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. Pharmaceutical compositions and methods of making various indene compounds are provided. The compounds are contemplated to be modulators of Ras (e.g., K-Ras).

Description

RAS INHIBITORS AND METHODS OF USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No.63 / 588,031, filed on October 5, 2023; U.S. Provisional Patent Application No. 63 / 667,196, filed on July 3, 2024; and U.S. Provisional Patent Application No.63 / 696,429, filed on September 19, 2024; the content of each of which is hereby incorporated by reference herein in its entirety. 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, non-small 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] For example, disclosed herein is a compound represented by Formula I:Formula I; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: R1is selected from the group consisting of halogen, C3-C4cycloalkyl, C1-C6alkyl, C2- C6alkenyl, and C2-C6alkynyl; wherein cycloalkyl, alkyl, alkenyl, and alkynyl may optionally be substituted with one, two, or three halogens; R2is hydrogen or C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; and ring A is selected from the group consisting of indazolyl, quinolinyl, quinolinonyl, benzothiophenyl, benzothiazolyl, pyrazolopyridyl, pyridyl, phenyl, and naphthyl, wherein ring A is substituted with one or more substituents each independently selected from RA; or: R1is hydrogen; R2is C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; and ring A is selected from the group consisting of: ,, , and ;or: R1is hydrogen; R2is hydrogen; and ring A is selected from the group consisting of:RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- 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)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; RA1is selected from the group consisting of hydrogen, deuterium, chloro, -CN, -NO2, - NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-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)C1- C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, - S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; R1’is hydrogen or halogen; R3is selected from the group consisting of -NRaRb, halogen, C1-C2alkyl, and hydrogen, wherein alkyl may optionally be substituted with one, two, or three halogens; R4is selected from the group consisting of hydrogen and C1-C2alkyl, wherein alkyl may optionally be substituted with one, two, or three halogens; R5is C1-C2alkyl optionally be substituted with one, two, or three halogens; R6is selected from the group consisting of halogen, hydrogen, deuterium, and C1- C3alkyl;R7is selected from the group consisting of hydrogen and C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; R8and R9are each independently selected from the group consisting of hydrogen, deuterium, and C1-C3alkyl; Ring B is selected from the group consisting of 4-12 membered heterocyclyl containing at least one ring nitrogen; RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, -COOH, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, =CHF, and =CH-C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydroxyl, halogen, and C1- C3alkoxy; or Ring B and RBare absent and replaced with a substituent selected from the group consisting of -CH2OH and C3-C4cycloalkyl, wherein cycloalkyl is substituted with a substituent selected from the group consisting of -CH2OH and -CH2-NRaRb, and Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand 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, C1- C6alkyl, and C1-C6alkoxy; m and n are each independently 0, 1, 2, 3, or 4; p is 1, 2, or 3; q, r, and s are each independently 0, 1, 2, or 3; and t is 0, 1, or 2.

[0007] Also disclosed herein is a compound represented by Formula II:Formula II; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: ring A is selected from the group consisting of indazolyl, quinolinyl, quinolinonyl, benzothiophenyl, benzothiazolyl, pyridinyl, pyrimidinyl, and phenyl; wherein ring A is substituted with one, two, or three substituents each independently selected from RA; RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- 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)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; R1is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, -CH(CH3)-(C3-C6cycloalkyl), -CH2-(C3-C6cycloalkyl), phenyl, 5-membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R11; R2is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C6cycloalkyl, -CH(CH3)-(C3-C6cycloalkyl), -CH2-(C3-C6cycloalkyl), phenyl, 5- membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R22; R11and R22are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, phenyl, - COOH, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1- C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl;R3is selected from the group consisting of hydrogen and C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; R4is selected from the group consisting of halogen, hydrogen, deuterium, and C1- C3alkyl; R5and R6are each independently selected from the group consisting of hydrogen, deuterium, and C1-C3alkyl; Ring B is selected from the group consisting of 5-10 membered heterocyclyl containing at least one ring nitrogen; RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand 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, C1- C6alkyl, and C1-C6alkoxy; and m is 0, 1, 2, 3, or 4; wherein if ring A is benzothiophenyl, then R1is CH3or substituted C1-C6alkyl.

[0008] Further disclosed herein is a compound represented by Formula III:Formula III; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: RA1and RA2are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- 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)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; R1’is hydrogen and R1is selected from the group consisting of hydrogen, -CH3, -CF3, - CH2CH2OH, -CH2C(CH3)2OH, C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, phenyl, 5-membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl is substituted with one, two, three, or four substituents each independently selected from R11; and wherein alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R22; and R2is selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, - CH2CH2CH2OH, -CH2CH(CH3)OH, -CH2C(CH3)2OH, C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3cycloalkyl, C5-C6cycloalkyl, phenyl, 5-membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl is substituted with one, two, three, or four substituents each independently selected from R11; and wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R22; or: R1and R1’, together with the carbon atom to which they are attached, may be joined together to form C3-cycloalkyl optionally substituted with one, two or three halogens or hydroxyl; and R2is C1-C6alkyl substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -COOH, and C(=O)NRaRb; or R1and R1’, together with the carbon atom to which they are attached, may be joined together to form C4-cycloalkyl optionally substituted with one, two or three halogens or hydroxyl; and R2is C1-C6alkyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -COOH, and C(=O)NRaRb; R11is independently selected for each occurrence from the group consisting of halogen, deuterium, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, - COOH, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1- C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl; R22is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -COOH, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl; R3is selected from the group consisting of halogen, hydrogen, deuterium, and C1- C3alkyl; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand 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, C1- C6alkyl, and C1-C6alkoxy; Rcand Rdare each independently selected from the group consisting of hydrogen and C1-C6alkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2; wherein: if R1is hydrogen, then R2is not hydrogen, -CH3, or CH2CH2OH; and if R1is -CH3, then R2is not hydrogen, -CH3, -CH2CF2, -CH2CF3, or -CH2CH(CH3)OH.

[0009] Also 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] 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.

[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 C1-6alkyl, C1-4alkyl, and C1- 3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-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 C1-C5alkenyl, C2-C6alkenyl, 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 C2-6alkynyl, and C3-6alkynyl, 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 C1-C5alkoxy, C1-C6alkoxy, and C2- C6alkoxy, 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 (“C6–14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; 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 in the 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 C1-C8alkyl, C1-C8haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 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, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, substituted C6-C10 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 not limited 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 C1- 6haloalkyl, C1-4 haloalkyl, and C1-3haloalkyl, 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 hydrocarbylgroups 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 4-10 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. 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. 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-1H-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 =O.

[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 Biologics 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, p-toluenesulfonate and pamoate (i.e., 1,1'-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 moiety may 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. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(- ),” “R” or “S,” 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 inaccordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a 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 Kvaerno, 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,17O,31P,32P,35S,18F, and36Cl, 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 (C1-8)alkyl, (C2-12)alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(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, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-2)alkylamino(C2-3)alkyl (such as - dimethylaminoethyl), carbamoyl-(C1-2)alkyl, N,N-di(C1-2)alkylcarbamoyl-(C1-2)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 (C1-6)alkylcarbonyloxymethyl, 1-((C1-6)alkylcarbonyloxy)ethyl, 1-methyl-1-((C1- 6)alkylcarbonyloxy)ethyl (C1-6)alkoxycarbonyloxymethyl, N-(C1-6)alkoxycarbonylaminomethyl, succinoyl, (C1-6)alkylcarbonyl, -amino(C1-4)alkylcarbonyl, arylalkylcarbonyl and - aminoalkylcarbonyl, or -aminoalkylcarbonyl- -aminoalkylcarbonyl, where each -aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-6)alkyl)2or 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 Simplício, 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 is a compound represented by Formula I:Formula I; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is selected from the group consisting of halogen, C3-C4cycloalkyl, C1-C6alkyl, C2- C6alkenyl, and C2-C6alkynyl; wherein cycloalkyl, alkyl, alkenyl, and alkynyl may optionally be substituted with one, two, or three halogens; R2is hydrogen or C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; and ring A is selected from the group consisting of indazolyl, quinolinyl, quinolinonyl, benzothiophenyl, benzothiazolyl, pyrazolopyridyl, pyridyl, phenyl, and naphthyl, wherein ring A is substituted with one or more substituents each independently selected from RA; : R1is hydrogen; R2is C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; and ring A is selected from the group consisting of:R1is hydrogen; R2is hydrogen; and ring A is selected from the group consisting of:RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- 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)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; RA1is selected from the group consisting of hydrogen, deuterium, chloro, -CN, -NO2, - NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-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)C1- C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, - S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; R1’is hydrogen or halogen; R3is selected from the group consisting of -NRaRb, halogen, C1-C2alkyl, and hydrogen, wherein alkyl may optionally be substituted with one, two, or three halogens; R4is selected from the group consisting of hydrogen and C1-C2alkyl, wherein alkyl may optionally be substituted with one, two, or three halogens; R5is C1-C2alkyl optionally be substituted with one, two, or three halogens; R6is selected from the group consisting of halogen, hydrogen, deuterium, and C1- C3alkyl; R7is selected from the group consisting of hydrogen and C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; R8and R9are each independently selected from the group consisting of hydrogen, deuterium, and C1-C3alkyl; Ring B is selected from the group consisting of 4-12 membered heterocyclyl containing at least one ring nitrogen; RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, -COOH, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, =CHF, and =CH-C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydroxyl, halogen, and C1- C3alkoxy; or Ring B and RBare absent and replaced with a substituent selected from the group consisting of -CH2OH and C3-C4cycloalkyl, wherein cycloalkyl is substituted with a substituent selected from the group consisting of -CH2OH and -CH2-NRaRb, and Ra and Rb are each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand 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, C1- C6alkyl, and C1-C6alkoxy; m and n are each independently 0, 1, 2, 3, or 4; p is 1, 2, or 3; q, r, and s are each independently 0, 1, 2, or 3; and t is 0, 1, or 2.

[0048] For example, in some embodiments R1is selected from the group consisting of fluoro, chloro, cyclopropyl, trifluoromethyl, -CH2CH2CH3, and propenyl; and R2is hydrogen or -CH3. In other embodiments, RAis independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, cyano, -NH2, -C(O)NH2,C1-C4alkyl, and C2- C4alkynyl, C1-C4alkoxy, and C3-C4cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens or -CN.

[0049] In some embodiments, or example, ring A is selected from the group consisting of: ,, , , , , , ,, , , , , , ,F N NH2 , , , , , , , ,

[0050] In other embodiments, ring A is selected from the group consisting of, for example ,, , , , , , ,F F F F F F Cl N N F , , , , , NH2, NH2 , ,

[0051] In still other embodiments, for example, R1is hydrogen and R2is -CH3. For example, in certain embodiments ring A is selected from the group consisting of:wherein: RAis selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, and C3-C4cycloalkyl; wherein alkyl and alkoxy are each substituted with one, two, or three halogens;and RA1is selected from the group consisting of chloro, -CH3, and -CF3.

[0052] In some embodiments, ring A is selected from the group consisting of, for example:

[0053] In some embodiments, R1is hydrogen and R2is hydrogen. In other embodiments, ring A is selected from the group consisting of, for example,

[0054] In further embodiments, R3is selected from the group consisting of, for example, - NH2, chloro, and -CHF2. In certain embodiments, R3is -NH2. In additional embodiments, for example, R4is hydrogen and R5is -CH3. In some embodiments, R6is fluoro. In other embodiments, for example, R7is hydrogen or -CH3. In still other embodiments, R8and R9are each independently selected from the group consisting of, for example, hydrogen, deuterium, and -CH3

[0055] In certain other embodiments, RBis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -COOH, =CHCH3, =CHF, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C1-C3alkyl optionally substituted with hydroxyl, halogen, or - OCH3. In some embodiments, RBis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CH3, =CHCH3, =CHF, -COOH, -CH2OH, -CH2CH2F, CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0056] In some embodiments, ring B is selected from the group consisting of, for example:

[0057] In other embodiments, ring B and RBare absent and replaced with -CH2OH or cyclopropyl; wherein cyclopropyl is substituted with -CH2OH or -CH2NRaRb. In still other embodiments, ring B and RBare absent and replaced with a substituent selected from the group consisting of, for example, -CH2OH, ,, , .

[0058] In some embodiments, for example, a compound of the present disclosure is represented by Formula IA:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: R1is halogen, R2is hydrogen or -CH3, and ring A is selected from the group consisting ofR1is hydrogen, R2is -CH3, and ring A is selected from the group consisting of:R1is hydrogen, R2is hydrogen, and ring A is selected from the group consisting of:, , , and ; R7is selected from the group consisting of hydrogen and -CH3; R8and R9are each independently selected from the group consisting of hydrogen, deuterium, and -CH3; and B is selected from the group consisting of and .

[0059] In other embodiments, for example, a compound of the present disclosure is selected from the group consisting ofor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

[0060] Also disclosed herein is a compound represented by Formula II:Formula II; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: ring A is selected from the group consisting of indazolyl, quinolinyl, quinolinonyl, benzothiophenyl, benzothiazolyl, pyridinyl, pyrimidinyl, and phenyl; wherein ring A is substituted with one, two, or three substituents each independently selected from RA;RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- 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)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; R1is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, -CH(CH3)-(C3-C6cycloalkyl), -CH2-(C3-C6cycloalkyl), phenyl, 5-membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R11; R2is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C6cycloalkyl, -CH(CH3)-(C3-C6cycloalkyl), -CH2-(C3-C6cycloalkyl), phenyl, 5- membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R22; R11and R22are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, phenyl, - COOH, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1- C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl; R3is selected from the group consisting of hydrogen and C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; R4is selected from the group consisting of halogen, hydrogen, deuterium, and C1- C3alkyl; R5and R6are each independently selected from the group consisting of hydrogen, deuterium, and C1-C3alkyl; Ring B is selected from the group consisting of 5-10 membered heterocyclyl containing at least one ring nitrogen;RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand 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, C1- C6alkyl, and C1-C6alkoxy; and m is 0, 1, 2, 3, or 4; wherein if ring A is benzothiophenyl, then R1is CH3or substituted C1-C6alkyl.

[0061] For example, in some embodiments R3is hydrogen or CH3. In other embodiments, R4is fluoro. In still other embodiments, R5and R6are each hydrogen. In certain embodiments, for example, a compound of the present disclosure is represented by Formula IIA:Formula IIA.

[0062] In some embodiments, ring A is selected from the group consisting of, for example, indazolyl, quinolinyl, quinolinonyl, benzothiazolyl, pyridinyl, pyrimidinyl, and phenyl; wherein ring A is substituted with one, two, or three substituents each independently selected from RA. In other embodiments, RAis independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, -NH2, C1-C4alkyl, and C2-C4alkynyl, C1- C4alkoxy, and C3-C4cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens.

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

[0064] In further embodiments, ring A is selected from the group consisting of, for example,

[0065] In some embodiments, R1is selected from the group consisting of, for example, C1- C6alkyl, C3-C4cycloalkyl, -CH(CH3)-(C3-C4cycloalkyl), and -CH2-(C3-C4cycloalkyl), wherein alkyl and cycloalkyl may optionally be substituted by one, two, three, or four groups eachindependently selected from the group consisting of halogen, hydroxyl, cyano, and - C(=O)NRaRb. In other embodiments, R1is selected from the group consisting of -CH3, - CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, - CH2CH2OH, -CH2CH2CH2OH, , , , , , , , , , and .

[0066] In further embodiments, R1is selected from the group consisting of, for example, 5- membered heteroaryl, -CH2-(5-membered heteroaryl), and -CH(CH3)-(5-membered heteroaryl), wherein heteroaryl may optionally be substituted with one or two substituents each independently selected from the group consisting of -NRaRband C1-C3alkyl, and wherein alkyl may optionally be substituted with one, two or three halogens. For example, in certain embodiments R1is selected from the group consisting of

[0067] In some embodiments, ring A is benzothiophenyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, cyano, -NH2, and -C(O)NH2. For example, in some embodiments ring A is selected from the group

[0068] In other embodiments, R1is selected from the group consisting of, for example, - CH3,-CH2CHF2, and -CH2CH2OH. In still other embodiments, R2is selected from the group consisting of hydrogen and C1-C6alkyl, wherein alkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of halogen and hydroxyl. In certain embodiments, R2is selected from the group consisting of hydrogen, -CH3, and -CH2CH2OH. In further embodiments, RBis selected from the group consisting of, for example, halogen, hydroxyl, and C1-C3alkyl. In additional embodiments, RBis selected from the group consisting of halogen, hydroxyl, and -CH3.

[0069] In some embodiments, ring B is selected from the group consisting of, for example:

[0070] In some embodiments, a compound of the present disclosure is represented by Formula IIB:Formula IIB; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting of ,, , , , , , ,, , , , , , , ,, and ; R1is selected from the group consisting of -CH3, -CH2CH3, -CH2CN, -CH2CHF2, - CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, -CH2CH2OH, -CH2CH2CH2OH,-CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, - CH2CH2OH, -CH2CH2CH2OH, , ONH2R2is selected from the group consisting of hydrogen, -CH3, and -CH2CH2OH; and R3is hydrogen or CH3.

[0071] In other embodiments, for example, a compound of the present disclosure is selected from the group consisting ofor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

[0072] Also disclosed is a compound represented by Formula III:Formula III; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: RA1and RA2are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- 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)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; R1’is hydrogen and R1is selected from the group consisting of hydrogen, -CH3, -CF3, - CH2CH2OH, -CH2C(CH3)2OH, C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, phenyl, 5-membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl is substituted with one, two, three, or four substituents each independently selected from R11; and wherein alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R22; andR2is selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, - CH2CH2CH2OH, -CH2CH(CH3)OH, -CH2C(CH3)2OH, C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3cycloalkyl, C5-C6cycloalkyl, phenyl, 5-membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl is substituted with one, two, three, or four substituents each independently selected from R11; and wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R22; or: R1and R1’, together with the carbon atom to which they are attached, may be joined together to form C3-cycloalkyl optionally substituted with one, two or three halogens or hydroxyl; and R2is C1-C6alkyl substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -COOH, and C(=O)NRaRb; or R1and R1’, together with the carbon atom to which they are attached, may be joined together to form C4-cycloalkyl optionally substituted with one, two or three halogens or hydroxyl; and R2is C1-C6alkyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -COOH, and C(=O)NRaRb; R11is independently selected for each occurrence from the group consisting of halogen, deuterium, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, - COOH, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1- C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl; R22is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -COOH, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl; R3is selected from the group consisting of halogen, hydrogen, deuterium, and C1- C3alkyl;Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand 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, C1- C6alkyl, and C1-C6alkoxy; Rcand Rdare each independently selected from the group consisting of hydrogen and C1-C6alkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2; wherein: if R1is hydrogen, then R2is not hydrogen, -CH3, or CH2CH2OH; and if R1is -CH3, then R2is not hydrogen, -CH3, -CH2CF2, -CH2CF3, or -CH2CH(CH3)OH.

[0073] For example, in some embodiments RA1and RA2are independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, cyano, -NH2, C1- C4alkyl, and C2-C4alkynyl, C1-C4alkoxy, and C3-C4cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens. In other embodiments, m is 1 or 2 and RA1is independently selected for each occurrence from the group consisting of halogen, C1-C4alkyl, C2-C4alkynyl, and C3-C4cycloalkyl. In still other embodiments, n is 1 and RA2is hydroxyl or -NH2.

[0074] In some embodiments,selected from the group consisting of, , , , , and .

[0075] In other embodiments, is selected from the group consisting of, , , , , and .

[0076] In some embodiments, R1’ is hydrogen. In other embodiments, R1is hydrogen. In further embodiments, R2is selected from the group consisting of, for example, -CH2CN, - CH2CH(OH)CH3, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3. In certain embodiments, R1is -CH3. In additional embodiments, R2is selected from the group consisting of, for example, -CH2CH2OH, -CH2CH2CH2OH, - CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, -CH2CH2C(O)NHCH3, , , and .

[0077] In some embodiments, R1is selected from the group consisting of -CF3, -CH2CF3, - ONH2CH2CH2OH, -CH2C(CH3)2OH, , ,N, and .

[0078] In other embodiments, R2is selected from the group consisting of hydrogen, -CH3, - CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3.

[0079] In some embodiments, R1’and R1, together with the carbon atom to which they are attached, are joined together to form C3-cycloalkyl optionally substituted with hydroxyl; and R2is -CH2CH2OH. For example, in certain embodiments R1’and R1, together with the carbon atom to which they are attached, are joined together to form C4-cycloalkyl optionally substituted with hydroxyl; and R2is -CH3. In other embodiments, R3is hydrogen.

[0080] In some embodiments, a compound of the present disclosure is represented by Formula IIIB: Formula IIIB; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:is selected from the group consisting of , , , ,, and ; andR1is hydrogen; and R2is selected from the group consisting of -CH2CN, - CH2CH(OH)CH3, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3; or R1is -CH3; and R2is selected from the group consisting of -CH2CH2OH, - CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, -CH2CH2C(O)NHCH3, , , and ; or R1is selected from the group consisting of -CF3, -CH2CF3, -CH2CH2OH, - CH2C(CH3)2OH,; and R2is selected from the group consisting of hydrogen, -CH3, -CH2CHF2, - CH2CF3, -CH2CH2OH, -CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3.

[0081] In other embodiments, a compound of the present disclosure is selected from the group consisting of, for example:or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

[0082] In further embodiments, a compound of the present disclosure is selected from the group consisting of, for example: , , , ,or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

[0083] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds.

[0084] 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 thoseskilled 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.

[0085] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatised 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.

[0086] 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).

[0087] 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.

[0088] 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

[0089] 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.

[0090] 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).

[0091] 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.

[0092] In certain embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, related to the cardiovascular system. Non- limiting examples contemplated herein include, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma.

[0093] 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.

[0094] 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).

[0095] 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).

[0096] 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.

[0097] 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.

[0098] 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 cell tumor chordoma, osteochronfroma (for example, osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.

[0099] 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).

[0100] 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).

[0101] 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).

[0102] In certain embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, of the skin. Non-limiting examples contemplated 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.

[0103] 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.

[0104] 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.

[0105] In some embodiments, the Ras protein is wild-type (Raswt). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Raswt(e.g., K-Raswt, H-Raswtor N-Raswt). 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).

[0106] 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.

[0107] 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.

[0108] 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.

[0109] In some embodiments, a compound disclosed herein inhibits Raswtin addition to one or more additional Ras mutations (e.g., K, H or N-Raswtand 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-Raswtand H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61 H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Raswtand 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).

[0110] 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, K117N, 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, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0111] 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 G12Dmutation. 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 pancreactic cancer and comprises a K-Ras G12D mutation. In further embodiments, the cancer is lung cancer or pancreactic 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 Raswt(e.g., K-, H- or N-Raswt) or Rasamp(e.g., K-, H- or N- Rasamp).

[0112] 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.

[0113] 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 additionaltherapeutic 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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-acetoxypregnenolone, 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, fluorometholone, 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.

[0119] 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.

[0120] 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, thecheckpoint 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, CD160, 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.

[0121] In some embodiments, a therapeutic agent contemplated herein may be an anti- cancer 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.

[0122] 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; callystatin; adozelesin; carzelesin; bizelesin; cryptophycins (e.g., cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin and synthetic analogues; eleutherobin; pancratistatin; 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, nilutarnide, bicalutarnide, leuprnlide, goserelin; chlorarnbucil; 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.

[0123] 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, dichloroacetic 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.

[0124] 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 anilidehydroamic acid, vorinostat, romidepsin, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors, DNA binding agents, Pl3K 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-lL-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.

[0125] 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 contemplatd anti- cancer agent is a SHP2 inhibitor an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a Pl3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor).

[0126] 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.

[0127] 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).

[0128] The methods described herein include administering to the patient a therapeutically effective amount of at least one compound as described herein, which is optionally formulatedin 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.

[0129] 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.

[0130] 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

[0131] 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.

[0132] 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.

[0133] 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, dicalcium 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 non-toxic 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.

[0134] 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 as fillers 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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 non- irritating 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0144] 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.

[0145] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptablecarrier 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 duodenum, jejunum, 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.

[0146] 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 dosageforms (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.

[0147] 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 one tablet 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

[0148] 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.

[0149] HPLC conditions: Method A A: Column: XBridge Prep OBD C18 Column, 30*150mm, 5 m; Mobile Phase A: water (10mmol / L NH4HCO3+0.05% NH3H2O), Mobile Phase B:MeCN; Flow rate: 60 mL / min; Method B: Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeCN; Flow rate: 60mL / min; Method C: Column: Xselect CSH C18 OBD Column 19*250mm 5 m; Mobile PhaseA: Water (0.1% FA), Mobile Phase B: MeCN; Flow rate: 30 mL / min; Method PL: Phenomenex Luna C18150*25mm*10um; Mobile phase: (water (0.225%FA)-MeCN). Synthesis of Intermediates: Synthesis of 5,7-dichloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate 1)Step 1: Synthesis of methyl (2,4,6-trichloronicotinoyl)carbamimidothioate

[0150] A mixture of methyl carbamimidothioate (33.4 g, 179.2 mmol) and NaHCO3 (37.8g, 448 mmol) in THF / H2O) (90 mL, 1:2) was stirred at rt for 10 min then 2,4,6-trichloronicotinoyl chloride (11g, 44 mmol) in THF (50 mL) was added and the reaction mixture stirred at rt for 1 h. The reaction was quenched with H2O (300 mL) and extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give the title compound as a yellow oil, (10.1 g, 75.3%) as a yellow oil. LCMS m / z = 300 [M+H]+ Step 2: Synthesis of 5,7-dichloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0151] DIPEA (10.93 g, 84.6 mmol) was added to a solution of methyl (2,4,6- trichloronicotinoyl)carbamimidothioate (10.1 g, 33.8 mmol) in dioxane (100 mL) and the reaction mixture was stirred at 100°C for 16 h under N2. The cooled mixture was concentrated in vacuo, the residue diluted with water and acidified to pH 4 with 2N HCl (aq). The precipitated solids were collected by filtration, washed with water (3x50 mL) and dried to give the title compound (6.1 g, 68.8%) as a yellow solid. LCMS m / z = 262 [M+H]+ Synthesis of tert-butyl (2-((tert-butyldiphenylsilyl)oxy)ethyl)(2-hydroxyethyl)carbamate (Intermediate 2)

[0152] Imidazole (1.99 g, 29.2 mmol) and tert-butyl(chloro)diphenylsilane (4.42 g, 16.08 mmol) was added to a solution of tert-butyl N,N-bis(2-hydroxyethyl)carbamate (3 g, 14.62 mmol) in anhydrous DMF (10 mL) and the reaction mixture was stirred for 2 h at rt under N2. The reaction was quenched with water (10 mL) and the mixture was extracted with EtOAc (25 mL x 3). The combined organic layer was washed with brine (10 mL x 3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (0.1% TFA), 10% to 50% gradient in 10 min, to give the title compound (2 g, 30.8%) as a colorless oil. LCMS m / z = 444 [M+H]+Synthesis of tert-butyl (S)-(2-((tert-butyldiphenylsilyl)oxy)ethyl)(1-hydroxypropan-2- yl)carbamate (Intermediate 3)Step 1: Synthesis of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)propan-1-ol

[0153] (2-Bromoethoxy)(tert-butyl)diphenylsilane (5.8 g, 15.96 mmol) was added to a solution of (2S)-2-aminopropan-1-ol (1.80 g, 23.94 mmol) in MeCN (20 mL) and the reaction mixture stirred for 3 h at 80°C under N2. The resulting mixture was cooled to rt and evaporated under reduced pressure to give the title compound (2.34 g, crude) as a white solid. LCMS m / z = 358 [M+H]+ Step 2: Synthesis of tert-butyl (S)-(2-((tert-butyldiphenylsilyl)oxy)ethyl)(1-hydroxypropan-2- yl)carbamate

[0154] (Boc)2O (1.71 g, 7.85 mmol) was added in portions to a solution of (S)-2-((2-((tert- butyldiphenylsilyl)oxy)ethyl)amino)propan-1-ol (2.34 g, 6.54 mmol) and TEA (1.36 mL, 9.82 mmol) in DCM (15 mL) and the reaction mixture was stirred for 3 h at rt under N2. The reaction was diluted with water (100 mL) and the mixture extracted with DCM (10 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to afford the title compound (1.7 g, 39.7%) as a colorless oil. LCMS m / z = 458 [M+H]+ Synthesis of tert-butyl (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)(2- hydroxyethyl)carbamate (Intermediate 4)Step 1: Synthesis of tert-butyl (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)carbamate

[0155] TBDPS-Cl (17.25 g, 62.78 mmol) was added to a solution of tert-butyl (R)-(2- hydroxypropyl)carbamate (10 g, 57.07 mmol) and imidazole (7.77 g, 114.1 mmol) in DMF (100 mL) at 0oC and the reaction mixture was stirred overnight at rt under N2. The reaction was quenched with water and the resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (5:1)) to afford the title compound (23 g, 97.4%) as colorless oil. LCMS m / z = 414 [M+H]+ Step 2: Synthesis of tert-butyl (R)-(2-(benzyloxy)ethyl)(2-((tert-butyldiphenylsilyl)oxy)propyl) carbamate

[0156] A solution of tert-butyl (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)carbamate (10 g, 24.18 mmol) in anhydrous DMF (100 mL) was treated with NaH (2.90 g, 72.5 mmol, 60%) at 0°C under N2and the mixture was stirred at 0oC for 10 min. ((2-Bromoethoxy)methyl)benzene (7.80 g, 36.26 mmol) was added and the reaction mixture was stirred for 16 h at rt. The reaction was quenched by water (100 mL) at 0°C and the resulting mixture extracted with EtOAc (3 x 150mL). The combined organic layers were washed with brine (3x200 mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse-phase column chromatography using C18 gel, eluting with MeCN in water (0.1% FA), 10% to 50% gradient in 10 min to afford the title compound (4.5 g, 34.0%) as a white oil. LCMS m / z = 548 [M+H]+ Step 3: Synthesis of tert-butyl (R)-(2-((tert-butyldiphenylsilyl)oxy)propyl)(2-hydroxyethyl) carbamate

[0157] Pd / C (4.71 g, 12.53 mmol) was added carefully to a solution of tert-butyl (R)-(2- (benzyloxy)ethyl)(2-((tert-butyldiphenylsilyl)oxy)propyl)carbamate (4.5 g, 8.58 mmol) in MeOH (50 mL) and the reaction mixture was stirred for 16 h at 20°C under H2. The mixture was filtered and the filter cake was washed with MeOH (3x40 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (0.1% TFA), 80% to 90%gradient in 10 min, to give the title compound (2.6 g, 66.2%) as a colorless oil. LCMS m / z = 458 [M+H]+ Synthesis of tert-butyl (S)-(2-((tert-butyldiphenylsilyl)oxy)propyl)(2- hydroxyethyl)carbamate (Intermediate 5)

[0158] The title compound was obtained as a colorless oil, from tert-butyl (S)-(2- hydroxypropyl)carbamate, following the 3-step procedure described in Intermediate 4. LCMS m / z = 458 [M+H]+ Synthesis of tert-butyl (R)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybutan-2- yl)(methyl)carbamate (Intermediate 6)Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-D-homoserine

[0159] Imidazole (24.84 g, 364.9 mmol) was added in portions to a solution of (tert- butoxycarbonyl)-D-homoserine (10 g, 45.6 mmol) in DCM (500 mL). TBDPSCl (18.81 g, 68.42 mmol) was then added portion-wise and the reaction mixture was stirred for 16 h at rt. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3x100mL), dried over anhydrousNa2SO4, filtered and the filtrate was evaporated under reduced pressure to afford the title compound, crude as a colorless oil. LCMS m / z = 480 [M+H]+ Step 2: Synthesis of methyl N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-N-methyl-D- homoserinate

[0160] CH3I (178.7 g, 1.26 mol) was added dropwise to a solution of N-(tert- butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-D-homoserine (28.8 g, 62.93 mmol) and Ag2O (72.92 g, 314.7 mmol) in DMF (500 mL) at 0°C under N2. The reaction mixture was slowly warmed to rt and stirred for 16 h. The reaction mixture was filtered, washing through with EtOAc and the filtrate washed with sat. brine. The brine was extracted with additional EtOAc (3 x 250 mL). The combined organic layers were washed with fresh brine (3x200mL), dried overanhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc: PE, 1:5) to afford the title compound (25.8 g, 84.4%) as a colorless oil. LCMS m / z = 486 [M+H]+ Step 3: Synthesis of tert-butyl (R)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybutan-2- yl)(methyl)carbamate

[0161] NaBH4 (30.14 g, 797 mmol) was added in portions to a solution of methyl N-(tert- butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-N-methyl-D-homoserinate (10 g, 20.5 mmol) in MeOH (150 mL) and THF (150 mL) at 0°C under N2. The reaction mixture was slowly warmed to rt and stirred for 1h. The reaction was quenched with water (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100mL), the combined organic layers were washed with brine (3x100mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc: PE (1:2) to afford the title compound (7g, 74.3%) as a colorless oil. LCMS m / z = 458 [M+H]+ Synthesis of tert-butyl (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybutan-2- yl)(methyl)carbamate (Intermediate 7)

[0162] The title compound was obtained as a colorless oil, from (tert-butoxycarbonyl)-L- homoserine following the same 3 step procedure described in Intermediate 6. Synthesis of tert-butyl (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybutan-2- yl)carbamate (Intermediate 8)Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-homoserine

[0163] The title compound was obtained, 12.5 g, 60%, as a colorless oil, from (tert- butoxycarbonyl)-L-homoserine, following a similar procedure to that described in Intermediate 6, step 1. LCMS m / z = 458 [M+H]+ Step 2: Synthesis of tert-butyl (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-hydroxybutan-2- yl)carbamate

[0164] LiAlH4 (1.85 g, 48.8 mmol) was added dropwise to an ice-cooled solution of the compound from step 1 (7.44 g, 16.3 mmol) in THF (80 mL) and the reaction mixture stirred at rt under N2 for 1 h. The reaction was quenched with water at 0°C and the mixture extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (3x100mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc: PE (1:3) to afford the title compound (3.5 g, 48.5%) as a colorless oil. LCMS m / z = 444 [M+H]+ Synthesis of (1-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)cyclopropyl)methanol (Intermediate 9)

[0165] tert-Butyl(2-iodoethoxy)diphenylsilane (4.38 g, 10.7 mmol) in DMSO (1.5 mL) was added dropwise to a solution of (1-aminocyclopropyl)methanol (1.5 g, 10.7 mmol) in DMSO (1.5 mL) and DIPEA (5.58 mL, 32.0 mmol) and the reaction mixture was stirred overnight at 60°C. The mixture was extracted with EtOAc (2 x 250mL), the combined organic layers were washed with brine (3x500 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to afford the title compound (880 mg, 22.3%) as a yellow oil. LCMS m / z = 370 [M+H]+ Synthesis of (R)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)propan-1-ol (Intermediate 10)

[0166] A mixture of (R)-(-)-2-amino-1-propanol (6.20 g, 82.6 mmol) and (2- bromoethoxy)(tert-butyl)diphenylsilane (20 g, 55.0 mmol) in MeCN (200 mL) was stirred for 3h at 80°C. The cooled reaction was quenched with water at rt, the layers separated and the aqueous phase extracted with DCM (3x200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN in Water (0.1% NH4HCO3), 15% to 35% gradient in 10 min, to afford the title compound (7.1 g, 36.1%) as a white solid. LCMS m / z = 358 [M+H]+Synthesis of 2-((3-((tert-butyldiphenylsilyl)oxy)propyl)amino)ethan-1-ol (Intermediate 11)

[0167] The title compound was obtained as a yellow solid, 2.63 g, 55.5%, from ethanolamine and (3-bromopropoxy)(tert-butyl)diphenylsilane, following a similar procedure to that described in Intermediate 10. LCMS m / z = 358 [M+H]+Synthesis of (S)-2-((3-((tert-butyldiphenylsilyl)oxy)propyl)amino)propan-1-ol trifluoroacetate (Intermediate 12)

[0168] (2S)-2-Aminopropan-1-ol (1.49 g, 19.9 mmol) was added to a solution of (3- bromopropoxy)(tert-butyl)diphenylsilane (5 g, 13.2 mmol) in MeCN (100 mL ) and theresulting mixture was stirred overnight at 80 . The mixture was concentrated under reducedpressure and the residue was purified by reverse-phase column chromatography on C18 silica gel eluting with MeCN in Water (0.1% TFA), 10% to 100% gradient in 20 min, to give the title compound (2 g, 40.6%) as a yellow oil. LCMS m / z = 372 [M+H]+ Synthesis of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-2-cyclopropylethan-1-ol (Intermediate 13)

[0169] To a stirred solution of (S)-2-amino-2-cyclopropylethan-1-ol hydrochloride (1 g, 9.9 mmol), KI (0.82 g, 4.94 mmol) and Cs2CO3 (9.66 g, 29.7 mmol) in DMF (10 mL) was added (2-bromoethoxy)(tert-butyl)diphenylsilane (4.67 g, 12.9 mmol) in portions at 60 °C under N2. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (2x20 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC eluting with EtOAc to afford the title compound (570 mg, 15%) as a yellow solid. LCMS m / z = 384 [M+H+Na]+Synthesis of (S)-4-((tert-butyldiphenylsilyl)oxy)-2-(ethylamino)butan-1-ol (Intermediate 14)Step 1: Synthesis of N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-homoserine

[0170] The title compound was obtained as a colorless oil, 12.5 g, 60%, from (tert- butoxycarbonyl)-L-homoserine, following a similar procedure to that described in Intermediate 6, step 1. LCMS m / z = 458 [M+H]+ Step 2: Synthesis of methyl N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-homoserinate

[0171] To a stirred solution of the compound from step 1 (12.5 g, 27.3 mmol) and Ag2O (19.0 g, 81.9 mmol) in DMF (300 mL) was added CH3I (4.65 g, 32.8 mmol) and the reaction mixture was stirred for 16 h at rt under N2. The resulting mixture was filtered, the filter cake was washed with EtOAc and the filtrate diluted with saturated brine. The aqueous layer was separated and extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (3x100mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc: PE (1:10) to afford the title compound (11.5 g, 89.3%) as a colorless oil.1H NMR (400 MHz, CDCl3) 7.73 – 7.61 (m, 4H), 7.47 – 7.32 (m, 6H), 4.46 (td, 1H), 3.71 (d, 5H), 2.18 – 1.85 (m, 2H), 1.45 (s, 9H), 1.07 (s, 9H). Step 3: Synthesis of methyl N-(tert-butoxycarbonyl)-O-(tert-butyldiphenylsilyl)-L-homoserinate

[0172] The title compound was obtained as a yellow oil, 3.12 g, crude, from the compound from step 2, following a similar procedure to that described in Example 2, step 2. LCMS m / z = 372 [M+H]+ Step 4: Synthesis of methyl O-(tert-butyldiphenylsilyl)-N-ethyl-L-homoserinate

[0173] To a stirred solution of the compound from step 3 (2.46 g, 6.6 mmol) and acetaldehyde (0.88 g, 7.9 mmol, 40%) in DCM (20 mL) was added TEA (2.01 g, 19.86 mmol)at 0°C and the reaction mixture was stirred at rt for 1.5 h under N2. NaBH(OAc)3 (2.81 g, 13.2 mmol) was added and the reaction mixture stirred for an additional 1.5 h at rt. The mixture was cooled to 0°C, diluted with brine (10 mL) and extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (3 x 50mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (10 mmol NH4CO3), 80% to 90% gradient in 10 min to afford the title compound (1.55 g, 58.6%) as a colorless oil. LCMS m / z = 400 [M+H]+ Step 5: Synthesis of (S)-4-((tert-butyldiphenylsilyl)oxy)-2-(ethylamino)butan-1-ol

[0174] The title compound was obtained as a yellow oil, 0.55 g, 39.4%, from the compound from step 4, following a similar procedure to that described in Intermediate 8, step 2. LCMS m / z = 372 [M+H]+ Synthesis of (3-((tert-butyldiphenylsilyl)oxy)-1-(methylamino)cyclobutyl)methanol (Intermediate 15)Step 1: Synthesis of 1-((tert-butoxycarbonyl)amino)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane- 1-carboxylic acid

[0175] TBDPSCl (8.9 g, 32.4 mmol) was added to a solution of 1-((tert- butoxycarbonyl)amino)-3-hydroxycyclobutane-1-carboxylic acid (5 g, 21.6 mmol) in DMF (50 mL) at 0°C under N2. Imidazole (4.4 g, 64.9 mmol) and DMAP (0.5 g, 4.32 mmol) were added in portions at 0°C and the reaction mixture was stirred overnight at 50°C under N2. The mixture was extracted with EtOAc, the combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (10 mmol NH4CO3), 10% to 40% gradient in 10 min. The combinedcolumn fractions were extracted with EtOAc (3 x 10 mL), the combined organic layers were washed with citric acid (3x10 mL), dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to afford the title compound (6.5 g, 64.0%) as a colorless oil. LCMS m / z = 471 [M+H]+Step 2 Synthesis of methyl 1-((tert-butoxycarbonyl)(methyl)amino)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane-1-carboxylate

[0176] To a stirred mixture of the compound from step 2 (6 g, 12.78 mmol) and NaH (919 mg, 38.3 mmol) in DMF (60 mL) was added MeI (5.4 g, 38.3 mmol) dropwise at 0°C under N2 and the reaction mixture was stirred for 1h at rt. The mixture was extracted with EtOAc, the combined organic layers were washed with brine and Na2S2O3 (3x10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to afford the title compound (6 g, 94.4%) as a yellow oil. LCMS m / z = 498 [M+H]+ Step 3: Synthesis of tert-butyl (3-((tert-butyldiphenylsilyl)oxy)-1-(hydroxymethyl)cyclobutyl) (methyl)carbamate

[0177] To a solution of the compound from step 2 (1.0 g, 2.0 mmol) in Et2O (20 mL) was added BF3.Et2O (427.7 mg, 3.0 mmol) dropwise at 0°C, followed by NH3.BH3(155 mg, 5.0 mmol) in portions at 0°C. The reaction mixture was stirred for 1h at rt. The reaction wasquenched with HCl (1M, 10mL) at 0 and extracted with EtOAc. The combined organic layerswere washed with brine (3x10 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (0.1% TFA), 10% to 85% gradient in 10 min, to afford the title compound (0.8 g, 84.8%) as a colorless oil. LCMS m / z = 470 [M+H]+ Step 4: Synthesis of (3-((tert-butyldiphenylsilyl)oxy)-1-(methylamino)cyclobutyl)methanol

[0178] A solution of the compound from step 3 (2.5 g, 5.32 mmol) and ZnBr2 (11.99 g, 53.2 mmol) in DCM (20 mL) was stirred for 1h at rt under N2. The resulting mixture was filtered and the filter cake was washed with DCM (20 mL). The filtrate was evaporated under reduced pressure to afford the title compound (740 mg, 37.6%) as a colorless oil. LCMS m / z = 370 [M+H]+ Synthesis of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-4,4,4-trifluorobutan-1-ol (Intermediate 16)Step 1: Synthesis of tert-butyl (S)-(4,4,4-trifluoro-1-hydroxybutan-2-yl)carbamate

[0179] A solution of (S)-2-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutanoic acid (1.0 g, 3.9 mmol) in THF (1.5 mL) was treated with borane THF complex (19.44 mL, 1M, 19.44 mmol) at 0°C and the reaction mixture was stirred for 2 h at rt. The reaction was quenched with MeOH (10 mL) at 0°C and the mixture was stirred for 1h at rt. The mixture was evaporated under reduced pressure to give the title compound (530 mg, 56.1%) as a yellow oil. LCMS m / z = 244 [M+H]+ Step 2: Synthesis of (2S)-2-amino-4,4,4-trifluorobutan-1-ol hydrochloride

[0180] A solution of the compound from step 1 (1.03 g, 4.2 mmol) and HCl in dioxane (2 mL, 4M, 8 mmol) in dioxane (2 mL) was stirred for 2 h at rt. The resulting mixture was evaporated under reduced pressure to afford the title compound (600 mg, crude) as a yellow oil. LCMS m / z = 144 [M+H]+ Step 3: Synthesis of (S)-2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-4,4,4-trifluorobutan-1- ol

[0181] The title compound was obtained as a yellow oil, 375 mg, 25%, from the compound from step 2, following a similar procedure to that described in Intermediate 9. LCMS m / z = 426 [M+H]+ Synthesis of (S)-4-((tert-butyldiphenylsilyl)oxy)-2-((2,2-difluoroethyl)amino)butan-1-ol (Intermediate 17)Step 1 Synthesis of methyl O-(tert-butyldiphenylsilyl)-L-homoserinate

[0182] TFA (5 mL) was added to a solution of methyl N-(tert-butoxycarbonyl)-O-(tert- butyldiphenylsilyl)-L-homoserinate (5 g, 10.6 mmol) in DCM (10 mL) and the reaction mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure, the residue was washed with water (5x5 mL). The resulting mixture was extracted with EtOAc (3 x 200mL). The combined organic layers were washed with brine (400 mL), dried over Na2SO4,filtered and the filtrate was evaporated under reduced pressure to give the title compound (3.5 g, 88.9%) as a yellow oil. LCMS m / z = 372 [M+H]+ Step 2: Synthesis of methyl O-(tert-butyldiphenylsilyl)-N-(2,2-difluoroethyl)-L-homoserinate

[0183] A solution of 2,2-difluoroethyl trifluoromethanesulfonate (5.19 g, 24.2 mmol) in MeCN (5 mL) was added to a solution of the compound from step 1 (3 g, 8.1 mmol) in MeCN (5 mL). DIPEA (28.13 mL, 161.5 mmol) was then added dropwise and the reaction mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1) to afford the title compound (1.98 g, 56.3%) as a colorless oil. LCMS m / z = 436 [M+H]+ Step 3: Synthesis of (S)-4-((tert-butyldiphenylsilyl)oxy)-2-((2,2-difluoroethyl)amino)butan-1-ol

[0184] The title compound was obtained as a colorless oil, 1.33 g, 90.3%, from the compound from step 2, following a similar procedure to that described in Intermediate 15, step 3. LCMS m / z = 408 [M+H]+ Synthesis of (2-bromo-3,3,3-trifluoropropoxy)(tert-butyl)diphenylsilane (Intermediate 18)

[0185] The title compound was obtained as a white oil, 2.05 g, 36%, from 2-bromo-1,1,1- trifluorobutane and TBDPSCl, following a similar procedure to that described in Intermediate 6, step 1.1H NMR (400 MHz, DMSO-d6) 1.02 (s, 9H), 3.95 (s, 1H), 4.05 (s, 1H), 5.02 – 5.15 (m, 1H), 7.42 – 7.55 (m, 6H), 7.65 (m, 4H). Synthesis of (3-(methylamino)tetrahydrofuran-3-yl)methanol (Intermediate 19)Step 1: Synthesis of methyl 3-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-carboxylate

[0186] (Boc)2O (1 g, 4.59 mmol) and Na2CO3(2.43 g, 22.9 mmol) were added to a solution of methyl 3-aminotetrahydrofuran-3-carboxylate hydrochloride (500 mg, 2.29 mmol) indioxane (2 mL) and H2O (2 mL) and the reaction mixture was stirred at rt overnight. The reaction was diluted with H2O, extracted with EtOAc, the combined organic extracts dried and evaporated under reduced pressure to afford the title compound (500 mg, 88.9%) as colorless oil. LCMS m / z = 246 [M+H]+ Step 2: Synthesis of methyl 3-((tert-butoxycarbonyl)(methyl)amino)tetrahydrofuran-3- carboxylate

[0187] The title compound was obtained as a colorless oil, 3 g, 63.9%, from the compound from step 1 and MeI, following a similar procedure to that described in Intermediate 14, step 2. LCMS m / z = 260 [M+H]+ Step 3: Synthesis of methyl 3-(methylamino)tetrahydrofuran-3-carboxylate

[0188] A mixture of the compound from step 2 (2.5 g, 9.64 mmol) and TFA (5.50 g, 48.2 mmol) in DCM (50 mL) was stirred at rt under N2. The mixture was basified to pH=8 with saturated NaHCO3(aq.) and the mixture was evaporated under reduced pressure, to give the title compound, crude as a white solid. LCMS m / z = 160 [M+H]+ Step 4: Synthesis of (3-(methylamino)tetrahydrofuran-3-yl)methanol

[0189] To a stirred mixture of the compound from step 3 (1.55 g, 9.74 mmol) and BF3.Et2O (2.76 g, 19.47 mmol) in Et2O (30 mL) was added NH3.BH3 (901.8 mg, 29.21 mmol) at 0 °C under N2. The mixture was acidified to pH=4 with conc. HCl. The aqueous layer was extracted with EtOAc (3x30 mL) and the combined organic extracts were evaporated under reduced pressure to afford the title compound, crude, 1 g, as a colorless oil. LCMS m / z = 131 [M+H]+ Synthesis of 3-chloro-4-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Intermediate 20)

[0190] A mixture of 3-bromo-5-chloro-4-cyclopropylphenol (630 mg, 2.55 mmol), bis(pinacolato)diboron (975 mg, 3.84 mmol), Pd(dppf)Cl2.CH2Cl2 (228 mg, 0.28 mmol) and KOAc (750 mg, 7.65 mmol) in dioxane (10 mL) was stirred for 2 h at 100 °C under N2. The reaction was quenched with water at rt and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluting with PE / EtOAc (5:1) to afford the title compound (330 mg, 41.8%) as a white solid.1H NMR (300 MHz, CDCl3) 6.97 – 6.86 (m, 2H), 3.50 (s, 3H), 1.95 (m, 1H), 1.37 (s, 12H), 1.31 (s, 1H), 1.26 (s, 5H), 1.08 – 0.85 (m, 3H), 0.59 – 0.42 (m, 2H). Synthesis of 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (Intermediate 21)Step 1: Synthesis of 1-bromo-3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzene

[0191] A solution of 1-bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene (2.20 g, 5.83 mmol), K3PO4(3.71 g, 17.49 mmol), cyclopropylboronic acid (0.74 g, 8.74 mmol) and Pd(dppf)Cl2(0.41 g, 0.58 mmol) in dioxane (20 mL) and H2O (4 mL) was stirred for 8 h at 100 °C under N2. The cooled mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water, 0% to 100% gradient in 20 min to afford the title compound (220 mg, 12.9%) as a brown oil.1H NMR (400 MHz, DMSO-d6) 7.19 (d, 1H), 7.03 (d, 1H), 5.11 (s, 2H), 3.46 (s, 3H), 1.69 – 1.64 (m, 1H), 1.19 – 1.07 (m, 2H), 0.78 – 0.62 (m, 2H). Step 2: Synthesis of 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane

[0192] The title compound was obtained as a yellow solid, 120 mg, 46.9%, from the compound from step 1, following a similar procedure to that described in Intermediate 20. LCMS: m / z = 339 [M+H]+ Synthesis of N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (Intermediate 22)Step 1: Synthesis of 4-bromo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine

[0193] NaH (1.60 g, 40.1 mmol) was added to a solution 4-bromo-6-methylpyridin-2-amine (3 g, 16.0 mmol) in DMF (30 mL) at 0 °C and the mixture stirred at rt for 30 min.1- (Chloromethyl)-4-methoxybenzene (5.53 g, 35.3 mmol) was added and the reaction mixture was stirred for 4 h at 25 °C. The reaction was diluted with DCM (50 mL), quenched with sat. aq NH4Cl solution and extracted with DCM (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography eluting with 0-30% EtOAc in hexane, to afford the title compound (6 g, 82%) as a white solid. LCMS m / z = 427 [M+H]+ Step 2: Synthesis of 4-bromo-5-iodo-N,N-bis(4-methoxybenzyl)-6-methylpyridin-2-amine

[0194] N-Iodosuccinimide (2.06 g, 9.17 mmol) was added to a solution of the compound from step 1 (4 g, 9.17 mmol) in AcOH (50 mL) at 0 °C and the reaction mixture was stirred for 2 h at 25 °C. The reaction was quenched with saturated Na2SO3 soln. and extracted with DCM (2 x 100 mL). The combined organic layer was washed with saturated NaHCO3 solution, washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (5 g, 88%) as a white solid. LCMS m / z = 553 [M+H]+ Step 3: Synthesis of 4-bromo-N,N-bis(4-methoxybenzyl)-6-methyl-5-(trifluoromethyl)pyridin-2- amine

[0195] Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.33 mL, 1.80 mmol), copper(I) iodide (430 mg, 2.25 mmol) and HPMA (800 mg, 4.52 mmol) were added to a solution of the compound from step 2 (500 mg, 0.90 mmol) in NMP (10 mL) and the reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentratedunder reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (300 mg, 51.6%) as a white solid. LCMS m / z = 497 [M+]+ Step 4: Synthesis of N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2- amine

[0196] The title compound was obtained, 200 mg, 29.1%, from the compound from step 3, following a similar procedure to that described in Intermediate 20. LCMS m / z = 543 [M+H]+ Synthesis of (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid (Intermediate 23)

[0197] A solution of 6-bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (1 g, 2.34 mmol), bis(pinacolato)diboron (1.19 g, 4.68 mmol), Pd(dppf)Cl2 (0.17 g, 0.23 mmol) and KOAc (0.46 g, 1.63 mmol) in dioxane (10mL) was stirred for 2 h at 80 °C. The cooled mixture was filtered and the filtrate evaporated under reduced pressure to afford the title compound, crude, as a yellow oil. LCMS m / z = 393 [M+H]+ Synthesis of (5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (Intermediate 24)Step 1: Synthesis of 4-bromo-5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0198] A mixture of 4-bromo-5,6-dimethyl-1H-indazole (1 g, 4.44 mmol), DHP (0.81 mL, 8.88 mmol) and TsOH.H2O (0.08 g, 0.44 mmol) in DCM (15 mL) was stirred for 3 h at rt under N2. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (25 mL) at 0 °C and the resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elutingwith PE / EtOAc (1: 2) to afford the title compound (1.3 g, 94.6%) as a yellow oil. LCMS m / z = 309 [M+H]+ Step 2: (5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid

[0199] A mixture of the compound from step 1 (500 mg, 1.62 mmol), bis(pinacolato)diboron (1.1 g, 4.85 mmol), Pd(dppf)Cl2.CH2Cl2 (131 mg, 0.16 mmol) andKOAc (476 mg, 4.85 mmol) in dioxane (20 mL) was stirred for 4 h at 100 under N2. Thereaction was quenched with water (100 mL) at rt and the resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (2x50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc 2:1) and the product further purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (10 mmol NH4CO3), 0% to 42% gradient in 30 min to give the title compound (426 mg, 76.9%) as a white solid. LCMS m / z = 275 [M+H]+ Synthesis of (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (Intermediate 25)Step 1: Synthesis of tert-butyl (4-bromo-7-fluorobenzo[d]thiazol-2-yl)carbamate

[0200] A mixture of 4-bromo-7-fluoro-1,3-benzothiazol-2-amine (2.0 g, 8.09 mmol), Boc2O (2.6 g, 12.14 mmol), TEA (2.5 g, 24.3 mmol) and DMAP (99 mg, 0.81 mmol) in DCM (30 mL) was stirred for 2 h at rt in air. The reaction was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc 20:1) to afford the title compound (1.7 g, 57.5%) as a white solid. LCMS m / z = 347 [M+H]+ Step 2: Synthesis of (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid

[0201] The title compound was obtained as a solid, 384 mg, 85%, from the compound from step 1, following a similar procedure to that described in Intermediate 24, step 2. LCMS m / z = 313 [M+H]+Synthesis of tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzo[b]thiophen-2-yl)carbamate (Intermediate 26)Step 1: Synthesis of tert-butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate

[0202] The title compound was obtained as a solid, 2.7 g, 98.5%, from 2-amino-4-bromo-7-fluorobenzo[b]thiophene-3-carbonitrile and (Boc)2O, following a similar procedure to thatdescribed in Intermediate 25, step 1. LCMS m / z = 368 [M+H]+ Step 2: Synthesis of tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzo[b]thiophen-2-yl)carbamate

[0203] A mixture of the compound from step 1 (2.8 g, 7.54 mmol), bis(pinacolato)diboron (15.7 g, 61.9 mmol), Pd(PPh3)4(1.0 g, 0.90 mmol) and KOAc (2.9 g, 30.2 mmol) in dioxane(80 mL) was stirred for 4 h at 95 under N2. The reaction was quenched with water (100 mL)at 0 and the mixture was extracted with DCM (3 x 150 mL). The combined organic layerswere washed with brine (3x50 mL), dried over Na2SO4, filtered the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (10 mmol NH4CO3), 0% to 48% gradient in 30 min to give the title compound (2.0 g, 63.3%) as a white solid. LCMS m / z = 417 [M-H]- Synthesis of 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-indazole (Intermediate 27)Step 1: Synthesis of 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene

[0204] To a solution of 1-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 and 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 Na2SO4, filtered and concentrated under reduced pressure to give the title compound (9 g, 78.8%) as a yellow oil.1H NMR (400 MHz, CDCl3) : 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

[0205] 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 NH4Cl (50 mL) at 0 °C, and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. 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, CDCl3) : 10.35 (s, 1H), 7.08 (d, 1H), 2.64 - 2.60 (m, 3H). Step 3: Synthesis of 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole

[0206] 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 1M HCl, 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 concentrated under reduced pressure to give the title compound (4.6 g, crude) as a yellow solid.1H NMR (400 MHz, CDCl3) 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-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H- indazole

[0207] 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 DHP (5.55 g, 65.94 mmol) in MeCN (20 mL) and the reaction mixture was stirred at 25 for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0 to 50% EtOAc / PE gradient @ 100 mL / min to give the title compound (5 g, 83.5%) as a yellow oil.1H NMR (400 MHz, CDCl3) : 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-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-indazole

[0208] 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)Cl2.CH2Cl2 (1.01 g, 1.24 mmol) and KOAc (4.86 g, 49.6 mmol) and the reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0~60% EtOAc / PE gradient @ 100mL / min to give the title compound (1.9 g, 36.7%) as a white solid. 1H NMR (400 MHz, CDCl3) : 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 (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-ethyl-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene (Intermediate 28)Step 1: Synthesis of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine

[0209] A solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)- one (4 g, 14.3 mmol), POCl3(17.52 g, 114.2 mmol) and DIPEA (5.54 g, 42.8 mmol) in anhydrous MeCN (15 mL) was stirred for 0.5 h at 80 °C under N2. The cooled mixture was evaporated under reduced pressure to afford the title compound, crude as a yellow solid. LCMS m / z = 299 [M+H]+ Step 2: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-ethyl-4-fluoro-2- (methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0210] To a stirred solution of Intermediate 14, 3.73 g, 10.0 mmol) and the compound from step 1 (3.00 g, 10.0 mmol) in THF (30 mL) was added DIPEA (3.90 g, 30.1 mmol) and the resulting yellow suspension stirred at 25°C for 1 h. LiOtBu (2.2 M, 13.7 mL) was added and the reaction mixture stirred at 25°C for 1 h. The mixture was quenched with sat. NH4Cl (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over MgSO4and concentrated. The residue was purified by silica gel chromatography eluting with 0~30%EtOAc / PE gradient @ 100 mL / min to give the title compound (2.50 g, 41.6%) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) : 7.65 - 7.56 (m, 4H), 7.51 - 7.36 (m, 6H), 4.62 (dd, 1H), 4.37 (d, 1H), 4.29 - 4.15 (m, 2H), 3.77 (br t, , 2H), 3.39 (qd, 1H), 2.53 (s, 3H), 1.97 - 1.83 (m, 1H), 1.80 - 1.72 (m, 1H), 1.25 (t, 3H), 1.00 (s, 9H) Step 3: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-ethyl-4-fluoro-2- (methylsulfonyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0211] To a solution of the compound from step 2 (2.50 g, 4.19 mmol) in THF (20 mL) and H2O (4 mL) was added m-CPBA (2.12 g, 10.4 mmol, 85% purity) and the reaction mixture wasstirred at 30 °C for 1h. The reaction was quenched with aq.10% Na2SO3 (100 mL) and stirred for 10 mins. The mixture was extracted with EtOAc (100 mL x 2), washed with aq.10% Na2SO3 (100 mL x 2), brine (20 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with 0~40% EtOAc / PE gradient @ 80 mL / min to give the title compound (1.70 g, 64.5%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) = 7.62 (ddd, 4H), 7.49 - 7.39 (m, 6H), 4.70 (dd, 1H), 4.47 (d, 1H), 4.39 - 4.31 (m, 1H), 4.23 (qd, 1H), 3.83 - 3.73 (m, 2H), 3.51 (qd, 1H), 3.38 (s, 3H), 1.95 (qd, 1H), 1.81 - 1.77 (m, 1H), 1.28 (t, , 3H), 1.01 (s, 9H) Step 4: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-ethyl-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene

[0212] To a stirred solution of the compound from step 3 (1.70 g, 2.70 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (516 mg, 3.24 mmol) in THF (20 mL) at 0 °C was added LiOtBu (2.2 M, 2.46 mL, 5.4 mmol) and the resulting yellow suspension stirred at 25 °C for 1 h. The reaction mixture was added to water (50 mL), the mixture extracted with EtOAc (50 mL x 2) and the combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 0-40% EtOAc / PE to give the title compound (1.1 g, 57.5%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) = 7.61 (ddd, 4H), 7.52 - 7.31 (m, 6H), 5.38 - 5.14 (m, 1H), 4.61 (dd, 1H), 4.34 (d, 1H), 4.21 (td, 2H), 4.14 - 4.07 (m, 1H), 4.06 - 3.98 (m, 1H), 3.77 (br t, 2H), 3.44 - 3.33 (m, 2H), 3.14 - 2.98 (m, 3H), 2.88 - 2.78 (m, 1H), 2.16 - 2.02 (m, 2H), 1.99 (s, 1H), 1.96 - 1.63 (m, 5H), 1.28 - 1.19 (m, 3H), 1.00 (s, 9H) Synthesis of (S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Intermediate 29)Step 1: Synthesis of (S)-2-((2,4-dimethoxybenzyl)amino)propan-1-ol

[0213] To a stirred solution of (2S)-2-aminopropan-1-ol (10 g, 133.1 mmol) and 2,4- dimethoxybenzaldehyde (22.12 g, 133.1 mmol) in MeOH (500 mL) was added Na2SO4 (9.46 g, 66.6 mmol) and the resulting mixture was stirred for 24h at rt under N2. The mixture was cooled to 0°C, NaBH4 (2.52 g, 66.6 mmol) was added in portions and the mixture stirred for 30 min. AcOH (4.00 g, 66.6 mmol) was added dropwise and the reaction mixture was stirred for 15 min. The reaction was quenched with water at 0°C and the resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (3x100mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford the title compound (33 g, crude) as a white solid. LCMS m / z = 226 [M+H]+ Step 2: Synthesis of (S)-7-chloro-5-(2-((2,4-dimethoxybenzyl)amino)propoxy)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0214] To a solution of the compound from step 1 (5 g, 22.2 mmol, crude) in THF (50 mL) was added NaH (60% in oil, 2.66 g, 66.6 mmol) at 0 °C and the mixture was stirred for 10 min. 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (6.22 g, 22.2 mmol) was added and the reaction stirred at 60°C for 2h. The cooled reaction mixture was quenched with water, and the resulting mixture was extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (3x100mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water, 30% to 40% gradient in 10 min to afford the title compound (10.2 g, 98.0%) as a yellow solid. LCMS m / z = 469 [M+H]+Step 3: Synthesis of ((S)-5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-9-methyl-2-(methylthio)- 9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0215] To a stirred solution of the compound from step 2 (10.2 g, 21.8 mmol) in DCM (100 mL) was added TEA (6.60 g, 65.3 mmol) and PyBOP® (16.98 g, 32.6 mmol) at rt and the reaction was stirred for 5h at rt under N2. The resulting mixture was diluted with brine and extracted with EtOAc (3 x 100mL). The combined organic layers were washed with brine (3x100mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water, 40% to 50% gradient in 10 min to afford the title compound (5.1 g, 52.%) as a yellow solid. LCMS m / z = 451 [M+H]+ Step 4: Synthesis of (9S)-5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-9-methyl-2- (methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0216] To a solution of the compound from step 3 (5.1 g, 11.3 mmol) in DCM (50 mL) was added a solution of m-CPBA (2.15 g, 12.4 mmol) in DCM dropwise at -15°C under N2 and the reaction was stirred for 1 h at -15°C under N2. The reaction was quenched by the addition of saturated NaHSO3soln. at -15°C. The resulting mixture was extracted with EtOAc (3 x 50mL), the combined organic layers were washed with brine (3x50mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford the title compound (5.28 g, crude) as a yellow solid. LCMS m / z = 467 [M+H]+ Step 5: Synthesis of (S)-5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0217] To a stirred solution of the compound from step 4 (5.28 g, 11.3 mmol) in toluene (50 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (5.40 g, 33.9 mmol) and the mixture was stirred for 30 min at rt under N2, then cooled to 0°C. NaOtBu (2.17g, 22.6 mmol) was added and the reaction stirred for 30 min at 0 . The mixture was dilutedwith brine, extracted with EtOAc (3 x 50mL), the combined organic layers were washed with brine (3x50mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water, 40% to 50% gradient in 10 min, to afford the title compound (4 g, 62.9%) as a white solid. LCMS m / z = 562 [M+H]+Step 6: Synthesis of (S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0218] TFA (20 mL) was added to a solution of the compound from step 5 (4 g, 7.1 mmol) in DCE (20 mL) and the reaction mixture stirred for 16 h at 80°C under N2. The cooled mixture was concentrated under reduced pressure and the residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water, 60% to 70% gradient in 10 min to afford the title compound (1.6 g, 54.6%) as an off-white solid. LCMS m / z = 412 [M+H]+ Synthesis of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Intermediate 30)Steps 1 to 3: Synthesis of 5-chloro-10-(2,4-dimethoxybenzyl)-4-fluoro-2-(methylthio)-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0219] The title compound was obtained as a white solid, from ethanolamine, 2,4- dimethoxybenzaldehyde and 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin- 4(3H)-one, following a similar 3 step procedure to that described in Intermediate 29, steps 1 to 3. LCMS m / z = 437 [M+H]+ Steps 4 to 6: Synthesis of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0220] The title compound was obtained as a white solid, from the compound from steps 1 to 3 and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, following a similar 3 step procedure to that described in Intermediate 29, steps 4 to 6. LCMS m / z = 398 [M+H]+

[0221] Synthesis of 5-chloro-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene (Intermediate 31)

[0222] TFA (5 mL) was added to a solution of Intermediate 30, step 3 (500 mg, 1.24 mmol) in DCE (5 mL) and the reaction mixture was stirred at 80oC for 16 h under N2. The cooled mixture was evaporated under reduced pressure to afford the title compound, crude. LCMS m / z = 287 [M+H]+ Synthesis of (S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene (Intermediate 32)

[0223] The title compound was obtained from Intermediate 29, step 3, following the procedure described in Intermediate 31. Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro-10H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-fluoro-N,N-bis(4- methoxybenzyl)pyridin-2-amine (Intermediate 33)Step 1: Synthesis of 3-bromo-5-fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0224] To a solution of 3-bromo-5-fluoropyridin-2-amine (150 g, 0.77 mol) in DMF (2 L) was added NaH (77.3 g, 1.93 mol, 60% purity) in portions at 0 °C under N2and the mixture was stirred at 0 °C for 1 h. PMBCl (266 g, 1.70 mol) was added dropwise at 0oC under N2and the reaction mixture was stirred at rt for 18 h. The mixture was cooled and quenched with sat. NH4Cl (2 L) dropwise and extracted with EtOAc (2 L x 2). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography, eluting with 0~25% EtOAc / PE to give the title compound (240 g, 72.0%) as a yellow oil. LCMS m / z = 431 / 433 [M+H]+ Step 2: Synthesis of 3-(1-ethoxyvinyl)-5-fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0225] To a solution of the compound from step 1 (120 g, 278 mmol) in DMF (1.5 L) was added tributyl(1-ethoxyvinyl)tin (151 g, 417 mmol), TEA (84.2 g, 834 mmol) and Pd(PPh3)2Cl2 (8.7 g, 11.2 mmol) and the reaction mixture was stirred at 80oC for 18 h under N2. The mixture was poured into water (2 L) and extracted with EtOAc (2 L x 2). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography, eluting with 0~20% THF / PE to give the title compound (151 g, 64.2%) as a yellow gum. LCMS m / z = 423 [M+H]+ Step 3: Synthesis of 1-(2-(bis(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)ethan-1-one

[0226] To a solution of the compound from step 2 (150 g, 355 mmol) in dioxane (1.5 L) was added HCl / dioxane (200 mL, 4 M) and the reaction was stirred at rt for 1 h. The mixture was concentrated and the residue was diluted with sat. NaHCO3(300 mL) and EtOAc (2 L). The EtOAc layer was washed with brine (500 mL), dried over Na2SO4, filtered and the filtratewas evaporated to give the title compound (130 g, 92.8%) as yellow oil. LCMS m / z = 395 [M+H]+ Step 4: Synthesis of (2S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-5-fluoropyridin-3- yl)ethyl)amino)propan-1-ol

[0227] To a solution of the compound from step 3 (150 g, 380.3 mmol) and (S)-2- aminopropan-1-ol (85.7 g, 1.14 mol) in dioxane (1.5 L) was added Ti(i-PrO)4 (162 g, 570 mmol) and 4Å molecular sieves (100 g, 380.3 mmol) and the mixture was stirred at 110 °C for 18 h under N2. The mixture was cooled to 0 °C and NaBH4 (28.8 g, 760 mmol) was added in portions while keeping the internal temperature below 20 °C. After the addition, the mixture was stirred at rt for 2 h. The mixture was cooled to 0 °C, sat. NaHCO3(200 mL) was added dropwise under N2and the mixture was stirred at rt for 1 h. The resulting mixture was poured into water (2 L) and filtered through a pad of Celite®. The filter cake was rinsed with EtOAc (1 L x 2). The separated organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography, eluting with 0~100% THF / PE to give the title compound (130 g, 75.4%) as a yellow gum. LCMS m / z = 454 [M+H]+ Step 5: Synthesis of 5-((2S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-5-fluoropyridin-3- yl)ethyl)amino)propoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0228] To a solution of the compound from step 4 (80.9 g, 178 mmol) in THF (1.5 L) was added NaH (25 g, 625 mmol, 60% purity) in portions at 0 °C under N2. The mixture was stirred at 0 °C for 30 min.5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (50 g, 178.5 mmol) was added in portions at 0 °C under N2 and the reaction mixture was stirred at 60 °C for 2.5 h. The mixture was cooled to 0 °C and sat. NH4Cl (500 mL) was added dropwise, while keeping the internal temperature below 15 °C. The mixture was extracted with EtOAc (1 L x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-40% of THF in PE to give the title compound (74 g, 59.4%) as a yellow solid. Step 6: Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro-10H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-fluoro-N,N-bis(4- methoxybenzyl)pyridin-2-amine

[0229] To a solution of the compound from step 5 (70 g, 100.4 mmol) in DCE (1.5 L) was added DIPEA (38.9 g, 301 mmol) and BOP-Cl (38.3 g, 150 mmol) and the reaction mixture wasstirred at 90 °C for 18 h. The mixture was washed with sat. NaHCO3 (1 L), brine (500 mL x 2), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Column, Eluent of 0~30% THF / PE gradient @ 100 mL / min) followed by prep-SFC (column: REGIS (s,s) WHELK-O1 (250mm*50mm,10um); mobile phase: CO2 / EtOH (0.1%NH3H2O) (45:55) isocratic elution mode) to give the title compound (28 g, 41.1%) as a yellow solid.1H NMR (400 MHz, DMSO- d6) ppm 8.41 (d, 1H), 7.97 (dd, 1H), 6.89 - 6.98 (m, 1 H), 6.70 (d, 4H), 6.54 (d, 4H), 4.38 - 4.49 (m, 1H), 4.21 - 4.32 (m, 1H), 4.09 (d, 2H), 3.96 - 4.03 (m, 1H), 3.83 (d, 2H), 3.64 (s, 6H), 2.66 (s, 3H), 1.39 (br d, 3H), -0.13 (d, 3H) Synthesis of 3-((1R)-1-((9S)-5-chloro-4-fluoro-9-methyl-2-(methylsulfinyl)-8,9-dihydro- 10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-fluoro-N,N-bis(4- methoxybenzyl)pyridin-2-amine (Intermediate 34)

[0230] To a mixture of the compound from Intermediate 33 (26 g, 34.45 mmol) in DCM (250 mL) was added m-CPBA (7.69 g, 37.90 mmol, 85% purity) and the mixture was stirred at rt for 30 min. The reaction mixture was quenched with sat. NaHCO3 (100 mL) and sat. Na2SO3 (50 mL), then extracted with DCM (200mL x 3). The combined organic phase was washed with brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (24 g, 90.2%). LCMS m / z = 695 [M+H]+ Synthesis of 5-chloro-3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro- 10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4- methoxybenzyl)pyridin-2-amine (Intermediate 35)Steps 1 and 2 Synthesis of 3-bromo-5-chloro-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0231] The title compound was obtained as a yellow oil, from 3-bromo-5-chloropyridin-2- amine, PMBCl and tributyl(1-ethoxyethenyl)stannane, following a similar procedure to that described in Intermediate 33, steps 1 and 2. LCMS m / z = 439 [M+H]+ Step 3 Synthesis of 1-(2-(bis(4-methoxybenzyl)amino)-5-chloropyridin-3-yl)ethan-1-one

[0232] A solution of the compound from steps 1 and 2 (21 g, 47.8 mmol) and 1M HCl (768.8 mL) in EtOAc (730 mL) was stirred at rt for 2h. The mixture was extracted with EtOAc (2 x 500 mL) and the combined organic layers were washed with NaHCO3 (3 x 100 mL) and brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to afford the title compound (17 g, 86.5%) as a yellow oil. LCMS m / z = 411 [M+H]+ Step 4 Synthesis of (2S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-5-chloropyridin-3-yl)ethyl)amino)propan-1-ol

[0233] Ti(i-PrO)4 (47.04 g, 165.5 mmol) was added to a solution of the compound from step 3 (17 g, 41.4 mmol) and (2S)-2-aminopropan-1-ol (9.32 g, 124.1 mmol) in EtOH (300 mL) and the resulting mixture was stirred at 80°C overnight. NaBH4 (4.70 g, 124.1 mmol) and HOAc (3.73 g, 62.1 mmol) were added at 0°C, and the reaction mixture was stirred at 0°C for 1h. The reaction was quenched with water / ice (100 mL) at 0°C, the resulting mixture was filtered and the filter cake was washed with EtOAc (4 x 500 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:8) to afford the title compound (16.85 g, 86.7%) as a yellow oil. LCMS m / z = 470 [M+H]+Step 5 Synthesis of 5-((2S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-5-chloropyridin-3-yl)ethyl)amino)propoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0234] The title compound was obtained as a brown solid(6 g, 32.9%) from the compound from step 4, following a similar procedure to that described in Intermediate 33, step 5. LCMS m / z = 713 [M+H]+Step 6 Synthesis of 5-chloro-3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4- methoxybenzyl)pyridin-2-amine

[0235] DIPEA (3.80 g, 29.4 mmol) was added to a solution of the compound from step 5 (7 g, 9.81 mmol) and BOPCl (7.49 g, 29.4 mmol) in CHCl3 (120 mL) and the resulting mixture was stirred at 80°C for 20 h. The reaction was quenched with ice-water at 0oC and the mixture was extracted with DCM (3 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2:1) to afford the title compound (1.7 g, 22.4%) as a yellow solid. LCMS m / z = 695 [M+H]+ Synthesis of 5-chloro-3-((R)-1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (Intermediate 36)Step 1 Synthesis of 5-chloro-3-((1R)-1-((9S)-5-chloro-4-fluoro-9-methyl-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4- methoxybenzyl)pyridin-2-amine

[0236] A solution of m-CPBA (526.5 mg, 2.59 mmol, 85%) in DCM (10 mL) was addeddropwise at -15 to a solution of Intermediate 35 (1.64 g, 2.36 mmol) in DCM (40 mL) andthe reaction mixture was stirred at -15°C for 1 h. The reaction was quenched with Na2SO3(aq) at 0oC, the aqueous layer was extracted with DCM (3 x 10 mL), the combinedorganic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (1.54 g, 91.9%) as a yellow solid . LCMS m / z = 711 [M+H]+Step 2: Synthesis of 5-chloro-3-((R)-1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0237] NaOtBu (243.1 mg, 2.53 mmol) was added at 0°C to a solution of the compound from step 1 (900 mg, 1.27 mmol) and ((2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl)methanol (604.0 mg, 3.80 mmol) in toluene (10 mL) and the mixture was stirred at 0°C for 30 min. The reaction was quenched with ice-water at 0oC. The aqueous layer was extracted with DCM (3 x 10 mL), the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1) to afford the title compound (600 mg, 58.8%) as a white solid. LCMS m / z = 806 [M+H]+Synthesis of 5-fluoro-3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4- methoxybenzyl)pyridin-2-amine (Intermediate 37)Step 1: Synthesis of 5-fluoro-3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2- amine

[0238] A mixture of Intermediate 27 (120.8 mg, 0.29 mmol), Intermediate 33 (200 mg, 0.99 mmol), CataCXium A Pd G3 (21.45 mg, 0.029 mmol) and K3PO4(187.52 mg, 0.88 mmol) in dioxane (4 mL) / H2O (1 mL) was stirred at 80°C for 1h under N2. The mixture was cooled to rt, the reaction was quenched with ice-water and the mixture was extracted with DCM (3x10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filteredand the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EtOAc 1:1) to afford the title compound (110 mg, 40.3%) as a light brown solid. LCMS m / z = 928 [M+H]+ Step 2: Synthesis of 5-fluoro-3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2- amine

[0239] The title compound was obtained as a solid, 100 mg, crude, from the compound from step 1, following the procedure described in Intermediate 34. LCMS m / z = 944 [M+H]+ Synthesis of 5-fluoro-3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Intermediate 38)Step 1: Synthesis of 3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0240] The title compound was obtained as pale-yellow foam (450 mg, 64.3%) from the compounds of Example 93, step 4 and Intermediate 27 following the procedure described in Step 1 of Example 101. LCMS m / z = 909 [M+H]+. Step 2: Synthesis of 3-((1R)-1-((9S)-4-fluoro-9-methyl-5-(6-methyl-1-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-1H-indazol-4-yl)-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0241] The title compound was obtained as pale-brown foam (200 mg, 91%) from the compound from Step 1, following a similar procedure to that described in Step 4 of Intermediate 34. LCMS m / z = 925 [M+H]+.Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (Intermediate 39)Step 1 Synthesis of 3-((1R)-1-((9S)-5-chloro-4-fluoro-9-methyl-2-(methylsulfinyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4- methoxybenzyl)pyridin-2-amine

[0242] The title compound was obtained as a yellow oil, 500 mg, crude, from the compound from step 4 of Example 93, following a similar procedure to that described in Example 1, step 3. LCMS m / z = 677 [M+H]+Step 2 Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0243] The title compound was obtained as a white solid, 455 mg, 79.7%, from the compound from step 1 and ((2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl)methanol, following a similar procedure to that described in Example 40, step 5. LCMS m / z = 772 [M+H]+ Synthesis of (1-azabicyclo[3.2.0]heptan-5-yl)methanol (Intermediate 40)Step 1: 1-tert-butyl 2-methyl (2R)-2-(2-chloroethyl)pyrrolidine-1,2-dicarboxylate

[0244] LDA (1.0M in THF, 10.5 mL, 34.9 mmol) was added dropwise at -78 to asolution of 1-tert-butyl 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate (4 g, 17.45 mmol) in THF(40 mL) under N2. The mixture was stirred at -78 for 2 h, then, 1-bromo-2-chloroethane (5.00g, 34.9 mmol) was added dropwise. The resulting mixture was stirred at rt overnight. The reaction was quenched with sat. NH4Cl (aq.), the layers separated and the aqueous layer extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (4 g, 78.6%) as a yellow oil. LCMS m / z = 236 [M+H]+ Step 2: methyl (2R)-2-(2-chloroethyl)pyrrolidine-2-carboxylate hydrochloride

[0245] 4M HCl / dioxane (50 mL) was added to a solution of the compound from step 1 (4 g, 13.7 mmol) in dioxane (0.5 mL) and the reaction was stirred at rt for 1h under N2.The resulting mixture was concentrated under reduced pressure to afford the title compound (3 g, 91.3%) as a yellow oil. LCMS m / z = 192 [M+H]+ Step 3:methyl (5R)-1-azabicyclo[3.2.0]heptane-5-carboxylate

[0246] A mixture of the compound from step 2 (3g, 15.66 mmol) and TEA (9.01 mL, 64.80mmol) in MeCN (45 mL) was stirred at 80 for 2 h under N2. The reaction was quenched withice-water and the aqueous layer was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to afford the title compound (1 g, 41.2%) as a brown oil. LCMS m / z = 156 [M+H]+ Step 4: 1-azabicyclo[3.2.0]heptan-5-ylmethanol

[0247] LiAlH4 (20 mL, 0.042 mmol, 1.0 M in THF solution) was added dropwise at 0 toa solution of the compound from step 3 (1 g, 6.44 mmol) in THF (10 mL) and the resultingmixture was stirred at 0 for 1 h. The reaction was quenched with Na2SO4.H2O, the mixturewas filtered and the filter cake was washed with DCM (3x10 mL). The filtrate was evaporated under reduced pressure to afford the title compound (300 mg, 36.6%) as a yellow oil. LCMS m / z = 128 [M+H]+ Synthesis of (6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 4-yl)boronic acid (Intermediate 41)Step 1: Synthesis of 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-(1-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)cyclopropyl)-1H-indazole

[0248] A solution of 4-bromo-6-chloro-5-iodo-1-(oxan-2-yl)indazole (1 g, 2.27 mmol), 2,2'- (cyclopropane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (998.9 mg, 3.40 mmol), Cs2CO3(1.48 g, 4.53 mmol) and Pd(dppf)Cl2(165.7 mg, 0.23 mmol) in dioxane (8 mL) and H2O (1 mL) was stirred at 100°C for 16 h under N2. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH 12:1) to afford the title compound (524 mg, 48.0%) as a white solid. LCMS m / z = 482 [M+H]+ Step 2: Synthesis of 1-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropan-1-ol

[0249] A solution of the compound from step 1 (524 mg, 1.09 mmol), H2O2 (74.01 mg, 2.18 mmol) and NaOH (87.03 mg, 2.18 mmol) in MeOH (10 mL) was stirred at 0°C for 30 min. The reaction was quenched with NaHCO3 (0.5 mL) at 0°C and the resulting mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH 30:1) to afford the title compound (201 mg, 49.7%) as a white solid. LCMS m / z = 372 [M+H]+ Step 3: Synthesis of 4-bromo-6-chloro-5-(1-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole

[0250] To a stirred solution of the compound from step 2 (110 mg, 0.30 mmol) in DCM (5 mL) was added DAST (95.41 mg, 0.59 mmol) in portions at -78°C under N2and the resulting mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (PE / EtOAc 5:1) to afford the title compound (67 mg, 60.6%) as a yellow oil. LCMS m / z = 374 [M+H]+Step 4: 6-chloro-5-(1-fluorocyclopropyl)-1-(oxan-2-yl)indazol-4-ylboronic acid

[0251] A solution of the compound from step 3 (60 mg, 0.16 mmol), tetrahydroxydiborane (28.79 mg, 0.32 mmol) and TEA (65.0 mg, 0.64 mmol) and CataCXium A Pd G3 (11.69 mg, 0.016 mmol) in MeOH (5 mL) was stirred at rt for 4 h under N2. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH 30:1) to afford the title compound (32 mg, 58.9%) as a yellow solid. LCMS m / z = 339 [M+H]+ Synthesis of 6-chloro-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate 42)Step 1: Synthesis of 4-bromo-6-chloro-5-cyclopropyl-1-(oxan-2-yl)indazole

[0252] A mixture of 4-bromo-6-chloro-5-iodo-1-(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)Cl2.CH2Cl2 (739.9 mg, 0.91 mmol) in dioxane (15 mL) and water (5 mL) was stirred at100 for 2 h under N2. The mixture was cooled to rt and diluted with water. The resultingmixture was extracted with EtOAc (3 x 50mL), the combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (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-1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indazole

[0253] The title compound was obtained as a colorless oil, 0.1 g, 23%, from the compound from step 1, following the procedure described in Intermediate 20. LCMS m / z = 403 [M+H]+ Synthesis of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol (Intermediate 43)Step 1: Synthesis of 4-bromo-6-methyl-1H-indazol-5-ol

[0254] To a solution of 6-methyl-1H-indazol-5-ol (5.0 g, 33.7 mmol) in THF (100 mL) was added NBS (6.61 g, 37.1 mmol) portionwise at 0 °C and the reaction was stirred at 25 °C for 14 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE: EtOAc=1:0 to 1:1) to give the title compound (7.0 g, crude) as a brown solid. LCMS m / z = 227 [M+H]+ Step 2: Synthesis of 4-bromo-6-methyl-1-tetrahydropyran-2-yl-indazol-5-ol

[0255] To a solution of the compound from step 1 (7.00 g, 30.8 mmol) and TsOH (531 mg, 3.08 mmol) in DMF (50 mL) was added a solution of DHP (5.19 g, 61.7 mmol) in DMF (5 mL) at rt slowly. The resulting solution was stirred at rt for 14 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (300 mL × 2). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE: EtOAc=1:0 to 3:1) and further purified by reverse-phase HPLC to give the title compound (3.60 g, 38%) as a yellow solid. LCMS m / z = 313 [M+H]+Synthesis of (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol- 4-yl)boronic acid (Intermediate 44)Step 1: Synthesis of 4-bromo-6-(trifluoromethyl)-1H-indazol-5-amine

[0256] The title compound was obtained as a yellow solid, 5.0 g, 41%, from 6- (trifluoromethyl)-1H-indazol-5-amine, following a similar procedure to that described in Intermediate 43, step 1. LCMS m / z = 280 [M+H]+ Step 2: Synthesis of 4-bromo-5-iodo-6-(trifluoromethyl)-1H-indazole

[0257] To a solution of the compound from step 1 (500 mg, 1.79 mmol, 8 batches) in MeCN (10 mL) was added CuI (1.02 g, 5.36 mmol) and t-BuONO (570 mg, 5.53 mmol) and thereaction mixture was stirred at 70°C for 2 h. The mixture was quenched with sat.aq NaHCO3 (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, NH3•H2O (3 mL), PE: DCM / MeOH=1 / 0 to 0 / 1, PE: EtOAc=5:1) and then re-purified by reverse-phase flash column to give the title compound (1.10 g, 20%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 13.97 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H). Step 3: Synthesis of 4-bromo-5-iodo-1-tetrahydropyran-2-yl-6-(trifluoromethyl)indazole

[0258] To a solution of the compound from step 2 (1.00 g, 2.56 mmol) and DHP (430 mg, 5.12 mmol) in THF (15 mL) was added camphor-10-sulfonic acid (89.1 mg, 0.38 mmol) and the reaction mixture was stirred at 70°C for 12 h. The mixture was quenched with sat.aq NaHCO3(10 mL) and then extracted with EtOAc (50 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 5 / 1) to give the title compound (700 mg, 52%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8.33 (s, 1H), 8.20 (s, 1H), 6.11 - 6.04 (m, 1H), 3.87 - 3.76 (m, 2H), 2.41 - 2.27 (m, 1H), 2.01 (s, 2H), 1.82 - 1.70 (m, 1H), 1.60 - 1.53 (m, 2H). Step 4: Synthesis of 4-bromo-5-cyclopropyl-1-tetrahydropyran-2-yl-6-(trifluoromethyl)indazole

[0259] A mixture of the compound from step 3 (100 mg, 0.21 mmol), cyclopropyl boronic acid (27.1 mg, 0.32 mmol), Na2CO3 (33.4 mg, 0.32 mmol) and Pd(dppf)Cl2 (15.4 mg, 21.0 mol) in 2-MeTHF (1 mL) and H2O (0.2 mL) was degassed and purged with N2 and the reaction mixture was stirred at 100°C for 12 h under N2. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (SiO2, PE: EtOAc = 10:1) to give the title compound (30 mg, 34%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 8.23 (s, 1H), 8.20 (s, 1H), 6.10 - 6.01 (m, 1H), 3.91 - 3.75 (m, 2H), 2.42 - 2.27 (m, 1H), 2.11 - 1.94 (m, 3H), 1.83 - 1.68 (m, 1H), 1.65 - 1.51 (m, 2H), 1.19 - 1.09 (m, 2H), 0.76 (d, 2H). Step 5: Synthesis of (5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H- indazol-4-yl)boronic acid

[0260] The title compound was obtained as a yellow solid, 40 mg, crude, from the compound from step 4 and tetrahydroxydiboron, following a similar procedure to that described in Intermediate 41, step 4. LCMS m / z = 355 [M+H]+ Synthesis of (6-chloro-5-(2-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 4-yl)boronic acid (Intermediate 45)Step 1: Synthesis of 1,3-dioxoisoindolin-2-yl 2-fluorocyclopropane-1-carboxylate

[0261] To a stirred mixture of 2-fluorocyclopropane-1-carboxylic acid (3.2 g, 30.75 mmol) and 2-hydroxy-2,3-dihydro-1H-isoindole-1,3-dione (5.52 g, 33.82 mmol) in DCM (20 mL) were added dicyclohexylcarbodiimide (0.46 g, 2.24 mmol) and DMAP (3.76 g, 30.75 mmol) and the reaction mixture was stirred at rt for 12 h. The resulting mixture was extracted with DCM (10 x mL). The combined organic layers were washed with NaHCO3(3x10 mL) and NaHSO4(10%), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure.to afford the title compound (7.6 g) as a yellow solid. LCMS m / z = 250 [M+H]+ Step 2: Synthesis of 2-(2-fluorocyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0262] To a stirred solution of the compound from step 1 (7.61 g, 30.54 mmol) and bis(pinacolato)diboron (8.53 g, 33.59 mmol) in EtOAc (100 mL) was added tert-butyl pyridine- 4-carboxylate (69.04 mg, 0.39 mmol) at rt under N2. The resulting mixture was stirred at 80°C overnight under N2. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (20:1) to afford the title compound (2.2 g, 38.7%) as a colorless oil. LCMS m / z = 205 [M+H]+Step 3 Synthesis of 4-bromo-6-chloro-5-(2-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0263] The title compound was obtained as a white solid, 120 mg, 23.6%, from the compound from step 2 and 4-bromo-6-chloro-5-iodo-1-(oxan-2-yl)indazole, following a similar procedure to that described in Intermediate 41, step 1. LCMS m / z = 373 [M+H]+Step 4 Synthesis of (6-chloro-5-(2-fluorocyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid

[0264] To a stirred solution of the compound from step 3 (80 mg, 0.214 mmol) and tetrahydroxydiborane (76.78 mg, 0.86 mmol) in MeOH (1.6 mL) was added CataCXium A Pd G3 (15.59 mg, 0.02 mmol) and K2CO3 (59.18 mg, 0.43 mmol) and the reaction mixture was stirred at 40°C for 1h under N2. The resulting mixture was concentrated in vacuo to give the title compound, crude. LCMS m / z = 339 [M+H]+ Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(((R)-1-methylazetidin-2- yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10- yl)ethyl)-5-fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine (Intermediate 46)Step 1: Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(methylsulfonyl)-8,9-dihydro- 10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-fluoro-N,N-bis(4- methoxybenzyl)pyridin-2-amine

[0265] A solution of Intermediate 33 (500 mg, 0.736 mmol) and m-CPBA (381.11 mg, 2.21 mmol) in DCM (5 mL) was stirred at rt for 2 h. The reaction was diluted with water (10 mL) and the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1) to afford the title compound (500 mg, 95.5%) as a yellow solid. LCMS m / z = 711 [M+H]+ Step 2: Synthesis of 3-((R)-1-((S)-5-chloro-4-fluoro-9-methyl-2-(((R)-1-methylazetidin-2- yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5- fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0266] To a stirred solution of the compound from step 1 (250 mg, 0.35 mmol) and ((2R)-1- methylazetidin-2-yl)methanol (42.67 mg, 0.42 mmol) in DCM (4 mL) was added LiOtBu (84.43 mg, 1.06 mmol) at 0°C and the reaction mixture was stirred at rt for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (PE / EtOAc 1:1) to give the title compound (163 mg, 63.3%) as a yellow solid. LCMS m / z = 733 [M+H]+Synthesis of 3-((R)-1-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9-methyl-5-(tributylstannyl)-8,9-dihydro-10H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine (Intermediate 47)

[0267] A mixture of Intermediate 39 (260 mg, 0.12 mmol), bis(tributyltin) (587 mg, 0.39 mmol), Pd2(dba)3(31 mg, 0.01 mmol), tricyclohexylphosphane (21 mg, 0.02 mmol) and LiCl (72 mg, 0.66 mmol) in dioxane (3 mL) was stirred at 110oC for 16 h under N2. The resulting mixture was concentrated under reduced pressure and the residue was purified by Prep-TLC (PE / EtOAc 1:2) to afford the title compound (254 mg, 73.3%) as a light-yellow oil. LCMS m / z = 1028 [M+H]+ Synthesis of (R)-(1,2-dimethylpyrrolidin-2-yl)methanol (Intermediate 48)Step 1: Synthesis of afford 1-(tert-butyl) 2-methyl (R)-2-methylpyrrolidine-1,2-dicarboxylate

[0268] To a solution of (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (500 mg, 2.18 mmol) in DMF (5 mL) was added K2CO3(904 mg, 6.54 mmol) followed by MeI (0.18 mL, 2.84 mmol) at 0°C. The reaction mixture was stirred at rt for 16 h, then diluted with ice-cold water (5 mL) and extracted with EtOAc (3 x 20 mL). The organic phase was washed with sat. NaCl (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, to yield the title compound (400 mg, 74.9%) as pale-yellow oil. LCMS m / z = 144 [M+H-Boc]+. Step 2: Synthesis of (R)-(1,2-dimethylpyrrolidin-2-yl)methanol

[0269] To a solution of the compound of Step 1 (300 mg, 1.23 mmol) in THF (5 mL) was added LiAlH4 (2M in THF) (3.08 mL, 6.17 mmol) at 0°C. The reaction mixture was stirred at rt for 16 h, then quenched with sat. Na2SO4 (3 mL) and diluted with 5% MeOH in DCM (20 mL). The mixture was filtered through Celite® and washed with 5% MeOH / DCM (2 x 20 mL). Thefiltrate was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (155 mg, 82%) as a pale -yellow oil. LCMS m / z = 130 [M+H]+. Synthesis of 2-(3-chloro-2-cyclopropyl-5-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (Intermediate 49)

[0270] The title compound was obtained as a pale-yellow solid, 0.61 g, 18.9%, from ethyl 3-bromo-5-chloro-4-iodobenzoate and cyclopropylboronic acid, following a similar procedure to that described in Intermediate 42, step 1. LCMS m / z = 305 [M+H]+. Step 2: Synthesis of 3-bromo-5-chloro-4-cyclopropylbenzoic acid

[0271] To a solution of the title compound of Step 1 (2.32 g, 7.64 mmol) in a mixture of THF (17.5 mL) and water (7.5 mL) was added LiOH.H2O (0.96 g, 22.9 mmol) and the reaction mixture was stirred at rt for 16 h, then diluted with water (20 mL) and the pH adjusted to 2 ~3 with HCl (1.5 N). The mixture was extracted with EtOAc (3 x 30 mL). The organic phase waswashed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reducedpressure to afford the title compound (2.1 g, 99%) as an off-white solid. LCMS m / z = 274 [(M+H]+Step 3: Synthesis of (3-bromo-5-chloro-4-cyclopropylphenyl)methanol

[0272] To a solution of the title compound of Step 2 (2.1 g, 7.62 mmol) in THF (21 mL) was added borane THF complex (15.2 mL, 15.2 mmol) at 0°C under N2. The reaction mixture was stirred at rt for 16 h, then diluted with water (20 mL). The pH was adjusted to 2~3 with HCl (1.5N) and extracted with EtOAc (3 x 30mL). The organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (1.5 g, 74.8%) as pale yellow solid.1H-NMR (400 MHz, DMSO-d6): 7.52 (s, 1H),7.37 (s, 1H), 5.38 (t, 1H), 4.45 (d, 2H), 1.99-1.73 (m, 1H), 1.18-1.12 (m, 2H), 0.65-0.55 (m, 2H). Step 4: Synthesis of 3-bromo-5-chloro-4-cyclopropylbenzaldehyde

[0273] To a solution of the title compound of Step 3 (400 mg, 1.53 mmol) in DCM (8 mL) was added pyridinium chlorochromate (494 mg, 2.29 mmol) and the reaction mixture was stirred at 0°C for 1 h. The mixture was diluted with DCM (10 mL) and filtered through Celite®and washed with DCM (3 x 20 mL). The organic phase was washed with brine (20 mL), dried over Na2SO, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0-100% EtOAc in hexane) to afford the title compound (300 mg, 73.3%) as a pale yellow solid.1H-NMR (400 MHz, CDCl3): 9.90 (s, 1H), 7.97 (d, 1H), 7.82 (d, 1H), 1.88-1.81 (m, 1H), 1.31-1.26 (m, 2H), 0.87-0.83 (m, 2H), Step 5: Synthesis of 1-bromo-3-chloro-2-cyclopropyl-5-(difluoromethyl)benzene

[0274] To a solution of the title compound of Step 4 (300 mg, 1.16 mmol) in DCM (6 mL) was added DAST (0.46 mL, 3.47 mmol) at -78°C. The reaction mixture was stirred at rt for 16 h, then diluted with 10% NaHCO3 solution (20 mL) and extracted with DCM (3 x 20 mL). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (270 mg, 83%) as a pale brown oil.1H- NMR (400 MHz, CDCl3): 7.63 (d, 1H), 7.47 (d, 1H), 6.70-6.42 (m, 1H), 1.83-1.78 (m, 1H), 1.30-1.21 (m, 2H), 0.86-0.78 (m, 2H). Step 6: Synthesis of 2-(3-chloro-2-cyclopropyl-5-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane

[0275] The title compound was obtained as a pale-yellow oil (200 mg, 66.5%), from the compound from Step 5, following a similar procedure to that described in Intermediate 20.1H- NMR (400 MHz, DMSO-d6): 7.58-7.56 (m, 2H), 6.59 (t, 1H), 2.12-2.07 (m, 1H), 1.43 (s, 12H), 1.12-1.05 (m, 2H), 0.62-0.57 (m, 2H). Example 1: Synthesis of 5-ethynyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 101)Step 1: Synthesis of (S)-7-chloro-5-(3-methyl-2-(methylamino)butoxy)-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0276] (2S)-3-Methyl-2-(methylamino)butan-1-ol (536.5 mg, 4.58 mmol) was added to a suspension of NaH (534.1 mg, 13.35 mmol, 60%) in THF (10 mL) at 0°C under N2 and the mixture was stirred for 10 min at 0°C. A solution of 5,7-dichloro-2-(methylsulfanyl)-3H- pyrido[4,3-d]pyrimidin-4-one (1 g, 3.82 mmol) in THF (10 mL) was added and the reaction mixture stirred for 1 h at 60°C. The reaction was cooled and quenched with ice-water (10mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 30mL), the combined organic layers were washed with brine (7 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (0.1% TFA), 10% to 70% gradient in 10 min, to give the title compound (650 mg, 50%) as a brown solid. LCMS m / z = 343 [M+H]+ Step 2: Synthesis of (S)-5-chloro-9-isopropyl-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene

[0277] PyBOP (1.14 g, 2.19 mmol) and TEA (1.18 g, 11.7 mmol) were added to a solution of (S)-7-chloro-5-(3-methyl-2-(methylamino)butoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (500 mg, 1.46 mmol) in DCM (10 mL) and the reaction mixture was stirred at rt for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (PE / EtOAc 1:1) to give the title compound (400 mg, 84.4%) as a white solid. LCMS m / z = 325 [M+H]+ Step 3: Synthesis of (9S)-5-chloro-9-isopropyl-10-methyl-2-(methylsulfinyl)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0278] m-CPBA (106.3 mg, 0.62 mmol) was added to a solution of (S)-5-chloro-9- isopropyl-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene (200 mg, 0.62 mmol) in DCM (6 mL) at -15°C under N2and the reaction mixture was stirred at -15°C for 1 h. The reaction was quenched with sat. NaHSO3(10 mL) at 0°C and the mixture extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (3x10mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give the title compound (200 mg, crude). LCMS m / z = 341 [M+H]+ Step 4: Synthesis of (S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)metho xy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0279] NaH (88.4 mg, 2.21 mmol) was added to a solution of ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (117.3 mg, 0.74 mmol) in anhydrous THF (2 mL) at 0°C under N2 and the mixture was stirred at 0°C for 10 min. A solution of (9S)-5- chloro-9-isopropyl-10-methyl-2-(methylsulfinyl)-9,10-dihydro-8H-7- oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene (200 mg crude) in THF (5 mL) was added and the reaction mixture was stirred at rt for 1 h. The reaction was quenched with ice-water (5mL) and the mixture extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (3 x10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase column chromatography (C18 silica gel eluting with MeCN in water (10mmol / L NH4HCO3), 10% to 70% gradient in 10 min) to give the title compound (70 mg, 21.2%) as a white solid. LCMS m / z = 436 [M+H]+Step 5: Synthesis of (S)-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0280] A mixture of (S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene (70 mg, 0.16 mmol), cataCXium-A-Pd-G3 (23.4 mg, 0.032 mmol), K3PO4 (102.3 mg, 0.48 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (164.6 mg, 0.32 mmol) in dioxane / H2O (6 mL, v / v=5:1) was stirred for 2 h at 60oC under N2. The cooled mixture was diluted with water (3mL), the mixture was extracted with DCM (10 x 5 mL), the combined organic layers were washed with brine (10 x 3 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-TLC (DCM / MeOH 10:1) to afford the title compound (130 mg, 96.9%) as a yellow solid. LCMS m / z = 786 [M+H]+ Step 6: Synthesis of 6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0281] A solution of (S)-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene (70 mg, 0.089 mmol) in 4N HCl in dioxane (2 mL). was stirred for 3h at rt under N2. The resulting mixture was evaporated under reduced pressure to give the title compound (60 mg, crude). LCMS m / z = 742 [M+H]+ Step 7: Synthesis of 5-ethynyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0282] CsF (194.5 mg, 1.28 mmol) was added to a solution of 6-fluoro-4-((S)-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-isopropyl-10-methyl-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-((triisopropylsilyl)ethynyl)naphthalen- 2-ol (95 mg, 0.128 mmol) in anhydrous DMF (2 mL) and the reaction mixture was stirred for 2 h at rt under N2. The reaction mixture was concentrated in vacuo and the residue purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (0.1% FA), 10% to 50% gradient in 10 min, to give the title compound (28.4 mg, 37.5%) as an off- white solid. LCMS m / z = 586 [M+H]+1H NMR (400 MHz, DMSO-d6) 11.33 (s, 1H), 10.22 (d, 1H), 7.94 (dd, 1H), 7.45 (t, 1H), 7.34 (d, 1H), 7.20 (d, 1H), 7.13 (s, 1H), 4.81 (ddd, 1H), 4.63 (dq, 2H), 4.43 (dd, 1H), 3.81 (dt, 5H), 3.45 (s, 3H), 2.64 – 2.52 (m, 1H), 2.48 (s, 1H), 2.31 (dd, 1H), 2.26 – 2.00 (m, 4H), 1.01 (td, 6H).Example 2: Synthesis of 5-ethynyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 103)Step 1: Synthesis of tert-butyl (S)-(4-((tert-butyldiphenylsilyl)oxy)-1-((7-chloro-2-(methylthio)- 4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)butan-2-yl)(methyl)carbamate

[0283] The title compound was obtained as a white solid, 209 mg, 7.7%, from 5,7-dichloro- 2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate 1) and tert-butyl (S)-(4-((tert- butyldiphenylsilyl)oxy)-1-hydroxybutan-2-yl)(methyl)carbamate (Intermediate 7), following the procedure described in Example 1, step 1. Step 2: Synthesis of (S)-5-(4-((tert-butyldiphenylsilyl)oxy)-2-(methylamino)butoxy)-7-chloro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0284] TFA (5 mL) was added to a stirred solution of tert-butyl (S)-(4-((tert- butyldiphenylsilyl)oxy)-1-((7-chloro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin- 5-yl)oxy)butan-2-yl)(methyl)carbamate (300 mg, 0.44 mmol) in DCM (20 mL) and the reaction mixture was stirred for 1 h at rt under N2. The resulting mixture was evaporated under reduced pressure to afford the title compound (400 mg crude) as a yellow oil. LCMS m / z = 583 [M+H]+Steps 3 to 5: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene

[0285] The title compound was obtained from (S)-5-(4-((tert-butyldiphenylsilyl)oxy)-2- (methylamino)butoxy)-7-chloro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, following the same 3 step procedure described in Example 1, steps 2 to 4. LCMS m / z = 676 [M+H]+ Step 6: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene

[0286] The title compound was obtained as a yellow oil, 30 mg, 98.8%, from (S)-9-(2- ((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane, following a similar procedure to that described in Example 1, step 5. LCMS m / z = 1026 [M+H]+ Step 7: Synthesis of 2-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2- (((2R,7a S)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)ethan-1-ol

[0287] The title compound was obtained as a white solid, 15 mg, 81.3%, from (S)-9-(2- ((tert-butyldiphenylsilyl)oxy)ethyl)-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene, following a similar procedure to that described in Example 1, step 7. LCMS m / z = 632 [M+H]+ Step 8: Synthesis of 5-ethynyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0288] To a solution of 2-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro- 8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)ethan-1-ol (15 mg, 0.024 mmol) inDCM (2 mL) was added 4 N HCl in dioxane (5 mL) dropwise and the reaction mixture was stirred for 1h at rt. The mixture was concentrated in vacuo at rt and the crude product was purified by Prep-HPLC (Method A, 23% to 48% B in 8 min), to afford the title compound (3.6 mg, 25.5%) as a white solid. LCMS m / z =588 [M+H]+.1H NMR (400 MHz, DMSO-d6) 10.06 (s, 2H), 7.92 (dd, 2H), 7.43 (t, 1H), 7.30 (d, 1H), 7.21 – 7.04 (m, 1H), 7.02 (s, 1H), 5.28 (d, 2H), 4.74 (t, 1H), 4.72 – 4.53 (m, 1H), 4.43 (d, 1H), 4.20 – 3.88 (m, 4H), 3.56 (d, 2H), 3.17 – 3.05 (m, 2H), 3.02 (s, 1H), 2.83 (q, 1H), 2.12 (d, 1H), 2.02 (d, 2H), 1.92 – 1.64 (m, 5H). Example 3: Synthesis of 3-((S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro- 8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)propanenitrile (Compound 105)Step 1: Synthesis of 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9- yl)ethan-1-ol

[0289] To a solution of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene (Example 2, step 5) (150 mg, 0.22 mmol) in anhydrous DMF (7.50 mL) was added CsF (336.9 mg, 2.22 mmol) and the reactionmixture was stirred for 1h at rt. The mixture was concentrated in vacuo and the residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (10 mmol / NH4HCO3), 10% to 50% gradient in 10 min, to afford the title compound (80 mg, 82.4%) as a white solid. LCMS m / z = 438 [M+H]+ Step 2: Synthesis of 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9- yl)ethyl methanesulfonate

[0290] To a solution of 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-9-yl)ethan-1-ol (40 mg, 0.09 mmol) and TEA (37.0 mg, 0.36 mmol) in DCM (4 mL) was added methanesulfonic anhydride (23.87 mg, 0.137 mmol) dropwise at 0°C under N2and the reaction mixture was stirred for 2h at 0°C. The reaction was quenched with water (2mL) and the mixture was extracted with DCM (3 x 10 mL). The combined organic layer was washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure, to afford the title compound, 46 mg, crude. LCMS m / z = 516 [M+H]+ Step 3: Synthesis of 3-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9- yl)propanenitrile

[0291] To a solution of 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-9-yl)ethyl methanesulfonate (46 mg, 0.09 mmol) and KI (119.6 mg, 0.72 mmol) in DMSO (4 mL) was added KCN (42.3 mg, 0.65 mmol) and the reaction mixture was stirred for 2 h at 100°C. The cooled reaction mixture was diluted with water (10 mL) and the mixture extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with sat. FeSO4to remove excess KCN then washed with brine (3 x 10 mL), dried over Na2SO4and concentrated in vacuo. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (10 mmol / L NH4CO3), 10% to 50% gradient in 10 min, to afford the title compound (23 mg, 57.7%) as a white solid. LCMS m / z = 447 [M+H]+ Step 4: Synthesis of 3-((S)-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-9-yl)propanenitrile

[0292] The title compound was obtained as a brown solid, 30 mg, 84.1%, from 3-((S)-5- chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)propanenitrile and ((2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane, following a similar procedure to that described in Example 1, step 5. LCMS m / z = 797 [M+H]+ Step 5: Synthesis of 3-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)propanenitrile

[0293] The title compound was obtained as a white solid, from 3-((S)-5-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)propanenitrile, following the procedure described in step 1. LCMS m / z = 641 [M+H]+ Step 6: Synthesis of 3-((S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)propanenitrile

[0294] To a solution of 3-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro- 8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)propanenitrile (18 mg, 0.028 mmol) in DCM (5 mL) was added TFA (1 mL) dropwise at 0°C and the reaction mixture was stirred for 1.5 h at 0°C. The mixture was concentrated in vacuo and the crude product was purified by prep-HPLC (Method C, Gradient: 15% to 30% B in 8 min), to afford the title compound (4.5 mg, 26.3%) as a white solid. LCMS m / z = 596 [M+H]+.1H NMR (400 MHz, DMSO-d6) 10.77 (s, 1H), 10.13 (d, 1H), 7.94 (dd, 1H), 7.45 (t, 1H), 7.33 (d, 1H), 7.13 (d, 2H), 5.58 (d, 1H), 4.86 – 4.65 (m, 1H), 4.58 (q, 2H), 4.45 (dd, 1H), 4.15 – 4.04 (m, 1H), 4.06 – 3.88 (m, 2H), 3.81 (d, 3H), 2.74 (dd, 2H), 2.29 (s, 1H), 2.27 – 2.10 (m, 2H), 2.02 (q, 3H). Example 4: Synthesis of 5-ethyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 104)Step 1: Synthesis of 2-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)ethan-1-ol

[0295] A mixture of 2-((S)-5-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-9-yl)ethan-1-ol (Example 3, step 1) (20 mg, 0.046 mmol), cataCXium A Pd G3 (6.65 mg, 0.009 mmol), K3PO4 (38.78 mg, 0.184 mmol) and 2-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24.7 mg, 0.069 mmol) in dioxane (3 mL) and H2O (0.3 mL) was stirred for 1 h at 100°C under N2. The cooled mixture was concentrated in vacuo and the residue was purified by reverse-phase column chromatography (C18 silica gel, eluting with MeCN in water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min), to afford the title compound (23 mg, 79.2%) as a white solid. LCMS m / z = 636 [M+H]+Step 2: Synthesis of 5-ethyl-6-fluoro-4-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0296] To a solution of 2-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)ethan-1-ol (30 mg, 0.047 mmol) in DCM (1 mL) was added TFA (0.2 mL) dropwise and the reaction mixture was stirred for 0.5 h at 0°C. The mixture was concentrated under reduced pressure and the crude product was purified by prep-HPLC (Method A, Gradient: 27% to 52% B in 7 min), to give the title compound (6.5 mg, 22.7%) as a white solid. LCMS m / z = 592 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 9.88 (s, 1H), 7.80 – 7.56 (m, 1H), 7.39 – 7.13 (m, 2H), 7.19 – 6.79 (m, 2H), 5.45 – 5.11 (m, 1H), 4.88 – 4.56 (m, 2H), 4.48 (d, 1H), 4.22 – 4.06 (m, 2H), 3.99 (d, 1H), 3.55 (s, 2H), 3.16 – 2.94 (m, 3H), 2.90 – 2.72 (m, 1H), 2.46 – 2.25 (m, 1H), 2.14 (ddd, 2H), 2.09 – 1.93 (m, 2H), 1.95 – 1.36 (m, 5H).Example 5: Synthesis of 2-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro- 10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol (Compound 106)Steps 1 and 2: Synthesis of 5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)ethoxy)-7-chloro- 8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0297] The title compound was obtained from tert-butyl (2-((tert- butyldiphenylsilyl)oxy)ethyl)(2-hydroxyethyl)carbamate (Intermediate 2) and 5,7-dichloro-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one, following the same 2 step procedure described in Example 2, steps 1 and 2. LCMS m / z = 587 [M+H]+ Step 3: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(methylthio)- 9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0298] TEA (499.8 mg, 4.94 mmol) and PyBOP® (771.1 mg, 1.48 mmol) were added to a solution of 5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)ethoxy)-7-chloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (580 mg, 0.99 mmol) in DCM (10 mL) and the reaction mixture was stirred at rt overnight under N2. The reaction mixture was concentrated in vacuo and the residue was purified by prep-TLC (DCM / MeOH 20:1) to afford the title compound (230 mg, 40.9 %) as a brown solid. LCMS m / z = 569 [M+H]+Steps 4 to 6: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0299] The title compound was obtained from 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5- chloro-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)triisopropylsilane, following the same 3 step procedure described in Example 1, steps 3 to 5. LCMS m / z = 1030 [M+H]+ Steps 7 and 8: Synthesis of 2-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol

[0300] The title compound was obtained as a white solid, from 10-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene, following a similar 2 step procedure to that described in Example 3, steps 5 and 6. LCMS m / z = 592 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 10.18 (s, 1H), 7.97 (dd, 1H), 7.46 (t, 1H), 7.38 (d, 1H), 7.15 (d, 1H), 5.55 (d, 1H), 4.90 (t, 1H), 4.57 (s, 3H), 4.15 – 3.98 (m, 4H), 3.88 – 3.66 (m, 5H), 2.30 (s, 2H), 2.09 (d, 4H), 1.35 – 1.12 (m, 1H). Example 6: Synthesis of 5-ethyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 113)Steps 1 and 2: Synthesis of (S)-5-(4-((tert-butyldiphenylsilyl)oxy)-2-(methylamino)butoxy)-7- chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one trifluoroacetate

[0301] The title compound was obtained from 5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one and tert-butyl (S)-(4-((tert- butyldiphenylsilyl)oxy)-1-hydroxybutan-2-yl)(methyl)carbamate (Intermediate 7), following the same 2 step procedure as described in Example 2, step 1 and 2. LCMS m / z = 601 [M+H]+ Step 3: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-10-methyl-2- (methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0302] PyBOP (233.7 mg, 0.45 mmol) was added to a solution of (S)-5-(4-((tert- butyldiphenylsilyl)oxy)-2-(methylamino)butoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4(3H)-one trifluoroacetate (180 mg, 0.30 mmol) and TEA (151.5 mg, 1.5 mmol) in DCM (2 mL) and the reaction mixture was stirred for 5 h at rt under N2. The reaction was quenched with water and the mixture extracted with DCM (3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column elutingwith PE / EtOAc (5:1) to afford the title compound (100 mg, 57.3%) as a white solid. LCMS m / z = 583 [M+H]+ Step 4: Synthesis of (9S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-10-methyl- 2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0303] The title compound was obtained from (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)- 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene, following the procedure described in Example 1, step 3. LCMS m / z = 599 [M+H]+Step 5: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene

[0304] A solution of (9S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-10- methyl-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (50 mg, 0.083 mmol, and ((2R,7aS)-2-fluoro-hexahydropyrrolizin-7a-yl)methanol (39.9 mg, 0.25 mmol) in toluene (1 mL) was stirred for 30 min at rt under N2, then cooled in an ice-bath. Sodium tert-butoxide (16.04 mg, 0.166 mmol) was added and the reaction mixture was stirred for 10 min at 0°C. The reaction was quenched with ice-water (5 mL) at 0°C and the mixture extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (3 x10 mL), dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1) to afford the title compound (30 mg, 51.8%) as a white solid. LCMS m / z = 694 [M+H]+ Step 6: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0305] A mixture of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (25 mg, 0.036 mmol), 2-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25.94 mg, 0.072 mmol), K3PO4 (22.93 mg, 0.108 mmol) and cataCXium-A-Pd-G3 (2.10 mg, 0.003 mmol) in dioxane / H2O (6 mL, v / v=5:1) was stirred for 1h at 100°C under N2. The cooled reaction mixture was concentrated in vacuo. The residue was purified by silica gel columnchromatography, eluting with DCM / MeOH (15:1) to afford the title compound (20 mg, 62.3%) as a white solid. LCMS m / z = 892 [M+H]+ Step 7: Synthesis of 2-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-9-yl)ethan-1-ol

[0306] CsF (42.57 mg, 0.28 mmol) was added to a solution of (S)-9-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (25 mg, 0.028 mmol) in DMF (1 mL) and the reaction mixture was stirred for 30 min at 60°C under N2. The cooled reaction mixture was purified directly by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (0.1% TFA), 60% to 70% gradient in 10 min, to give the title compound (10 mg, 54.%) as a white solid. LCMS m / z = 654 [M+H]+ Step 8: Synthesis of 5-ethyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0307] TFA (0.2 mL) was added to a solution of 2-((S)-5-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-9-yl)ethan-1-ol (10 mg, 0.015 mmol) in DCM (1 mL) and the reaction mixture was stirred for 30 min at rt under N2. The mixture was concentrated in vacuo and the residue purified by prep-HPLC (Method B, Gradient: 20% B to 35% B in 7 min), to give the title compound (1.0 mg, 9.0%) as a yellow solid. LCMS m / z = 610 [M+H]+.1H NMR (400 MHz, DMSO-d6) 10.02 – 9.93 (m, 1H), 7.75 (dd, 1H), 7.39 – 7.29 (m, 1H), 4.75 – 4.52 (m, 2H), 4.52 – 4.43 (m, 1H), 2.19 (d, 2H), 2.05 (d, 1H), 1.80 (d, 1H), 1.24 (s, 1H), 0.80 (dt, 2H). Example 7: Synthesis of 5-ethynyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 102)Step 1: Synthesis of tert-butyl (2-((tert-butyldiphenylsilyl)oxy)ethyl)(2-((7-chloro-2- (methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)carbamate

[0308] tert-Butyl (2-((tert-butyldiphenylsilyl)oxy)ethyl)(2-hydroxyethyl)carbamate, Intermediate 2 (2 g, 4.51 mmol) was added to a suspension of NaH (378.6 mg, 15.78 mmol) inTHF (10 mL) at 0 and the mixture stirred for 15 mins. A solution of 5,7-dichloro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one, Intermediate 1 (1.18 g, 4.51 mmol) in THF (2 mL) was added dropwise at 0°C and the reaction mixture was stirred for 1 h at 60oC under N2. The cooled reaction was quenched with ice-water (10 mL) and the mixture extracted with EtOAc (25 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (0.1% TFA), 10% to 50% gradient in 10 min, to give the title compound (800 mg, 26.5%) as a white oil. LCMS m / z = 670 [M+H]+ Step 2: Synthesis of 5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)ethoxy)-7-chloro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one trifluoroacetate

[0309] TFA (2.67 mL, 35.9 mmol) was added to a solution of tert-butyl (2-((tert- butyldiphenylsilyl)oxy)ethyl)(2-((7-chloro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3- d]pyrimidin-5-yl)oxy)ethyl)carbamate (800 mg, 1.2 mmol) in DCM (10 mL) and the reaction mixture was stirred for 0.5 h at rt under N2. The mixture was evaporated under reduced pressure to give the title compound, crude, 600 mg. LCMS m / z = 570 [M+H]+ Step 3: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(methylthio)-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0310] TEA (231.1 mg, 2.29 mmol) and PyBOP® (356.6 mg, 0.69 mmol) were added to a solution of 5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)ethoxy)-7-chloro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one trifluoroacetate (260 mg, 0.457 mmol) in DCM (5 mL) and the reaction mixture was stirred overnight at rt under N2. The solvent was removed under reduced pressure and the residue purified by prep-TLC (DCM / MeOH 20:1) to afford the title compound (170 mg, 67.5%) as a brown solid. LCMS m / z = 551 [M+H]+ Step 4: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(methylsulfinyl)-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0311] m-CPBA (13.3 mg, 0.54 mmol) was added to a solution of 10-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (300 mg, 0.544 mmol) in DCM (10 mL) at -15 and thereaction mixture stirred at this temperature for 1 h. The reaction was quenched with Na2SO3 solution and extracted with DCM (3x10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na2SO4 and evaporated under reduced pressure to give the title compound (200 mg, 64.8%) as a brown solid. LMS m / z = 267 [M+H]+ Step 5: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0312] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (61.75 mg, 0.39 mmol) was added to a suspension of NaH (25.4 mg, 1.06 mmol) in anhydrous THF (5 mL) at 0°C and the mixture stirred for 15 min at 0°C under N2. A solution of 10-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene (200 mg, 0.35 mmol) in THF (2 mL) was added dropwise at 0°C and the reaction mixture was stirred for 1 h at rt. The reaction was quenched with water (5mL) at 0°C and then extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4, filtered and concentrated invacuo. The residue was purified by prep-TLC (DCM / MeOH 20:1) to afford the title compound (100 mg, 77.9%) as a white solid. LCMS m / z = 662 [M+H]+ Step 6: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0313] A mixture of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene (70 mg, 0.11 mmol), ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (132.1 mg, 0.212 mmol), cataCXium-A-Pd-G3 (15.40 mg, 0.021 mmol) and K3PO4(67.31 mg, 0.318 mmol) in dioxane / H2O (5 mL, v / v=4:1) was stirred for 1h at 80°C under N2. The cooled reaction was diluted with water (10 mL) and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH 20:1) to afford the title compound (75 mg, 63.1%) as a brown solid. LCMS m / z = 1124 [M+H]+ Step 7: Synthesis of 5-ethynyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0314] A mixture of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene (70 mg, 0.062 mmol) and CsF (94.5 mg, 0.62 mmol) in anhydrous DMF (2 mL) was stirred for 1 h at 60°C under N2. The reaction mixture was cooled to rt and purified by prep-HPLC (Method C, Gradient: 15% to 30% B in 7 min), to afford the title compound (12.6 mg, 24.0%) as a white solid. LCMS m / z = 574 [M+H]+.1H NMR (400 MHz, DMSO-d6) 10.36 – 10.59 (s, 1H), 8.15 (s, 1H), 7.92 (dd, 1H), 7.43 (t, 1H), 7.31 (d, 1H), 5.29 (d, 1H), 4.88 (s, 1H), 4.64 – 4.41 (m, 3H), 4.14 – 3.92 (m, 8H), 3.85 – 3.65 (m, 6H), 3.17 – 3.07 (m, 4H), 3.03 (s, 3H), 2.93 – 2.78 (m, 2H), 2.19 – 1.90 (m, 4H), 1.90 – 1.69 (m, 4H). Examples 8 to 13

[0315] The compounds in Table 2 were obtained from the appropriate 5,7-dichloro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one, the appropriate alcohol, ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, following a similar 7 step procedure to that described in Example 7. Table 2.Example 14: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 114)Steps 1 to 5: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene

[0316] The title compound was obtained as a solid, from 5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one, Intermediate 8 and ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, following a similar 5 step procedure to that described in Example 7, steps 1 to 5. LCMS m / z = 680 [M+H]+ Steps 6 and 7: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0317] The title compound was obtained as an off-white solid, from the compound from steps 1 to 5 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane, following a similar 2 step procedure to that described in Example 7, steps 6 and 7. LCMS m / z = 592 [M+H]+.1H NMR (400 MHz, DMSO-d6) 9.22 (dd, 1H), 7.95 (dd, 1H), 7.45 (t, 1H), 7.36 (d, 1H), 7.16 (dd, 1H), 5.44 - 5.16 (m, 1H), 4.46 (d, 2H), 4.17 - 3.86 (m, 4H), 3.61 (d, 2H), 3.13 - 2.93 (m, 3H), 2.89 - 2.63 (m, 2H), 2.13 - 1.92 (m, 3H), 1.87 - 1.68 (m, 5H). Example 15: Synthesis of 3-((S)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)- 8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)propenamide (Compound 178)Step 1: Synthesis of 3-((S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)propanenitrile

[0318] To a stirred mixture of Example 14, steps 1 to 5, 230 mg, 0.34 mmol) and acrylonitrile (26.9 mg, 0.51 mmol) in DCM (5 mL) were added benzyltrimethylazaniumoxidanide (11.31 mg, 0.07 mmol) and the reaction mixture was stirred for 2h at rt under N2. Theresulting mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (DCM / MeOH= 12:1) to afford the title compound (150 mg, 54.5%) as an off-white solid. LCMS m / z = 733 [M+H]+ Step 2: Synthesis of 3-((S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)propanamide

[0319] A mixture of the compound from step 1 (30 mg, 0.041 mmol) and Parkin’s catalyst (3.50 mg, 0.008 mmol) in EtOH (1 mL) was stirred for 2h at 80°C under N2. The resulting mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (DCM / MeOH=10:1) to afford the title compound (20 mg, 59.9%) as a brown solid. LCMS m / z = 752 [M+H]+ Step 3: Synthesis of 3-((S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10- yl)propanamide

[0320] The title compound was obtained as a solid, 25 mg, 41.8%, from the compound from step 2 and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane, following a similar procedure to that described in Example 7, step 6. Step 4: Synthesis of 3-((S)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-8,9- dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)propanamide

[0321] HCl in dioxane (1 mL) was added to a mixture of the compound from step 3 (30 mg, 0.032 mmol) in DCM (0.2 mL) and the reaction stirred for 1h at rt under N2. The resulting mixture was concentrated under reduced pressure and the crude was purified by Prep-HPLC (Method D, Gradient: 11% B to 33% B in 7 min) to afford the title compound (3.1 mg, 11.8%) as an off-white solid. LCMS m / z = 713 [M+H]+.1H NMR (400 MHz, DMSO-d6) 7.76 (dd, 1H), 7.45 - 7.28 (m, 2H), 7.03 (dd, 1H), 5.66 - 5.23 (m, 2H), 4.69 - 4.65(m, 1H), 4.39 - 4.35 (m, 2H), 4.33 - 4.22 (m, 3H), 3.76 - 3.57 (m, 3H), 3.46 - 3.17 (m, 3H), 2.98 - 2.93 (m, 1H), 2.87 - 2.71 (m, 1H), 2.63 - 2.60 (m, 1H), 2.45 - 2.41 (m, 2H), 2.35 - 2.27 (m, 1H), 2.24 - 2.18 (m, 2H), 2.11 - 2.02 (m, 2H), 2.98 - 2.02 (m, 3H), 1.85 - 1.72 (m, 2H), 1.51 - 1.40 (m, 1H). Example 16: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(3-hydroxypropyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol formate (Compound 146)Steps 1 to 3: Synthesis of 10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-2- (methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0322] The title compound was obtained as a white solid, from Intermediate 11 and 5,7- dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one, following a similar 3 step procedure to that described in Example 1, steps 1 to 3. LCMS m / z = 599 [M+H]+ Step 4: Synthesis of 10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0323] A solution of the compound from steps 1 to 3 (0.36 g, 0.60 mmol) and ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.29 g, 1.80 mmol) in toluene (5 mL) wasstirred for 30 min at rt under N2, then cooled to 0 . NaOtBu (0.12 g, 1.20 mmol) was addedand the reaction mixture stirred for a further 30 min at 0°C. The resulting mixture was diluted with brine and extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (3x10mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water (10 mmol NH4CO3), 60% to 70% gradient in 10 min to afford the title compound (0.176 g, 42.2%) as a white solid. LCMS m / z = 694 [M+H]+ Step 5: Synthesis of 10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-4-fluoro-5-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0324] To a stirred solution of the compound from step 4 (0.176 g, 0.25 mmol) and ((6- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen- 2-yl)oxy)triisopropylsilane (237.6 mg, 0.38 mmol) in dioxane (4 mL) and H2O (1 mL) were added K3PO4(161.4 mg, 0.76 mmol) and cataCXium-A-Pd-G3 (18.46 mg, 0.025 mmol) and the reaction mixture was stirred for 1h at 80°C under N2. The cooled mixture was diluted with brine and extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (3x20mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH: DCM (1:20) to afford the title compound (0.22 g, 74.7%) as an off-white solid. LCMS m / z = 615 [M+H]+ Step 6: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-10-(3-hydroxypropyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol formate

[0325] To a stirred solution of the compound from step 5 (0.22 g, 0.19 mmol) in DMF (2 mL) was added CsF (0.43 g, 2.84 mmol) in portions at rt under N2. The resulting mixture was stirred for 1h at 60°C under N2, then cooled to rt. The resulting mixture was diluted with brine and extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (3x50mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC (Method D, Gradient: 15% B to 30% B in 7 min) to give the title compound (32.7 mg, 26.5%) as an off-white solid. LCMS m / z = 597 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 10.15 (br s, 1H), 8.15 (s, 1H), 7.96 (dd, 1H), 7.46 (t, 1H), 7.37 (d, 1H), 7.14 (d, 1H), 5.39 – 5.18 (m, 1H), 4.53 (t, 2H), 4.18 – 3.74 (m, 7H), 3.51 (t, 2H), 3.17 – 2.98 (m, 3H), 2.89 – 2.78 (m, 1H), 2.18 – 1.94 (m, 3H), 1.92 – 1.70 (m, 5H). Example 17: Synthesis of 4-((S)-10-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 138)

[0326] The title compound was obtained as a white solid, from Intermediate 14, 5,7- dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one, ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, following a similar 6 step process to that described in Example 16. LCMS m / z = 620 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 10.14 (s, 1H), 7.95 (dd, 1H), 7.46 (d, 1H), 7.36 (d, 1H), 7.19 (d, 1H), 5.39 – 5.17 (m, 1H), 4.84 – 4.57 (m, 2H), 4.38 – 4.19 (m, 2H), 4.19 – 3.92 (m, 4H),3.55 (t, 3H), 3.16 – 2.96 (m, 3H), 2.84 (td, 1H), 2.19 – 1.93 (m, 3H), 1.91 – 1.68 (m, 5H), 1.36 – 1.19 (m, 3H). Example 18: Synthesis of 5-ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-methyl-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 119)Steps 1 to 3: Synthesis of (9R)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-9- methyl-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0327] The title compound was obtained as a white solid, from Intermediate 10 and 5,7- dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one, following a similar 3 step procedure to that described in Example 1, steps 1 to 3. LCMS m / z = 599 [M+H]+ Step 4: Synthesis of (R)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0328] A solution of the compound from steps 1 to 3 (1.36 g, 2.27 mmol) and ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.72 g, 4.54 mmol) in toluene (20 mL) was stirred for 30 min at rt under N2. NaOtBu (0.65 g, 6.81 mmol) was added at 0°C and the resulting mixture was stirred for 10 min at 0°C under N2. The reaction was quenched with water. The aqueous layer was extracted with DCM (3x30 mL), the combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH=15:1) to afford the title compound (400 mg, 25.4%) as a white solid. LCMS m / z = 694 [M+H]+Steps 5 to 6: Synthesis of 5-ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0329] The title compound was obtained as a yellow solid, from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane, following a similar 2 step procedure to that described in Example 16, steps 5 and 6. LCMS m / z = 668 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 10.10 (s, 1H), 7.95 (dd, 1H), 7.45 (td, 1H), 7.36 (d, 1H), 7.15 (dd, 1H), 5.21(d,1H), 4.88 (s, 1H), 4.55 (td, 1H), 4.41 (dd, 1H), 4.21 (dt, 3H), 4.12 - 3.95 (m, 4H), 3.91 - 3.73 (m, 2H), 3.13 - 2.99 (m, 3H), 2.84 (q, 1H), 2.17 - 1.94 (m, 3H), 1.80 (dt, 2H), 1.28 (d, 3H). Example 19: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-methyl-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 120)Step 1: Synthesis of (S)-5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)propoxy)-7-chloro-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0330] NaH (2.35 g, 58.7 mmol, 60%) was added slowly at 0oC to a solution of (S)-2-((2- ((tert-butyldiphenylsilyl)oxy)ethyl)amino)propan-1-ol (Intermediate 3, step 1, 7 g, 19.6 mmol) in THF (100 mL) and the mixture was stirred for 10 min at 0°C under N2.5,7- Dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one (10.97 g, 39.2 mmol)in THF (20 mL) was added dropwise at 0°C and the reaction mixture was stirred for 1h at rt. The reaction was quenched with water at 0°C and the aqueous layer was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (column, C18 silica gel; mobile phase, MeOH in Water (0.1% TFA), 95% to 100% gradient in 10 min) to afford the title compound (4.6 g, 39.1%) as a white solid. LCMS m / z = 601 [M+H]+ Steps 2 to 4: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0331] The title compound was obtained as a white solid, from the compound from step 1 and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, following a similar 2 step procedure to that described in Example 18, steps 2 to 4. LCMS m / z = 694 [M+H]+ Steps 5 to 6: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0332] The title compound was obtained as a white solid, from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane, following a similar 2 step procedure to that described in Example 18, steps 5 to 6. LCMS m / z = 606 [M+H]+1H NMR (400 MHz, DMSO-d6) 10.10 (s, 1H), 7.95 (dd, 1H), 7.52 – 7.31 (m, 2H), 7.15 (dd, 1H), 5.40 – 5.16 (m, 1H), 4.55 (td, 1H), 4.41 (dd, 1H), 4.28 – 4.16 (m, 2H), 4.11 (dd, 1H), 4.07 – 3.93 (m, 2H), 3.91 – 3.74 (m, 2H), 3.68 (dd, 1H), 3.58 (dt, 2H), 3.16 – 3.07 (m, 3H), 3.03 (s, 1H), 2.84 (q, 1H), 2.18 – 1.94 (m, 2H), 1.91 – 1.66 (m, 2H), 1.28 (d, 3H). Example 20: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(3-hydroxypropyl)-9-methyl-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 145)Step 1: Synthesis of (S)-5-(2-((3-((tert-butyldiphenylsilyl)oxy)propyl)amino)propoxy)-7-chloro- 8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0333] The title compound was obtained as a yellow solid, 3 g, 90.6%, from Intermediate 12 and 5,7-dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one, following a similar procedure to that described in Example 1, step 1. LCMS m / z = 631 [M+H]+ Step 2: Synthesis of (S)-10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-9-methyl- 2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0334] The title compound was obtained as a white solid, 560 mg, 57.7%, from the compound from step 1, following a similar procedure to that described in Example 1, step 2, except the residue was purified by reverse-phase chromatography (column, C18; mobile phase, MeCN in Water (0.1% TFA), 10% to 100% gradient in 30 min. LCMS m / z = 597 [M+H]+ Step 3: Synthesis of (9S)-10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-9- methyl-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0335] The title compound was obtained as a yellow solid, 830 mg, 89.8%, from the compound from step 2, following the procedure described in Example 7, step 4. LCMS m / z = 613 [M+H]+ Step 4: Synthesis of (S)-10-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5-chloro-4-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0336] The title compound was obtained as a white solid, 135 mg, 14.3%, from ((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and the compound from step 3, followinga similar procedure to that described in Example 16, step 4, except reverse-phase chromatography ( column, C18; mobile phase, MeCN in Water (0.1% TFA), 10% to 100% gradient in 10 min). LCMS m / z = 708 [M+H]+ Steps 5 to 6: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(3-hydroxypropyl)-9-methyl-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol formate

[0337] The title compound was obtained as a white solid, from the compound from step 4 and tert-butyl((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6- ((triisopropylsilyl)oxy)naphthalen-1-yl)ethynyl)diphenylsilane, following a similar 2 step procedure to that described in Example 16, steps 5 and 6. LCMS m / z = 620 [M+H]+.1H NMR (400 MHz, DMSO-d6) 10.13 (s, 1H), 7.96 (dd, 1H), 7.46 (td, 1H), 7.37 (d, 1H), 7.15 (dd, 1H), 5.28 (d, 1H), 4.80 – 4.48 (m, 2H), 4.37 (dd, 1H), 4.29 – 3.93 (m, 5H), 3.50 (d, 3H), 3.19 – 2.94 (m, 3H), 2.83 (t, 1H), 2.19 – 1.62 (m, 8H), 1.37 – 1.09 (m, 3H). Example 21: Synthesis of 4-((S)-9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 144)Step 1: Synthesis of (S)-5-(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-2- cyclopropylethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0338] The title compound was obtained as a yellow solid, 100 mg, 30.6%, from Intermediate 13 and 5,7-dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4- one, following a similar procedure to that described in Example 19, step 1. LCMS m / z = 627 [M+H]+Step 2: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-9-cyclopropyl-4- fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0339] To a stirred mixture of the compound from step 1 (250 mg, 0.4 mmol) and TEA (201.7 mg, 2.0 mmol) in DCM (3 mL) was added PyBOP® (311.1 mg, 0.6 mmol) dropwise 0 °C under N2. The reaction mixture was irradiated with microwave radiation for 15 h at 0°C. The resulting mixture was extracted with EtOAc (2 x 20 mL), the combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to afford the title compound (210 mg) as an off-white solid. LCMS m / z = 609 [M+H]+ Step 3: Synthesis of (9S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-9-cyclopropyl-4- fluoro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0340] The title compound was obtained from the compound from step 2, following the procedure described in Example 1, step 3. LCMS m / z = 625 [M+H]+ Step 4: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-9-cyclopropyl-4- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0341] A solution of the compound from step 3 (190 mg, 0.3 mmol) in toluene (9.50 mL) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (193.5 mg, 1.22 mmol) was stirred for 30 min at rt under N2. NaOtBu (58.4 mg, 0.61 mmol) was added portion wise at 0 °C and the reaction mixture was irradiated with microwave radiation for 10 min at 0°C. The mixture was extracted with EtOAc (2 x 30 mL), the combined organic layers were washed with brine (2x20 mL) dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc 3:1) to afford the title compound (150 mg, 68.5%) as a white solid. LCMS m / z = 720 [M+H]+ Step 5: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-9-cyclopropyl-4-fluoro-5-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0342] The title compound was obtained as a yellow solid, 95 mg, from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane, following a similar procedure to that described in Example 16, step 5. LCMS m / z = 1070 [M+H]+ Step 6: Synthesis of 4-((S)-9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0343] The title compound was obtained as a white solid, 63.9 mg, 87.1%, from the compound from step 5, following a similar procedure to that described in Example 6, step 7. LCMS m / z = 632 [M+H]+1H NMR (400 MHz, DMSO-d6) 10.17 (d, 1H), 8.02 - 7.93 (m, 1H), 7.54 -7.43 (m, 1H), 7.41 - 7.36 (m, 1H), 7.25 - 7.06 (m, 1H), 5.63-5.50 (m, 1H), 4.86 (s, 1H), 4.75 - 4.63 (m, 1H), 4.63 - 4.48 (m, 2H), 4.47 - 4.36 (m, 2H), 4.05 -3.96 (m, 1H), 3.90 - 3.80 (m, 3H), 3.79 - 3.66 (m, 4H), 3.32 - 3.30 (m, 3H), 2.29 - 2.18 (s, 3H), 2.02 - 1.96 (m, 1H), 1.03 - 0.96 (m, 1H), 0.66 - 0.55 (m, 3H), 0.45 - 0.38 (m, 1H). Example 22: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-(2,2,2- trifluoroethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5- yl)naphthalen-2-ol (Compound 169)Steps 1 to 5: Synthesis of (S)-10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(2,2,2-trifluoroethyl)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0344] The title compound was obtained as a yellow solid, from Intermediate 16, 5,7- dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane, following a similar 5 step procedure to that described in Example 21, steps 1 to 5. LCMS m / z = 1224 [M+H]+ Step 6: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-(2,2,2-trifluoroethyl)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0345] The title compound was obtained as an off-white solid, 5.7 mg, 29.6%, from the product from steps 1 to 5, following a similar procedure to that described in Example 3, step 1. LCMS m / z = 674 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 10.76 (s, 1H), 10.18 (d, 1H), 7.98 (dd, 1H), 7.52 – 7.43 (m, 1H), 7.39 (t, 1H), 7.21 (d, 1H), 5.63 (s, 0.5H), 5.50 (s, 0.5H), 5.01 (s, 1H), 4.78 – 4.66 (m, 1H), 4.57 (dd, 3H), 4.50 (d, 1H), 4.38 (t, 1H), 4.03 (s, 1H), 3.87 (s, 1H), 3.78 (s, 5H), 2.83 (dd, 1H), 2.30 (d, 1H), 2.17 (s, 3H), 2.02 (s, 1H), 1.51 (d, 1H), 1.23 (s, 1H). Example 23: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-8H,10H-7-oxa-1,3,6,10- tetraazaspiro[cyclohepta[de]naphthalene-9,1'-cyclopropan]-1(10a),2,3a,3a1(6a),5-pentaen- 5-yl)naphthalen-2-ol (Compound 170)Step 1: Synthesis of 5-((1-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)cyclopropyl)methoxy)-7- chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0346] The title compound was obtained as a yellow solid, 170 mg, 38.1%, from Intermediate 9 and 5,7-dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one, following a similar procedure to that described in Example 1, step 4. LCMS m / z = 613 [M+H]+ Step 2: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(methylthio)- 8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,1'-cyclopropan]- 1(10a),2,3a,3a1(6a),5-pentaene

[0347] The title compound was obtained as a white solid, 200 mg, 58.9%, from the compound from step 1, following the procedure described in Example 16, step 2. LCMS m / z = 595 [M+H]+Step 3: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (methylsulfinyl)-8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,1'- cyclopropan]-1(10a),2,3a,3a1(6a),5-pentaene

[0348] m-CPBA (126.1 mg, 0.73 mmol) was added to a solution of the compound from step 2 (290 mg, 0.49 mmol) in DCM (3 mL) at 0°C and the reaction mixture was stirred at rt for 15 min. The mixture was extracted with DCM (2 x 10mL), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the title compound (290 mg, crude) as a white solid. LCMS m / z = 985 [M+H]+Step 4: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8H,10H-7-oxa-1,3,6,10- tetraazaspiro[cyclohepta[de]naphthalene-9,1'-cyclopropan]-1(10a),2,3a,3a1(6a),5-pentaene

[0349] ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (226.6 mg, 1.42 mmol) was added to a solution of the compound from step 3 (290 mg, 0.47 mmol) in toluene (5 mL) and the mixture was stirred at rt for 1h. NaOtBu (91.20 mg, 0.95 mmol) was added in portions and the reaction mixture was stirred at rt for 2h. The mixture was extracted with EtOAc (3 x 50mL), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:10) toafford the title compound (220 mg, 65.7%) as a colorless oil. LCMS m / z = 706 [M+H]+Step 5: Synthesis of 10-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8H,10H-7-oxa-1,3,6,10- tetraazaspiro[cyclohepta[de]naphthalene-9,1'-cyclopropan]-1(10a),2,3a,3a1(6a),5-pentaene

[0350] ((6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (351.6 mg, 0.56 mmol) and cataCXium-A-Pd-G3 (20.62 mg, 0.03 mmol) were added to a solution of the compound from step 4 (200 mg, 0.28 mmol) in dioxane (1 mL). K2CO3(117.4 mg, 0.85 mmol) and then H2O (0.1 mL) were added and the reaction mixture was stirred at rt for 1h under N2. The resulting mixture was extracted with EtOAc (3 x 10mL), the combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to afford the title compound (320 mg, 96.7%) as a brown solid. LCMS m / z = 1169 [M+H]+ Step 6: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-8H,10H-7-oxa-1,3,6,10- tetraazaspiro[cyclohepta[de]naphthalene-9,1'-cyclopropan]-1(10a),2,3a,3a1(6a),5-pentaen-5- yl)naphthalen-2-ol

[0351] CsF (415.9 mg, 2.74 mmol) was added to a solution of the compound from step 5 (160 mg, 0.137 mmol) in DMF (2 mL) and the reaction mixture was stirred at 60°C for 30 min. The resulting mixture was filtered, the filter cake was washed with DMF (2 mL). The crude product was purified by Prep-HPLC (Method D, Gradient: 5% B to 35% B in 7 min) to afford the title compound (44.0 mg, 51.9%) as a yellow solid. LCMS m / z = 618 [M+H]+1H NMR (400 MHz, DMSO-d6) 10.14 (s, 1H), 8.04 – 7.86 (m, 1H), 7.46 (m, 1H), 7.37 (s, 1H), 7.18 (s, 1H), 5.41 – 5.18 (m, 1H), 5.09 – 4.91 (s, 1H), 4.88 – 4.61 (m, 1H), 4.32 – 4.05 (m, 4H), 4.05 – 3.95 (s, 1H), 3.81 – 3.49 (s, 4H), 3.19 – 2.89 (m, 2H), 2.32 – 2.01 (m, 3H), 2.01 – 1.71 (m, 3H), 1.62 – 1.40 (s, 1H), 1.34 – 1.21 (m, 2H), 1.21 – 1.13 (m, 1H), 1.13 – 0.95 (m, 1H). Example 24: Synthesis of 5'-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4'-fluoro-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'- oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalen]- 1'(10a'),2',3a',3a1'(6a'),5'-pentaen-3-ol (Compound 154)Steps 1 and 2: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-5'-chloro-4'-fluoro-10'-methyl-2'- (methylthio)-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'- cyclohepta[de]naphthalen]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene

[0352] The title compound was obtained as a yellow solid, from Intermediate 15 and 5,7- dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one, following a similar procedure to that described in Example 1, steps 1 and 2. LCMS m / z = 596 [M+H]+ Step 3: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-5'-chloro-4'-fluoro-10'-methyl-2'- (methylthio)-8'H,10'H-7'-oxa-1',3',6',10'-tetraazaspiro[cyclobutane-1,9'- cyclohepta[de]naphthalen]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene

[0353] A solution of the compound from steps 1 and 2 (590 mg, 0.99 mmol) and m-CPBA (256.5 mg, 1.49 mmol) in DCM (10 mL) was stirred for 0.5h at rt. The resulting mixture was evaporated under reduced pressure to afford the title compound (600 mg, crude) as a white solid. LCMS m / z = 612 [M+H]+ Step 4: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-5'-chloro-4'-fluoro-2'-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa-1',3',6',10'- tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalen]-1'(10a'),2',3a',3a1'(6a'),5'-pentaene

[0354] A solution of the compound from step 3 (570 mg, 0.93 mmol) and ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (222.7 mg, 1.40 mmol) in toluene (20 mL) was stirred for 1h at rt. NaOtBu (179.2 mg, 1.87 mmol) was added portion wise over 2 min at rt and the reaction mixture was stirred for 0.5h. The mixture was concentrated in vacuo and theresidue was purified by silica gel column chromatography, eluting with DCM / EtOAc (1:1) to afford the title compound (310 mg, 47.1%) as a white solid. LCMS m / z = 707 [M+H]+ Steps 5 to 6: Synthesis of 5'-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4'-fluoro-2'- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10'-methyl-8'H,10'H-7'-oxa- 1',3',6',10'-tetraazaspiro[cyclobutane-1,9'-cyclohepta[de]naphthalen]- 1'(10a'),2',3a',3a1'(6a'),5'-pentaen-3-ol formate.

[0355] The title compound was obtained as a yellow solid, from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane, following a similar 2 step procedure to that described in Example 16, steps 5 and 6. LCMS m / z = 618 [M+H]+.1H NMR (400 MHz, DMSO-d6) 7.96 (m, 1H), 7.46 (m, 1H), 7.37 - 7.31 (m 1H), 7.15 (m, 1H), 5.35 - 5.32 (m, 1H), 4.70 (s, 1H), 4.52 - 4.37 (m, 1H), 4.12 (m, 1H), 4.06 - 3.97 (m, 2H), 3.30 - 3.34(m, 3H), 3.17 - 3.00 (m, 3H), 2.99 - 2.89 (m, 1H), 2.89 - 2.75 (m, 2H), 2.62 - 2.54 (m, 1H), 2.44 - 2.29 (m, 1H), 2.24 - 1.94 (m, 4H), 1.91 - 1.72 (m, 3H). Example 25: Synthesis of 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 158)Step 1: Synthesis of (S)-5-(4-((tert-butyldiphenylsilyl)oxy)-2-((2,2-difluoroethyl)amino)butoxy)- 7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0356] A solution of Intermediate 17 (1 g, 2.45 mmol) in THF (5 mL) was added to a solution of NaH (294.4 mg, 7.36 mmol, 60%) in THF (5 mL) at 0°C under N2 and the mixturewas stirred for 30 min at 0°C under N2.5,7-Dichloro-8-fluoro-2-(methylsulfanyl)-3H- pyrido[4,3-d]pyrimidin-4-one (687.2 mg, 2.45 mmol) in THF (5 mL) was added dropwise at 0°C and the reaction mixture was stirred for 1 day at 80°C. The reaction was quenched with HCl (1M) at 0°C and the mixture was extracted with EtOAc (2 x 50mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 45% gradient in 20 min to give the title compound (523 mg, 19.6%) as a brown oil. LCMS m / z = 651 [M+H]+ Step 2: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-(2,2- difluoroethyl)-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0357] PyBOP® (958.9 mg, 1.84 mmol) was added in portions at 0°C to a solution of the compound from step 1 (800 mg, 1.23 mmol) and TEA (372.9 mg, 3.68 mmol) in THF (2 mL) and the reaction mixture was stirred overnight at 40°C. The mixture was extracted with EtOAc (3 x 80mL), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to afford the title compound (240 mg, 24.7%) as a white oil. LCMS m / z = 633 [M+H]+ Step 3: Synthesis of (9S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-(2,2- difluoroethyl)-4-fluoro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0358] The title compound was obtained as a white solid, 460 mg crude, from the compound from step 2, following a similar procedure to that described in Example 24, step 3. LCMS m / z = 649 [M+H]+ Step 4: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-chloro-10-(2,2- difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0359] ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (176.6 mg, 1.11 mmol) was added to A solution of the compound from step 3 (240 mg, 0.37 mmol) in toluene (1.5 mL) and the mixture was stirred for 1h at rt under N2. NaOtBu (71.1 mg, 0.74 mmol) was added in portions and the reaction mixture was stirred overnight at rt. The residue was purifiedby prep-TLC (EtOAc) to afford the title compound (200 mg, 62.5%) as a white solid. LCMS m / z = 744 [M+H]+ Step 5: Synthesis of (S)-9-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-10-(2,2-difluoroethyl)-4-fluoro- 5-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalene

[0360] The title compound was obtained as a yellow solid, 150 mg, 84.1%, from the compound from step 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane, following a similar procedure to that described in Example 16, step 5. LCMS m / z = 1206 [M+H]+ Step 6: Synthesis of 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9-(2-hydroxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0361] The title compound was obtained as a yellow solid, 35 mg, 4%, from the compound from step 5, following a similar procedure to that described in Example 23, step 6, except the compound was purified by Prep-HPLC (Method A, 25% B to 52% B in 7 min). LCMS m / z = 656 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 10.14 (m, 1H), 7.96 (m, 1H), 7.46 (m, 1H), 7.38 (m, 1H), 7.28 – 7.01 (m, 1H), 6.78 – 6.17 (m, 1H), 5.45 – 5.02 (m, 1H), 4.83 – 4.60 (m, 1H), 4.45 (m, 2H), 4.41 (m, 1H), 4.22 (m, 1H), 4.17 – 4.10 (m, 1H), 4.08 (m, 1H), 4.02 – 3.79 (m, 1H), 3.98 (m, 1H), 3.97 – 3.69 (s, 2H), 3.19 – 2.90 (m, 3H), 2.84 (m, 1H), 2.18 – 1.97 (m, 3H), 1.96 – 1.68 (m, 5H). Example 26: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10- tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaen-5- yl)naphthalen-2-ol (Compound 165)Step 1: Synthesis of 7-chloro-8-fluoro-5-((3-(methylamino)tetrahydrofuran-3-yl)methoxy)-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0362] To a solution of Intermediate 19 (1 g, 7.62 mmol) in THF (20 mL) was added NaH(548.8 mg, 22.9 mmol) at 0 and the mixture was stirred for 15 min. 5,7-Dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one (1.07 g, 3.81 mmol) was added and the reaction was warmed and stirred at rt for 1 h. The reaction was quenched with water and extracted with EtOAc (3 x 40 mL). The combined organic extracts were concentrated under reduced pressure to give the title compound (1 g, crude) as an off-white solid. LCMS m / z = 375 [M+H]+ Step 2: Synthesis of 5-chloro-4-fluoro-10-methyl-2-(methylthio)-4',5'-dihydro-2'H,8H,10H-7- oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5- pentaene

[0363] The title compound was obtained as a light yellow solid, 400 mg, 47.3%, from the compound from step 1, following a similar procedure to that described in Example 1, step 2. LCMS m / z= 357 [M+H]+. Steps 3 and 4: Synthesis of 5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10- tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaene

[0364] The title compound was obtained as an off-white solid, from the compound from step 2, following a similar 2 step procedure to that described in Example 23, steps 3 and 4. LCMS m / z = 468 [M+H]+Steps 5 and 6: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10- tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaen-5- yl)naphthalen-2-ol

[0365] The title compound was obtained as a white solid, from the compound from steps 3 and 4 and ((6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane, following a similar 2 step procedure to that described in Example 16, steps 5 and 6. LCMS m / z = 618 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 10.21 (s, 1H), 8.01-7.96 (m, 1H), 7.46 (t, 1H), 7.37 (d, 1H), 7.25 - 7.07 (m, 1H), 5.42 - 5.18 (m, 1H), 4.54 (s, 2H), 4.24 - 4.00 (m, 5H), 3.95 - 3.72 (m, 2H), 3.26 (s, 3H), 3.15 - 3.06 (m, 2H), 3.04 - 3.01 (m, 1H), 2.91 - 2.85 (m, 1H), 2.38 - 2.31 (m, 1H), 2.19 - 2.00 (m, 4H), 1.92 - 1.76 (m, 3H). Example 27: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-(trifluoromethyl)-9,10-dihydro- 8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol trifluoroacetate (Compound 157)Step 1: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5,7-dichloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-amine

[0366] A solution of Intermediate 28, step 1 (4.8 g, 16.1 mmol), (2-aminoethoxy)(tert- butyl)dimethylsilane (5.64 g, 32.2 mmol) and DIPEA (6.23 g, 48.2 mmol) in anhydrous DCM (15 mL) was stirred for 0.5 h at rt. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (MeOH / DCM 1:10) to give the title compound (2.4 g, 34.1%) as a yellow solid. LCMS m / z = 437 [M+H]+ Step 2: Synthesis of 10-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(methylthio)- 9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0367] A solution of the compound from step 1 (1.87 g, 4.28 mmol), 2-bromo-3,3,3- trifluoropropan-1-ol (1.65 g, 8.55 mmol) and NaH (307.8 mg, 12.8 mmol) in anhydrous THF (10 mL) was stirred for 2 days at 60 °C. The mixture was allowed to cool to rt and the reaction was quenched with water (15 mL). The mixture was concentrated under reduced pressure, the residue was extracted with EtOAc (3x20 mL), the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (1:10) to afford the title compound (190 mg, 8.7%) as a yellow solid. LCMS m / z = 513 [M+H]+ Step 3: Synthesis of 10-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2- (methylsulfinyl)-9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0368] A solution of the compound from step 2 (190 mg, 0.37 mmol) and m-CPBA (191.7 mg, 1.11 mmol) in anhydrous DCM (3 mL) was stirred for 1 h at rt. The resulting mixture was concentrated under reduced pressure and the residue was purified by Prep-TLC (MeOH / DCM 1:20) to give the title compound (110 mg, 54.5%) as a yellow solid. LCMS m / z = 529 [M+H]+ Step 4: Synthesis of 10-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-chloro-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(trifluoromethyl)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0369] A mixture of the compound from step 3 (100 mg, 0.18 mmol), ((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (43.8 mg, 0.27 mmol) and LiOtBu (29.4 mg, 0.37 mmol) in anhydrous DCM (2 mL) was stirred for 1h at rt. The resulting mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (MeOH / DCM=1:10) to give the title compound (40 mg, 33.9%) as a yellow solid. LCMS m / z = 624 [M+H]+Step 5: Synthesis of 10-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro-5-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-(trifluoromethyl)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0370] A mixture of the compound from step 4 (40 mg, 0.064 mmol), ((6-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (80.1 mg, 0.13 mmol), cataCXium-A-Pd-G3 (4.67 mg, 0.006 mmol) and K3PO4 (40.81 mg, 0.19 mmol) in anhydrous dioxane (2 mL) was stirred for 2 h at 80°C. The resulting mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (MeOH / DCM=1:10) to give the title compound (crude) as a yellow solid. LCMS m / z = 1087 [M+H]+ Step 6: Synthesis of 2-(4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9-(trifluoromethyl)-8,9-dihydro-10H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-10-yl)ethan-1-ol

[0371] TFA (20.5 mg, 0.18 mmol) was added to a solution of the compound from step 5 (65 mg, 0.06 mmol) in anhydrous DCM (1 mL) and the reaction stirred for 1h at rt. The resulting mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (MeOH / DCM 1:10) to give the title compound (48 mg, 76.8%) as a yellow solid. LCMS m / z = 972 [M+H]+ Step 7: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9-(trifluoromethyl)-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol trifluoroacetate

[0372] CsF (70.3 mg, 0.46 mmol) was added to a solution of the compound from step 6 (45 mg, 0.046 mmol) in DMF (1 mL) and the reaction mixture was stirred for 3h at rt. The residue was dissolved in water (5 mL), the mixture was extracted with EtOAc (3x10 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude was purified by HPLC (Method E, Gradient: 22% B to 47% B in 9 min) to afford the title compound. (2 mg, 5.6%) as a yellow solid. LCMS m / z = 660 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 10.77 (s, 1H), 10.19 (s, 1H), 7.99 (s, 1H), 7.48 (s, 1H), 7.40 (d, 1H), 7.17 (dd, 1H), 5.72 – 5.42 (m, 2H), 5.09 – 4.60 (m, 1H), 4.66 – 4.50 (m, 2H), 4.38 (dd, 2H), 4.26 – 4.04 (m, 2H), 4.04 – 3.88 (m, 1H), 3.92 – 3.43(m, 3H), 3.31 (s, 1H), 2.51 (s, 1H), 2.50 – 2.39 (m, 2H), 2.39 – 2.21 (m, 1H), 2.16 (m, 2H), 2.03 (s, 1H). Example 28: Synthesis of 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9- (trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5- yl)naphthalen-2-ol (Compound 161)Example 27 (10 mg, 0.015 mmol) was purified by Prep-chiral-HPLC: Column: (CHIRALPAK IE3; Mobile Phase A: MtBE: Hex (0.2%DEA): (EtOH: DCM=1:1) = 30: 70 at 1mL / min; Gradient: isocratic; to afford Peak 1 (1 mg, 8.5%) as a white solid: LCMS m / z = 660 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 10.17 (d, 1H), 8.05 – 7.90 (m, 1H), 7.47 (s, 1H), 7.39 (d, 1H), 7.17 (dd, 1H), 5.53 (s, 1H), 5.32 (d, 1H), 5.05 – 4.82 (m, 1H), 4.46 – 4.24 (m, 2H), 4.24 – 3.84 (m, 4H), 3.77 (s, 3H), 3.12 – 3.04 (m, 2H), 3.01 – 2.55 (m, 1H), 2.38 – 1.98 (m, 3H), 1.82 (s, 3H), 1.42 – 1.05 (m, 1H); Example 29: Synthesis of 5-ethynyl-6-fluoro-4-((R)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-(2-hydroxyethyl)-9- (trifluoromethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5- yl)naphthalen-2-ol (Compound 162)

[0373] Example 27 (10 mg, 0.015 mmol) was purified by Prep-chiral-HPLC: Column: (CHIRALPAK IE3; Mobile Phase A: MtBE: Hex (0.2%DEA): (EtOH: DCM=1:1) = 30: 70 at 1mL / min; Gradient: isocratic; to afford Peak 2 (Example 29, 1.6 mg, 13.6%) as a white solid: LCMS m / z = 660 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 10.20 (d, 1H), 7.99 - 7.92 (m, 1H), 7.53 - 7.45 (m, 1H), 7.45 - 7.37 (m, 1H), 7.21-7.17 (m, 1H), 5.72 - 5.41 (m, 2H), 4.97 (d,1H), 4.58 (s, 2H), 4.50 - 4.30 (m, 2H), 4.27 - 3.98 (m, 3H), 3.95 - 3.66 (m, 5H), 2.39 - 2.12 (m, 3H), 2.03 - 1.98 (m, 2H), 1.26 -1.23 (m, 1H), 1.21 - 1.08 (m, 1H). Example 30: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-((1s,3R)-3-hydroxycyclobutyl)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 124)Step 1: Synthesis of 2-((3-(benzyloxy)cyclobutyl)amino)ethan-1-ol

[0374] Ti(OPr)4(4.84 g, 17.0 mmol) was added to a solution of 3-(benzyloxy)cyclobutan-1- one (3 g, 17.0 mmol) and ethanolamine (2.08 g, 34.2 mmol) in MeOH (20 mL) and the mixture was stirred for 2h at 80°C under N2, then cooled to rt. NaBH3CN (2.14 g, 34.1 mmol) was added and the reaction mixture was stirred for 2h at 80°C under N2. The reaction was quenched with water at 0°C, the mixture was filtered and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase chromatography: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; to afford the title compound (2.5 g, 66.4%) as a white solid. LCMS m / z = 222 [M+H]+ Step 2: Synthesis of 5-(2-((3-(benzyloxy)cyclobutyl)amino)ethoxy)-7-chloro-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0375] A solution of NaH (1.25 g, 31.2 mmol, 60%) in THF (60 mL) and the compound from step 1 (2.3 g, 10.4 mmol) was stirred for 10 min at 0°C under N2.5,7-Dichloro-8-fluoro-2- (methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one (1.46 g, 5.2 mmol) was added at 0°C and the reaction mixture was stirred for 1h at 60°C under N2. The reaction was quenched with water at 20°C and the mixture concentrated under vacuum. The residue was purified by reverse-phase chromatography: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; to afford the title compound (1.9 g, 39.3%) as a yellow oil. LCMS m / z = 465 [M+H]+ Step 3: Synthesis of 10-(3-(benzyloxy)cyclobutyl)-5-chloro-4-fluoro-2-(methylthio)-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0376] The title compound was obtained as a white solid, 1.2 g, 65.7%, from the compound from step 2, following a similar procedure to that described in Example 1, step 2. LCMS m / z = 447 [M+H]+ Step 4: Synthesis of 10-(3-(benzyloxy)cyclobutyl)-5-chloro-4-fluoro-2-(methylsulfinyl)-9,10- dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0377] A solution of the compound from step 3 (300 mg, 0.67 mmol) and m-CPBA (127.4 mg, 0.74 mmol) in DCM (4 mL) was stirred for 2h at 25°C under N2. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase chromatography: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; to afford the title compound (300 mg, 96.6%) as a white solid. LCMS m / z = 463 [M+H]+ Step 5: Synthesis of 10-(3-(benzyloxy)cyclobutyl)-5-chloro-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0378] A solution of NaH (46.66 mg, 1.94 mmol, 60%) in THF (3 mL) and ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (113.5 mg, 0.71 mmol) was stirred for 20 min at 0°C under N2. The compound from step 4 (300 mg, 0.65 mmol) was added at 0°C, and the reaction mixture was stirred for 2h at 25°C under N2. The reaction was quenched with water (5 mL) at 0°C and the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; to afford the title compound (100 mg, 27.7%) as a white solid. LCMS m / z = 558 [M+H]+Step 6: Synthesis of 10-((1s,3R)-3-(benzyloxy)cyclobutyl)-4-fluoro-5-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene and 10-((1r,3S)-3-(benzyloxy)cyclobutyl)-4-fluoro-5-(7- fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene

[0379] A solution of the compound from step 5 (80 mg, 0.072 mmol) and ((6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (73.5 mg, 0.14 mmol), K3PO4 (45.7 mg, 0.22 mmol) and cataCXium- A-Pd-G3 (10.44 mg, 0.014 mmol) in dioxane (4 mL) and H2O (0.8 mL) was stirred for 1 h at 80°C under N2. The cooled mixture was concentrated under reduced pressure and the residue was purified by Prep-TLC (PE / EtOAc 5:1) to afford Peak 1, 10-((1s,3R)-3- (benzyloxy)cyclobutyl)-4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (80 mg, 54.7%) and Peak 2, 10-((1r,3S)-3-(benzyloxy)cyclobutyl)-4-fluoro-5-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene (50 mg, 34.2%) as a yellow solid. LCMS m / z = 1020 [M+H]+ Step 7: Synthesis of (1R,3s)-3-(4-fluoro-5-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10- yl)cyclobutan-1-ol

[0380] A solution of step 6, Peak 1 (25 mg, 0.024 mmol) and Pd / C (7.82 mg, 0.07 mmol) in THF (3 mL) was stirred for 30 mins at 60°C under H2. The reaction mixture was filtered through a Celite® pad and the filtrate concentrated under reduced pressure to give the title compound, crude as a light-yellow oil. LCMS m / z = 930 [M+H]+ Step 8: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-10-((1s,3R)-3-hydroxycyclobutyl)-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0381] CsF (19.63 mg, 0.13 mmol) was added to a solution of the compound from step 7 (10 mg, 0.013 mmol) in DMF (1 mL) and the reaction mixture stirred until no starting material remained. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Method D, Gradient: 20% B to 44% B in 7 min) to afford the title compound (1 mg, 12.3%) as a white solid. LCMS m / z = 619 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 10.15 (s, 1H), 7.96 (dd, 1H), 7.46 (t, 1H), 7.37 (d, 1H), 7.14 (d, 1H), 5.22 (d, 1H), 4.69 (t, 1H), 4.56 (dd, 2H), 4.09 (s, 1H), 4.02 (s, 4H), 3.07 (d, 2H), 2.56 (dd, 5H), 2.06 – 2.04 (m, 4H), 1.85 (s, 2H), 1.24 (s, 2H), 0.84 (s, 1H). Example 31: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-((1r,3S)-3-hydroxycyclobutyl)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 125)

[0382] The title compound was obtained as a white solid, from Peak 2, Example 30, step 6, following the 2 step procedure described in Example 30, steps 7 and 8. LCMS m / z = 619 [M+H]+.1H NMR (400 MHz, DMSO-d6) 10.16 (s, 1H), 7.95 (dd, 1H), 7.45 (t, 1H), 7.36 (d, 1H), 7.14 (d, 1H), 5.55 (t, 1H), 5.39 - 5.33 (m, 1H), 5.24 - 5.15 (m, 1H), 4.58 - 4.46 (m, 3H), 4.30 - 4.24 (m, 1H), 4.15 - 4.07 (m, 2H), 4.06 - 3.94 (m, 2H), 3.90 - 3.77 (m, 1H), 3.14 - 3.05 (m, 3H), 3.04 - 3.00 (m, 1H), 2.86 - 2.83 (m, 1H), 2.35 - 2.18 (m, 2H), 2.17 - 2.11 (m, 1H), 2.08 - 1.94 (m, 2H), 1.89 - 1.70 (m, 3H). Example 32: Synthesis of 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-((1s,3R)-3-hydroxycyclobutyl)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 136)Step 1: Synthesis of 4-(10-((1s,3R)-3-(benzyloxy)cyclobutyl)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0383] A mixture of Peak 1, Example 30, step 6, (22 mg, 0.022 mmol) and CsF (32.8 mg, 0.22 mmol) in DMF (2 mL) was stirred at rt for 2 h. The mixture was concentrated under reduced pressure, and the residue diluted with water (20mL). The aqueous layer was extracted with DCM (3 x 20mL), the combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the title compound, 20 mg, 72%, as a yellow solid. LCMS m / z = 708 [M+H]+ Step 2: Synthesis of 4-(10-((1s,3R)-3-(benzyloxy)cyclobutyl)-4-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0384] To a solution of the compound from step 1 (22 mg, 0.003 mmol) in MeOH (2 mL) was added Pd / C (10%, 25 mg) under N2and the reaction mixture was hydrogenated at rt for 15 min under an atmosphere of H2. The mixture was filtered through Celite® and evaporated under reduced pressure to give the title compound as a yellow solid, 20 mg, crude. LCMS m / z = 712 [M+H]+ Step 3: Synthesis of 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-10-((1s,3R)-3-hydroxycyclobutyl)-9,10-dihydro-8H-7-oxa- 1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol

[0385] A mixture of the compound from step 2 (10 mg, 0.014 mmol) and Pd / C (3.0 mg, 0.03 mmol) and HCO2NH4 (6.20 mg, 0.1 mmol) in MeOH (2 mL) was stirred at 60°C for 30mins. The mixture was filtered through Celite® and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Method C, Gradient: 12% B to 35% B in 8 min) to afford the title compound (2 mg, 22.0%) as a white solid. LCMS m / z = 622 [M+H]+.1H NMR (400 MHz, DMSO-d6): 7.74 (dd, 1H), 7.35 - 7.30 (m, 2H), 7.00 (s, 1H), 5.35 - 5.21 (m, 1H) , 4.57 - 4.53 (m, 3H), 4.22 - 4.13 (m, 2H), 4.14 - 3.84 (m, 3H), 3.10 - 3.08 (m, 3H), 3.06 - 3.01 (m, 1H), 2.90 - 2.82 (m, 2H), 2.26 - 2.18(m, 2H), 2.09 - 2.03 (m, 4H), 1.85 - 1.78 (m, 4H), 1.42 - 1.35 (m, 1H), 1.24 (t, 3H). Example 33: Synthesis of 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-((1r,3S)-3-hydroxycyclobutyl)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 137)

[0386] The title compound was obtained as a white solid, from Peak 2, Example 30, step 6, following the three-step procedure described in Example 32. LCMS m / z = 622 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 10.71 (br s, 1H), 7.74 - 7.30 (m, 2H), 7.23-7.01 (m, 2H), 5.65 - 5.61 (m, 1H), 5.35 -5.21 (m, 1H), 4.55 - 4.53 (m, 2H), 4.51 - 4.27 (m, 2H), 4.15 - 4.13 (m, 1H), 4.07 - 3.94 (m, 4H), 3.88 - 3.82 (m, 3H), 2.89-2.67 (m, 2H), 2.50-2.24 (m, 2H), 2.14-2.00 (m, 2H), 1.86-1.82 (m, 2H), 1.57-1.54 (m, 2H), 1.45-1.37 (m, 2H), 1.25-1.21 (m, 3H). Example 34: Synthesis of 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-10-((1R*,2S*)-2-hydroxycyclobutyl)-9,10-dihydro-8H- 7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol formate and 5- ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-10-((1S*,2R*)-2-hydroxycyclobutyl)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Compound 141)Step 1 Synthesis of 2-((2-(benzyloxy)cyclobutyl)amino)ethan-1-ol

[0387] The title compound was obtained as a yellow oil, 1 g, 79.6%, from 2-(benzyloxy) cyclobutan-1-one and ethanolamine, following a similar procedure to that described in Example 30, step 1. LCMS m / z = 222 [M+H]+Step 2 Synthesis of 5-(2-((2-(benzyloxy)cyclobutyl)amino)ethoxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one

[0388] To a solution of the compound from step 1 (1 g, 4.52 mmol) in THF (20 mL) was added NaH (0.54 g, 13.6 mmol, 60%) at 0°C and the mixture was stirred for 10 min.5,7- Dichloro-8-fluoro-2-(methylsulfanyl)-3H-pyrido[4,3-d]pyrimidin-4-one (1.52 g, 5.4 mmol) was added and the reaction mixture was stirred for 1h at rt. The reaction was quenched with ice / water at 0 °C, the resulting mixture was filtered and the filter cake was washed with MeCN (3x10 mL). The filtrate was concentrated under reduced pressure and the crude product was purified by reverse phase chromatography (MeCN / H2O=65%) to afford the title compound (1.5 g, 71.4%) as a yellow solid. LCMS m / z = 465 [M+H]+Step 3 Synthesis of 10-(2-(benzyloxy)cyclobutyl)-5-chloro-4-fluoro-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0389] The title compound was obtained as a white solid, 450 mg, 46.8%, from the compound from step 2, following a similar procedure to that described in Example 30, step 3. LCMS m / z = 447 [M+H]+Step 4 Synthesis of 10-(2-(benzyloxy)cyclobutyl)-5-chloro-4-fluoro-2-(methylsulfinyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0390] A solution of the compound from step 3 (200 mg, 0.45 mmol) in DCM (4 mL) was treated with m-CPBA (109.0 mg, 0.54 mmol) at -15°C under N2and the reaction mixture was stirred for 40 min at -15°C. The reaction was quenched with water / ice (10 mL) at rt, the aqueous layer was extracted with DCM (3x10 mL) and the combined organic extracts were concentrated under reduced pressure to afford the title compound (150 mg, 72.4%) as a yellow solid. LCMS m / z = 463 [M+H]+Step 5 Synthesis of 10-((1R*,2S*)-2-(benzyloxy)cyclobutyl)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10- tetraazacyclohepta[de]naphthalene and 10-((1S*,2R*)-2-(benzyloxy)cyclobutyl)-5-chloro-4- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7- oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene

[0391] A solution of the compound from step 4 (300 mg, 0.65 mmol) and ((6-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (309.5 mg, 1.94 mmol) in toluene (8 mL) was stirred for 30 min atrt under N2, then cooled to 0 . NaOtBu (124.6 mg, 1.30 mmol) was added in portions and thereaction mixture was stirred f...

Claims

CLAIMS What is claimed is:

1. A compound represented by Formula I:Formula I; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: R1is selected from the group consisting of halogen, C3-C4cycloalkyl, C1-C6alkyl, C2- C6alkenyl, and C2-C6alkynyl; wherein cycloalkyl, alkyl, alkenyl, and alkynyl may optionally be substituted with one, two, or three halogens; R2is hydrogen or C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; and ring A is selected from the group consisting of indazolyl, quinolinyl, quinolinonyl, benzothiophenyl, benzothiazolyl, pyrazolopyridyl, pyridyl, phenyl, and naphthyl, wherein ring A is substituted with one or more substituents each independently selected from RA; : R1is hydrogen; R2is C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; and ring A is selected from the group consisting of:R1is hydrogen; R2is hydrogen; and ring A is selected from the group consisting of:RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- 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)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; RA1is selected from the group consisting of hydrogen, deuterium, chloro, -CN, -NO2, - NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-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)C1- C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, - S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; R1’is hydrogen or halogen; R3is selected from the group consisting of -NRaRb, halogen, C1-C2alkyl, and hydrogen, wherein alkyl may optionally be substituted with one, two, or three halogens; R4is selected from the group consisting of hydrogen and C1-C2alkyl, wherein alkyl may optionally be substituted with one, two, or three halogens; R5is C1-C2alkyl optionally be substituted with one, two, or three halogens; R6is selected from the group consisting of halogen, hydrogen, deuterium, and C1- C3alkyl; R7is selected from the group consisting of hydrogen and C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; R8and R9are each independently selected from the group consisting of hydrogen, deuterium, and C1-C3alkyl;Ring B is selected from the group consisting of 4-12 membered heterocyclyl containing at least one ring nitrogen; RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, -COOH, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, =CHF, and =CH-C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydroxyl, halogen, and C1- C3alkoxy; or Ring B and RBare absent and replaced with a substituent selected from the group consisting of -CH2OH and C3-C4cycloalkyl, wherein cycloalkyl is substituted with a substituent selected from the group consisting of -CH2OH and -CH2-NRaRb, and Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand 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, C1- C6alkyl, and C1-C6alkoxy; m and n are each independently 0, 1, 2, 3, or 4; p is 1, 2, or 3; q, r, and s are each independently 0, 1, 2, or 3; and t is 0, 1, or 2.

2. The compound of claim 1, wherein R1is selected from the group consisting of fluoro, chloro, cyclopropyl, trifluoromethyl, -CH2CH2CH3, and propenyl; and R2is hydrogen or -CH3.

3. The compound of claim 1 or 2, wherein RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, -C(O)NH2,C1-C4alkyl, and C2- C4alkynyl, C1-C4alkoxy, and C3-C6cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens or -CN.

4. The compound of any one of claims 1-3, wherein ring A is selected from the group consisting of:

5. The compound of any one of claims 1-4, wherein ring A is selected from the group consisting of:

6. The compound of claim 1, wherein R1is hydrogen and R2is -CH3.

7. The compound of claim 1 or 6, wherein ring A is selected from the group consisting of:wherein: RAis selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, and C3- C4cycloalkyl; wherein alkyl and alkoxy are each substituted with one, two, or three halogens; and RA1is selected from the group consisting of chloro, -CH3, and -CF3.

8. The compound of any one of claims 1 and 6-7, wherein ring A is selected from the group consisting of:

9. The compound of claim 1, wherein R1is hydrogen and R2is hydrogen.

10. The compound of claim 1 or 9, wherein ring A is selected from the group consisting of, , , and .

11. The compound of any one of claims 1-10, wherein R3is selected from the group consisting of -NH2, chloro, and -CHF2.

12. The compound of any one of claims 1-11, wherein R3is -NH2.

13. The compound of any one of claims 1-12, wherein R4is hydrogen and R5is -CH3.

14. The compound of any one of claims 1-13, wherein R6is fluoro.

15. The compound of any one of claims 1-14, wherein R7is hydrogen or -CH3.

16. The compound of any one of claims 1-15, wherein R8and R9are each independently selected from the group consisting of hydrogen, deuterium, and -CH3.

17. The compound of any one of claims 1-16, wherein RBis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -COOH, =CHCH3, =CHF, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and C1-C3alkyl optionally substituted with hydroxyl, halogen, or -OCH3.

18. The compound of any one of claims 1-17, wherein RBis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CH3, =CHCH3, =CHF, -COOH, - CH2OH, -CH2CH2F, CH2CH2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

19. The compound of any one of claims 1-18, wherein ring B is selected from the group consisting of:, , , , , , , , , ,, , , , , , and .

20. The compound of any one of claims 1-16, wherein ring B and RBare absent and replaced with -CH2OH or cyclopropyl; wherein cyclopropyl is substituted with -CH2OH or -CH2NRaRb.

21. The compound of any one of claims 1-16 and 20, wherein ring B and RBare absent andreplaced with a substituent selected from the group consisting of -CH2OH, , ,, and .

22. The compound of claim 1, wherein the compound is represented by Formula IA: Formula IA; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: R1is halogen, R2is hydrogen or -CH3, and ring A is selected from the group consisting ofR1is hydrogen, R2is -CH3, and ring A is selected from the group consisting of:R1is hydrogen, R2is hydrogen, and ring A is selected from the group consisting of:R7is selected from the group consisting of hydrogen and -CH3; R8and R9are each independently selected from the group consisting of hydrogen, deuterium, and -CH3; and B is selected from the group consisting of23. The compound of claim 1, wherein the compound is selected from the group consisting of, , ,461, , , , 462463or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

24. A compound represented by Formula II:Formula II; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: ring A is selected from the group consisting of indazolyl, quinolinyl, quinolinonyl, benzothiophenyl, benzothiazolyl, pyridinyl, pyrimidinyl, and phenyl; wherein ring A is substituted with one, two, or three substituents each independently selected from RA; RAis independently selected for each occurrence from the group consisting of hydrogen, halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- 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)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; R1is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, -CH(CH3)-(C3-C6cycloalkyl), -CH2-(C3-C6cycloalkyl), phenyl, 5-memberedheteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R11; R2is selected from the group consisting of hydrogen, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C3-C6cycloalkyl, -CH(CH3)-(C3-C6cycloalkyl), -CH2-(C3-C6cycloalkyl), phenyl, 5- membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R22; R11and R22are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, phenyl, - COOH, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1- C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl; R3is selected from the group consisting of hydrogen and C1-C6alkyl optionally substituted with one or more halogens or hydroxyl; R4is selected from the group consisting of halogen, hydrogen, deuterium, and C1- C3alkyl; R5and R6are each independently selected from the group consisting of hydrogen, deuterium, and C1-C3alkyl; Ring B is selected from the group consisting of 5-10 membered heterocyclyl containing at least one ring nitrogen; RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand 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, C1- C6alkyl, and C1-C6alkoxy; andm is 0, 1, 2, 3, or 4; wherein if ring A is benzothiophenyl, then R1is CH3or substituted C1-C6alkyl.

25. The compound of claim 24, wherein R3is hydrogen or CH3.

26. The compound of claim 24 or 25, wherein R4is fluoro.

27. The compound of any one of claims 24-26, wherein R5and R6are each hydrogen.

28. The compound of any one of claims 24-27, wherein the compound is represented by Formula IIA: Formula IIA.

29. The compound of any one of claims 24-28, wherein ring A is selected from the group consisting of indazolyl, quinolinyl, quinolinonyl, benzothiazolyl, pyridinyl, pyrimidinyl, and phenyl; wherein ring A is substituted with one, two, or three substituents each independently selected from RA.

30. The compound of any one of claims 24-29, wherein RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NH2, C1-C4alkyl, and C2-C4alkynyl, C1-C4alkoxy, and C3-C4cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens.

31. The compound of any one of claims 24-30, wherein ring A is selected from the group consisting of:

32. The compound of any one of claims 24-31, wherein ring A is selected from the group consisting of33. The compound of any one of claims 24-32, wherein R1is selected from the group consisting of C1-C6alkyl, C3-C4cycloalkyl, -CH(CH3)-(C3-C4cycloalkyl), and -CH2-(C3- C4cycloalkyl), wherein alkyl and cycloalkyl may optionally be substituted by one, two, three, or four groups each independently selected from the group consisting of halogen, hydroxyl, cyano, and -C(=O)NRaRb.

34. The compound of any one of claims 24-33, wherein R1is selected from the group consisting of -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2,-CH2CH2OH, -CH2CH2CH2OH, , and .

35. The compound of any one of claims 24-32, wherein R1is selected from the group consisting of 5-membered heteroaryl, -CH2-(5-membered heteroaryl), and -CH(CH3)-(5-membered heteroaryl), wherein heteroaryl may optionally be substituted with one or two substituents each independently selected from the group consisting of -NRaRband C1-C3alkyl, and wherein alkyl may optionally be substituted with one, two or three halogens.

36. The compound of any one of claims 24-32 and 35, wherein R1is selected from the group consisting of , , and .

37. The compound of any one of claims 24-28, wherein ring A is benzothiophenyl substituted with one, two or three substituents each independently selected from the group consisting of halogen, cyano, -NH2, and -C(O)NH2.

38. The compound of any one of claims 24-28 and 37, wherein ring A is selected from the group consisting of and .

39. The compound of any one of claims 24-28 and 37-38, wherein R1is selected from the group consisting of -CH3,-CH2CHF2, and -CH2CH2OH.

40. The compound of any one of claims 24-39, wherein R2is selected from the group consisting of hydrogen and C1-C6alkyl, wherein alkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of halogen and hydroxyl.

41. The compound of any one of claims 24-40, wherein R2is selected from the group consisting of hydrogen, -CH3, and -CH2CH2OH.

42. The compound of any one of claims 24-41, wherein RBis selected from the group consisting of halogen, hydroxyl, and C1-C3alkyl.

43. The compound of any one of claims 24-42, wherein RBis selected from the group consisting of halogen, hydroxyl, and -CH3.

44. The compound of any one of claims 24-43, wherein ring B is selected from the group consisting of:

45. The compound of any one of claims 24-44, wherein ring B is.

46. The compound of claim 24, wherein the compound is represented by Formula IIB:Formula IIB; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: Ring A is selected from the group consisting ofR1is selected from the group consisting of -CH3, -CH2CH3, -CH2CN, -CH2CHF2, - CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, -CH2CH2OH, -CH2CH2CH2OH, -CH3, -CH2CH3, -CH2CN, -CH2CHF2, -CH2F2Cl, -CH2CF3, -CH2CH2CHF2, -CH(CH3)CHF2, - CH2CH2OH, -CH2CH2CH2OH, R2is selected from the group consisting of hydrogen, -CH3, and -CH2CH2OH; and R3is hydrogen or CH3.

47. The compound of claim 24, wherein the compound is selected from the group consisting ofor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

48. A compound represented by Formula III:Formula III; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: RA1and RA2are independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- 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) C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-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, C1-C6alkyl, and C1-C6alkoxy; R1’is hydrogen and R1is selected from the group consisting of hydrogen, -CH3, -CF3, - CH2CH2OH, -CH2C(CH3)2OH, C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, phenyl, 5-membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl is substituted with one, two, three, or four substituents each independently selected from R11; and wherein alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R22; and R2is selected from the group consisting of hydrogen, -CH3, -CH2CH2OH, - CH2CH2CH2OH, -CH2CH(CH3)OH, -CH2C(CH3)2OH, C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3cycloalkyl, C5-C6cycloalkyl, phenyl, 5-membered heteroaryl, and -CRcRd-(5-membered heteroaryl); wherein alkyl is substituted with one, two, three, or four substituents each independently selected from R11; and wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one, two, three, or four substituents each independently selected from R22; or: R1and R1’, together with the carbon atom to which they are attached, may be joined together to form C3-cycloalkyl optionally substituted with one, two or three halogens or hydroxyl; and R2is C1-C6alkyl substituted with one, two, or three substituents eachindependently selected from the group consisting of halogen, hydroxyl, cyano, -COOH, and C(=O)NRaRb; or R1and R1’, together with the carbon atom to which they are attached, may be joined together to form C4-cycloalkyl optionally substituted with one, two or three halogens or hydroxyl; and R2is C1-C6alkyl optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, -COOH, and C(=O)NRaRb; R11is independently selected for each occurrence from the group consisting of halogen, deuterium, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, - COOH, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SC1- C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl; R22is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, phenyl, -COOH, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, - NRa(C=O)NRaRb, -(C=O)C1-C6alkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1- C6alkyl, -SH, -SC1-C6alkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and - NRaS(O)2C1-C6alkyl; R3is selected from the group consisting of halogen, hydrogen, deuterium, and C1- C3alkyl; Raand Rbare each independently selected from the group consisting of hydrogen and C1- C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; or Raand 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, C1- C6alkyl, and C1-C6alkoxy; Rcand Rdare each independently selected from the group consisting of hydrogen and C1-C6alkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2;wherein: if R1is hydrogen, then R2is not hydrogen, -CH3, or CH2CH2OH; and if R1is -CH3, then R2is not hydrogen, -CH3, -CH2CF2, -CH2CF3, or -CH2CH(CH3)OH.

49. The compound of claim 48, wherein RA1and RA2are independently selected for each occurrence from the group consisting of halogen, hydroxyl, cyano, -NH2, C1-C4alkyl, and C2- C4alkynyl, C1-C4alkoxy, and C3-C4cycloalkyl, wherein alkyl, alkynyl, alkoxy, and cycloalkyl may optionally be substituted with one, two, or three halogens.

50. The compound of claim 48 or 49, wherein m is 1 or 2 and RA1is independently selected foreach occurrence from the group consisting of halogen, C1-C4alkyl, C2-C4alkynyl, and C3- C4cycloalkyl.

51. The compound of any one of claims 48-50, wherein n is 1 and RA2is hydroxyl or -NH2.

52. The compound of any one of claims 48-51, wherein is selected from thegroup consisting of53. The compound of any one of claims 48-52, whereinselected from thegroup consisting of54. The compound of any one of claims 48-53, wherein R1’ is hydrogen.

55. The compound of any one of claims 48-54, wherein R1is hydrogen.

56. The compound of any one of claims 48-55, wherein R2is selected from the group consisting of -CH2CN, -CH2CH(OH)CH3, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, - CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3.

57. The compound of any one of claims 48-54, wherein R1is -CH3.

58. The compound of any one of claims 48-54 and 57, wherein R2is selected from the group consisting of -CH2CH2OH, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, - CH2CH2C(O)NH2, -CH2CH2C(O)NHCH3, , , and .

59. The compound of any one of claims 48-54, wherein R1is selected from the group consisting ONH2of -CF3, -CH2CF3, -CH2CH2OH, -CH2C(CH3)2OH, , ,N, and ONH2N .

60. The compound of any one of claims 48-54 and 59, wherein R2is selected from the group consisting of hydrogen, -CH3, -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2C(O)NH2, and - CH2CH2C(O)NHCH3.

61. The compound of any one of claims 48-53, wherein R1’and R1, together with the carbon atom to which they are attached, are joined together to form C3-cycloalkyl optionally substituted with hydroxyl; and R2is -CH2CH2OH.

62. The compound of any one of claims 48-53, wherein R1’and R1, together with the carbon atom to which they are attached, are joined together to form C4-cycloalkyl optionally substituted with hydroxyl; and R2is -CH3.

63. The compound of any one of claims 48-54, wherein R3is hydrogen.

64. The compound of claim 48, wherein the compound is represented by Formula IIIB: Formula IIIB; or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:is selected from the group consisting of , , , ,, and ; andR1is hydrogen; and R2is selected from the group consisting of -CH2CN, - CH2CH(OH)CH3, -CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3; or R1is -CH3; and R2is selected from the group consisting of -CH2CH2OH, - CH2CH2CH2OH, -CH2C(O)NH2, -CH2C(O)NHCH3, -CH2CH2C(O)NH2, -CH2CH2C(O)NHCH3, , , and ; or R1is selected from the group consisting of -CF3, -CH2CF3, -CH2CH2OH, - CH2C(CH3)2OH,; and R2is selected from the group consisting of hydrogen, -CH3, -CH2CHF2, - CH2CF3, -CH2CH2OH, -CH2CH2C(O)NH2, and -CH2CH2C(O)NHCH3.

65. The compound of claim 49, wherein the compound is selected from the group consisting ofor a pharmaceutically acceptable salt and / or a stereoisomer thereof.

66. A compound selected from the group consisting of:or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

67. A pharmaceutical composition comprising a compound of any one of claims 1-66, or a pharmaceutically acceptable salt and / or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

68. 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 1-66.

69. The method of claim 68, wherein the disease or disorder is characterized by aberrant Ras activity in the patient due to a Ras mutation.

70. The method of claim 68 or 69, wherein the Ras mutation is a K-Ras mutation, a H-Ras mutation, or a N-Ras mutation.

71. The method of any one of claims 68-70, wherein the disease or disorder is a cancer.

72. 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 1-66.

73. The method of claim 72, wherein the cancer is a Ras-mutated cancer.

74. The method of claim 72 or 73, wherein the cancer is a K-Ras-mutated cancer.

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