd-(5-6 membered heteroaryl); wherein alkyl or heteroaryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, - NH2, -S(O)2NH2, and -C(=0)NH2; orR1 and R2, together with the adjacent atoms to which they are attached, are joined together to form a 6-7 membered heterocyclyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -C(0)NH2, -SO2NH2, -CH20H, -CHF2, Cl-C4alkyl, and Cl-C4alkoxy;R3 is halogen or hydrogen;RB is halogen; andq is 2 or 3.

41. The compound of claim 40, wherein ring A is selected from the group consisting of:

42. The compound of claim 40 or 41, wherein R1is selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, -S(O)2NH2, and -CH2-S(O)2NH2.

43. The compound of any one of claims 40-42, wherein R2is selected from the group consisting of -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH(CH3)SO2NH2, -44. A compound selected from the group consisting of:

45. A pharmaceutical composition comprising a compound of any one of claims 1-44, or a pharmaceutically acceptable salt and / or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

46. A method of treating a Ras-related disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-44, or the pharmaceutical composition of claim 45.

47. The method of claim 46, wherein the disease or disorder is characterized by aberrant Ras activity in the patient due to a Ras mutation.

48. The method of claim 46 or 47, wherein the Ras mutation is a K-Ras mutation, a H-Ras mutation, or a N-Ras mutation.

49. The method of any one of claims 46-48, wherein the disease or disorder is a cancer.

50. A method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-44 or the pharmaceutical composition of claim 45.

51. The method of claim 50, wherein the cancer is a Ras-mutated cancer.

52. The method of claim 50 or 51, wherein the cancer is a K-Ras-mutated cancer.

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