Fused azines as ras inhibitors and methods of use thereof

Abstract

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

Description

FUSED AZINES AS RAS INHIBITORS AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 619,158, filed on January 9, 2024; the content 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 anticanccr therapy. Dysrcgulation 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-sma.ll 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 pharmacally 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 Fonnula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:Ring A is selected from the group consisting of naphthyl, 8-10 membered bicyclic heteroaryl phenyl, and 5-6 membered monocyclic heteroaryl;RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkcnyl, 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-C6 alkoxy;Ring B is a 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;R1is selected from the group consisting of hydrogen, C1-C6alkyl. C2-Cealkenyl, C2- C6alkynyl, -(CRcRd)m-(C3-C6Cycloalkyl), -(CRcRd)m-(phenyl), -(CRcRd)m-(4-7 membered heterocyclyl), -(CRcRd)m-(5-6 membered heteroaryl), and (C3-C6cycloalkyl)-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R11;R11is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, C1-C6alkyl, C1-C6alkoxy, Ci-Crtcycloalkyl. 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, -SCi- Cealkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl; wherein Cj-Cealkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, and C1-C6alkoxy;R1is selected for each occurrence from the group consisting of hydrogen and Ci- Caalkyl;R2is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- Cecycloalkyl. and 4-7 membered monocyclic heterocyclyl; wherein R2may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alko xy ;R3is selected from the group consisting of hydrogen, deuterium, halogen, and C1- Csalkyl;RaandRbare each independently selected from the group consisting of hydrogen and C1- Cealkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1- C6alkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1- Cealkyl, and C1-C6 alkoxy;Rcand Rdare each independently selected from die group consisting of hydrogen, deutenum, halogen, hydroxyl, and C1-C6alkyl; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and t is 1 or 0.

[0007] Also disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certainembodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent.

[0008] 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.

[0009] 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, utenne cancer, thyroid, acute myelocytic leukemia, bladder carcinoma, gastric cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0010] 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

[0011] 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

[0012] 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

[0013] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but arc not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-6alkyl, Ci-4alkyl, and C1-salkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -butyl, 3 -methyl -2 -butyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4- methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3,3-dimethyl-l-butyl, 2 -ethyl -1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0014] 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.

[0015] 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 arc not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0016] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Ci-Csalkoxy, C1-C6alkoxy, and C2- Cealkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0017] 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-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR5SSO2R59, COOalkyl, COOaryl, CONR58R59, CONR5SOR59, NR5SR59, SChNR58R59, S-alkyl, SOalkyl, SChalkyl, Saryl, SOaryl, SCharyl; 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.

[0018] The term “carbonyl” as used herein refers to the radical -C(O)-.

[0019] The term “cyano” as used herein refers to the radical -CN.

[0020] 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 4 -6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0021] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or 1

[0022] 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 Ci- ehaloalkyl, C1-4 haloalkyl, and Ci-3haloalkyl, respectively.

[0023] The term ’ hetero " when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0024] 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.

[0025] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 3-12 membered ring structures, for example, 4-10 membered ring structures, for example, 4-8 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur, wherein the sulfur atom may be oxidized to SO or SO2.. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. Further examples include Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyi, piperidonyl, 4-piperidinonyl, quinudidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro- 1 H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro- 1 H,3'H- spiro [cyclopropane- 1 ,2'-pyrrolizine] , hexahy dro- 1 H-pyrroliziny 1, hexahy dro- 1 H-pyrrolo [2,1- c][l]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls,oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyI 1 -oxide and tetrahydro-2H-thiopyranyl 1,1 -dioxide. In some embodiments, the heterocycle is a spiro heterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro- 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.

[0026] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH

[0027] The term “oxo” as used herein refers to the radical =0.

[0028] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0029] 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.

[0030] 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.

[0031] “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.

[0032] 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.

[0033] 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, bitartratc, ascorbate, succinate, maleate, gcntisinatc, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethane sulfonate, benzenesulfonate, / 2-tohicnc sulfonate and pamoate (i.e., l,T-methylene-bis-(2- hydroxy-3-naphthoatc)) salts. Compounds included in the present compositions that arc 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.

[0034] 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. Tire 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.

[0035] 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” andare 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.

[0036] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from tire arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents 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.”

[0037] 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 duringthe creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0038] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmacally 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 cry stalline form.

[0039] 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 number usually 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,1SO,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0040] Certain isotopically labeled disclosed compounds (e g., those labeled with3H and14C) are usefill 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.

[0041] Tire tenn “prodrug” refers to compounds that are transfonned 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, etal, Nature Reviews Drug Discovery 2008, 7,255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci x)alkyl. (C2-i2)alkyl carbonyloxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxy carbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3 -phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-2)alkylamino(C2-3)alkyl (such as P- dimethylaminoethyl), carbamoyl-(C1-2)alkyl, N,N-di(C1-2)alkylcarbamoyl-(C1-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl.

[0042] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-6)alkylcarbonyloxymethyl, l-((C1-6)alkylcarbonyloxy)ethyl, 1 -methyl- l-((C1- 6)alkylcarbonyloxy)cthyl (Ci-6)alkoxycarbonyloxymcthyl, N-(Ci-6)alkoxycarbonylaminomcthyl, succinoyl, ( C1-6)alkylcarbonyl, a-amino(C1-4)alkylcarbonyl, arylalkylcarbonyl and a- aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a-aminoalkylcarbonyl, where each a - aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6) alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0043] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al., Molecules 2008, 13, 519 and references therein.I. Compounds

[0044] 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 Rasactivity 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.

[0045] For example, disclosed herein is a compound represented by Fomrula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:Ring A is selected from the group consisting of naphthyl, 8-10 membered bicyclic heteroaryl phenyl, and 5-6 membered monocyclic heteroaryl;RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, Cb-Coalkenyl. Cb-Coalkynyl. 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)OCi- Cealkyl, -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;Ring B is a 5-10 membered hctcrocyclyl containing at least one ring nitrogen;RBis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NRaRb, Ci -Coalkyl, and Ci -Coalkoxy:R1is selected from the group consisting of hydrogen, Ci -Coalkyl. C2-C6alkenyl, C2- Coalkynyl, -(CRcRd)m-(C3-C6cycloalkyl), -(CRcRd)m-(phenyl), -(CRcRd)m-(4-7 membered heterocyclyl), -(CRcRd)m-(5-6 membered heteroaryl), and (Q-C6cycloalkyl)-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R11;R11is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, Ci-Coalkyl, Ci -Coalkoxy. Co-Cocycloalkyl. phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb-NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)Ci -Coalkyl, -(C=O)OC1-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OC1-C6alkyl, -SH, -SCi- Cealkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl; whereinC1-C6alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, and C1-C6alkoxy;R1is selected for each occurrence from the group consisting of hydrogen and Ci- Csalkyl;R2is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- Cecycloalkyl, and 4-7 membered monocyclic heterocyclyl; wherein R2may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy;R3is selected from the group consisting of hydrogen, deuterium, halogen, and Ci- Csalkyl;RaandRbare each independently selected from the group consisting of hydrogen and Ci- Cealkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci- Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci- Cealkyl, and C1-C6alkoxy;Rcand Rdare each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and C1-C6alkyl; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and t is 1 or 0.

[0046] For example, in some embodiments A is selected from the group consisting of naphthyl, indazolyl, quinolinyl, isoquinolinyl, phenyl, and pyridyl. In other embodiments, RAis independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, -NRaRb, -CN, C1-C6alkyl, C2-C6alkynyl, and Ca-Cecvcloalkyl. wherein C1-C6alkyl may optionally be substituted with one, two, or three halogens. In still other embodiments, q is, for example, 2, 3, or 4. For example, in certain embodiments ring A is selected from the group consisting of:

[0047] In further embodiments, R1is hydrogen or -CH3. In some embodiments, R1is, for example, C1-C6alkyl substituted with one, two, or three R11. In additional embodiments, R1is C1-C6alkyl substituted with one, two, or three substituents each independently selected from the group consisting of, for example, halogen, hydroxyl, -NRaRb, -C(O)NRaRb, and C1-C6alkoxy. For example, in some embodiments R1is selected from the group consisting of -CH2CH2OH, - CH2CH2CH2OH, -CH2CH(OH)CH3, -CH2C(CH3)2OH, -CH2CH2CH2NH2, -CH2CH2NH2, - CH2CH2CH2C(O)NH2, -CH(CH3)C(CH3)2OH, -CH2CHF2, -CH2CH(CH3)-OCH3, -CH(CH3)- C(O)N(CH3)2, -CH2CHFCH2OH, -CH(-cyclopropyl)-CH2OH, -CH(CH3)C(O)NH2, - CH2CH(CH3)CN, -CH(-isopropyl)CH2OH, and -CH(CH3)CH(OH)CH(CH3)2.

[0048] In some embodiments, R1is selected from the group consisting of, for example, C3- Cecycloalkyl, (C3-C6cycloalkyl)-(5-6 membered he ternary I). -CH2-(C3-C6cycloalkyl), and - CH2-CH2-( C3-C6cycloalkyl), wherein cycloalkyl and heteroaryl may optionally be substituted with one, two, or three R11. In other embodiments, R1is selected from the group consisting of, for example, C3-C6cycloalkyl, ( C3-C6cycloalkyl)-(5-6 membered heteroaryl), and CH2-(C3- C6cycloalkyl), wherein cycloalkyl and heteroaryl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, - CH3, -CH2OH, -CHF2, -CH2CF3, -CH2CN, -CN, -NH2, and -CONH2. For example, in certain embodiments R1is selected from the group consisting of

[0049] In some embodiments, R1is selected from the group consisting of, for example, 4-7 membered heterocyclyl, -CH2-(4-7 membered heterocyclyl), -CH(CH3)-(5-6 membered heterocyclyl), -CH2-(5-6 membered heteroaryl), -CH(CH3)-(5-6 membered heteroaryl), and - CH2-CH2-(5-6 membered heteroaryl), wherein heterocyclyl and heteroaryl may optionally be substituted with one, two, or three R11. In other embodiments, R1is selected from the group consisting of, for example, 4-7 membered heterocyclyl, -CH2-(4-7 membered heterocyclyl), - CH(CH3)-(5-6 membered heterocyclyl), -CH2-(5-6 membered heteroaryl), -CH(CH3)-(5-6 membered heteroaryl), and -CH2-CH2-(5-6 membered heteroaryl), wherein heterocyclyl and heteroaryl may optionally be substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, oxo, -CH3, -CF3, -CN, -NH2, and - CONH2. For example, in certain embodiments R1is selected from the group consisting of

[0050] In some embodiments, R2is selected from the group consisting of, for example, Ci-Cealkyl, C.i-Cecycloalkyl. and 4-7 membered monocyclic heterocyclyl, wherein alkyl, cycloalkyl, and heterocyclyl may optionally be substituted with one, two, or three substituents each independently selected from halogen and hydroxyl. In other embodiments, R2is selected from the group consisting of, for example, -CH3, -CHF2, -CF3, -CH(CH3)2, -CH2CH2OH, -CH(CH2CH2OH)2, cyclopropyl, and oxetanyl.

[0051] In further embodiments, m is 0, 1, or 2. In other embodiments, R3is selected from the group consisting of, for example, hydrogen, halogen, and -CH3. In additional embodiments. is hydrogen or fluoro. In certain embodiments, ring B is, for example,

[0052] In some embodiments, for example, p is 1. In other embodiments, ring B is

[0053] In some embodiments, RBis, for example, halogen. In other embodiments, RBis fluoro. In further embodiments, n is 1. In some embodiments, a compound of the present disclosure may be represented by, for example, Formula II:

[0054] In some embodiments, tire compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.Table 1. Exemplary compounds.

[0055] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein.Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0056] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify disclosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups.

[0057] 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).

[0058] 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.

[0059] 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 least99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.II. Methods

[0001] 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.

[0002] In some embodiments, the present disclosure provides a method of treating a disease or disorder charactenzed 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).

[0003] 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.

[0004] In certain embodiments, the compounds, compositions and methods disclosed herein can be used to treat cancers, including tumors, related to the cardiovascular system. Nonlimiting examples contemplated herein include, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma.

[0005] 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.

[0006] 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).

[0007] 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, tcratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).

[0008] 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.

[0009] 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.

[0010] 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.

[0011] 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).

[0012] 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).

[0013] 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).

[0014] 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.

[0015] In some embodiments, the methods described herein may be useful to treat cancers including, but not limited to, pancreatic cancer, colorectal cancer, multiple myeloma, lungadenocarcinoma, melanoma, endometrial cancer, uterine cancer, thyroid, acute myelocytic leukemia, bladder carcinoma, gastric cancer, cervical cancer, and head and neck squamous cell carcinoma.

[0016] 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.

[0017] 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 treatmg 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).

[0018] 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, G l 2V. G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, KI 17N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, GBR, GI2L. or G13V, and combinations thereof); aH-Ras mutation (for example, Q61 R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, KI 17N, A59T, G12V, G13C, Q61H, G13S, A18V, DI 19N, G13N, A146T, A66T, G12A, A146V, GI2N. or G12R, and combinations thereof); and a N-Ras mutation (for example, Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G I 2V. G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof); or a combination of any thereof.

[0019] In some embodiments, the cancer comprises a K-Ras mutation selected from the group consisting of, for example, G12C, G12D, G13C, GI2V. G13D, G12R, G12S, Q61H, Q6 IK and Q6 IL. 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 Q6 IL. In further embodiments, the cancer comprises a Ras mutation selected from the group consisting of, for example, G12C, G13C, G12A, G12D, G13D, G12S, G13S, G 12V 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, G I 2V and G13V.

[0020] 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 G 12C and K-Ras G 12C. 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.

[0021] In some embodiments, a compound disclosed herein inhibits Ras"1in 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, GBR, G12L, or G13V; K, H, or N-Raswtand H-Ras Q61R, GBR, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61 H, G13S, ABV, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or GBR; or K, H, or N-Raswtand N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, GBR, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T501, A146V, or A59T).

[0022] 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, Q61 K, L 19F, Q22K, V 141, A59T, A 146P, G 13 R, G 12L, or G 13 V; K-, H- or N-Rasampand H- Ras Q61R, GBR, Q61K, G12S, Q61L, G12D, G13V, G13D,G12C, KI 17N, A59T, G12V, G13C, Q61H ,G13S, ABV, DI 19N, G13N, A146T, A66T, G12A, A146V, G12N, or GBR; 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, A 146V, or A59T).

[0023] 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 KEAPl, an EPHA5 or an NFl mutation. In certainembodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12V mutation. In further embodiments, the cancer is colorectal cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12D mutation. In other embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12V mutation. In still other embodiments, the cancer is endometrial cancer and comprises a K-Ras G12C mutation. In certain embodiments, the cancer is lung cancer, colorectal cancer, or pancreatic cancer and comprises a K-Ras G12D mutation. In further embodiments, the cancer is lung cancer or pancreatic cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is colorectal cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is gastric cancer and comprises a K-Ras G12C mutation. In addition, a disclosed compound may inhibit Raswt(e.g., K-, H- or N-Raswt) or Rasamp(e.g., K-, H- or N- Rasamp).

[0024] 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.

[0025] 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 beformulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a disclosed compound and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so

[0026] 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.

[0027] 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.

[0028] 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 additionaltherapies 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.

[0029] 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.

[0030] 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. Nonlimiting examples contemplated herein include, but are not limited to, 21 -acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, dcflazacort, dcsonidc, dcsoximctasonc, dexamethasone, diflorasonc, diflucortolonc, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fhiocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluoromethoIone, fluperolone acetate, fluprcdnidcnc acetate, fluprcdnisolonc, flurandrcnolidc, 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.

[0031] 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.

[0032] In other embodiments, a therapeutic agent contemplated herein may be a T-cell checkpomt inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g.,humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fe-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, which interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 . In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L 1 . In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e g., an inhibitory antibody or Fe fusion or small molecule inhibitor) of PD-L2 (e g., a PD-L2 / lg fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, 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.

[0033] In some embodiments, a therapeutic agent contemplated herein may be an anticancer agent. Non-limiting examples contemplated herein include, but arc 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.

[0034] Other non-limiting examples of anti -cancer agents include, e.g., imatinib mesylate, carfilzomib, bortezomib, bicalutamide, 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, chlomaphazine, 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, cyanomorpholmo-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 fludarabinc, 6-mcrcaptopurinc, thiamiprinc, thioguaninc; pyrimidine analogs such as ancitabinc, 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; mavtansinoids 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)-imidazoles; 4- tiydroxytamoxifen; trioxifene; keoxifene; onapnstone; toremifene; flutamide, nilutamide, bicalutamide, leupmlidc. goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide; ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan; topoisomerase inhibitors; difluoromethylomithine; retinoids such as retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts of any of the aforementioned agents.

[0035] 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, antmeoplastics (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, dichloroacctic acid, discodcrmolidc, clsamitrucin, cnocitabinc, cnbulm, cxatccan, cxisulind, ferruginol, forodesine, fosfestrol, imexon, imiquimod, indolocarbazole, irofiilven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, ncdaplatin, olaparib, ortataxcl, pawpaw, pixantronc, protcasomc inhibitors, rcbcccamycin, 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.

[0036] 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 carboplatm), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HD AC) inhibitors (e.g.. trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, romidepsin, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors, DNA binding agents, P13K delta and gamma inhibitors, copanlisib, alpelisib and idelalisib; multi-kinase inhibitors (e.g., sorafenib), hormones (e.g., estrogen), goserelin, leuprolide, triptorelin, IKK inhibitors, p38MAPK inhibitors, anti -IL-6, telomerase inhibitors, aurora kinase inhibitors, cell surface monoclonal antibodies, elotuzumab, HSP90 inhibitors, P13K / Akt inhibitors, Akt inhibitors, PKC inhibitors (e.g., enzastaurin), Torcl / 2 specific kinase inhibitors, ER / UPR targeting agents, cFMS inhibitors, JAK1 / 2 inhibitors, PARP inhibitors (e g., olaparib and ve liparib), 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.

[0037] In some embodiments, the anti-cancer agent is a HER2 inhibitor, for example, monoclonal antibody such as trastuzumab and pcrtuzumab; 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, cntrcctinib, cnsartinib, or lorlatinib. In other embodiments, a contcmplatd anticancer agent is a SHP2 inhibitor an S0S1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a P13K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., mTORC 1 inhibitor or mT0RC2 inhibitor).

[0038] 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.

[0039] In certain embodiments, the methods described herein further comprises administering to the patient one or more additional therapeutic agents that treats a disease ordisorder that is affected by, associated with, or would benefit from inhibition of Ras protein (e.g., K-Ras).

[0040] Tire methods described herein include administering to the patient a therapeutically effective amount of at least one compound as described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the patient an additional therapeutic agent that treats a cancer, or that treats a disease or disorder that is affected by, associated with, or would benefit from inhibition of Ras, e.g., K-Ras.

[0041] 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 cnhancc(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.

[0042] 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

[0043] 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 fonnulated together with one or more pharmacally 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 fonn 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 fonnulated as a unit dose, and / or may be fonnulated for oral or subcutaneous administration.

[0044] 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. Tire 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.

[0045] 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 com 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.

[0046] 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.

[0047] 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), surfaceactive 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.

[0048] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage fonns 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, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodcxtrins and mixtures thereof.

[0049] 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.

[0050] Formulations for rectal or vaginal administration may be presented as a suppository’, which may be prepared by mixing a subject composition with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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 earners 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.

[0055] 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.

[0056] 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.

[0057] In another aspect, the disclosure provides enteral pharmaceutical fonnulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the 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 mcthylccllulosc 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 copolvmcr. natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L3OD55, Eudragit FS30D, Eudragit L100, Eudragit S 100, 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.

[0058] 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 medicalpersonnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage fonns (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.

[0059] 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

[0060] 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 thereforeindicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

[0061] HPLC conditions (Basic): Method A: column: SHIMPACK C18 (150*20mM*5u), lOmM NH.1HCO3 in H2O: 100% MeCN, at 15 mL / min, unless otherwise stated; Method B: column: Shimpack C18 (250*) 10MM NH4HCO3inH2O: 100% MeCN, at 14 mL / min; Method C: column: X Bridge C18 (250*21.0, 5u), mobile phase: 0.1% NH4HCO3 inH2O: 100% MeCN, at 15 mL / min; Method D: column: X-Bridge Cis (250* 19*5u), lOmM NH4HCO3: 100 % MeCN in water: 100% MeCN, at 15 mL / min, unless otherwise stated; MethodE: column: X Bridge (C18 150*19mm, 5u), lOmM NH4HCO3 inH2O: 100% MeCN, at 15 mL / min; HPLC Method F: column: Xselect C-18 (20x250mm,5um), 10 mm NH4HCO3 in H2O : MeCN at 15 mL / min; Method G: column: Rf Gold C18-Teledyne ISCO 50 g; 10 111M NH 1HCO3 inH2O: MeCN.

[0062] HPLC conditions (Acidic): Method H: column: SHIMPACK C18 (150*20mM*5u), 0.1% Formic acid in H2O: 100% MeCN, at 15 mL / min; Method I: column: X Bridge C18 (250*21 .0, 5u), 0. 1% FA in H2O: 100% MeCN, at 15 mL / min unless otherwise stated; Method J: column: X-Bridge C18 (250* 19*5u), 0.1% FA in water: 100% MeCN, at 20 mL / min; Method K: column: X-Bridge C18 (150* 19*5u) 0.1% Formic acid in H2O: MeCN; Method L: column: X-SELECT CSH C18 (250* 19*5u), 0.1% FA in H2O: 100% MeCN; Method M: column: Xselect C-18 (20x250mm,5um), 0.1% TFA in H2O: MeCN, at 15 mL / min; HPLC Method N: column: ATLANTIS T3 C18 (250X19mm, 5u), 0.1% TFA in H2O: 100% MeCN, at 15 mL / min.Synthesis of IntermediatesSynthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)inethoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-ol (Intermediate 1)Step 1: Synthesis of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0063] Into a stirred solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-4(3H)-one (3 g, 10.71 mmol) in THF (72 mL) and DMF (18 mL) were added MeOH (0.95 mL, 23,56 mmol) followed by NaHMDS (23.56 mL, 23.56 mmol) drop wise at 0 °C under N2. The resulting mixture was stirred at rt for 2 h. The reaction mixture was quenched with ice-cold water (25 mL) and the solvents were removed under reduced pressure. The residue was acidified with 1 .5 N HC1 to pH 5 and the mixture stirred for 5 min. The precipitated solid was fdtered off and dried under vacuum to obtain the title compound (2.1 g, 59.7 %) as a white solid. LCMS m / z = 276 [M+H]+Step-2: Synthesis of 8-fl.uoro-7-(7 -fluoro- 3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4- ol

[0064] Into a stirred solution of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol (1 g, 3.63 mmol) in DMA (40 mL) and water (5 mL) were added ((2-fluoro-6- (methoxymethoxy)- 8-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)naphthalen- 1 - yl)ethynyl)triisopropylsilane (2.79 g, 5.44 mmol) and K3PO4 (2.31 g, 10.88 mmol). The mixture was degassed with N2 and Xphos Pd G3 (0.307 g, 0.363 mmol) was added. The reaction mixture was further degassed and then stirred at 80 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with ice-cold water (2 x 15 mL), dried over NaiSOi. filtered and concentrated under reduced pressure. The crude compound was purified by silica-gel column chromatography using a gradient of 0-100 % EtOAc in hexane, to give the title compound (2 g, 79 %) as a light yellow solid. LCMS m / z = 627 [M+H]+Step 3: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-( (triisopropylsilyl) ethynyl)naphthalen-l -yl)-5-methoxy-2-(methylsulfinyl)pyrido[4, 3- d ]pyrimidin-4-ol

[0065] Into a stirred solution of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin- 4-ol (800 mg, 1 .27 mmol) in DCM (25 mL) was added mCPBA (331 mg, 1 .91 mmol) portion wise at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction was quenched with sodium sulfite solution (20 mL) and extracted with DCM (2 x 40 mL). The combined organic layer was washed with NaHCCL solution (2 x 20 mL) then dried over NaiSOi and evaporated under reduced pressure to give the title compound, 730 mg, 68.5 %. LCMS m / z = 642 [M+H]+Step 4: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-ol

[0066] Into a stirred solution of ( (2R,7aS)-2 -fluorotetrahydro- lH-pyrrolizin-7a(5H)- yl)methanol (362 mg, 2.27 mmol) and 8-fhioro-7-(7-fhioro-3-(methoxymethoxy)-8- ((triisopropylsilyl)etliynyl)naphthalen-l -yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3- d]pyrimidin-4-ol (730 mg, 1,13 mmol) in toluene (10 mL) was added NaOtBu (219 mg, 2,27 mmol) portion wise at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was cooled to 0 °C, quenched with ice-cold water, and extracted with EtOAc (2 x 20 mL). The combined organic layer was dned over Na2SO+, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica-gel, using a gradient of 0-10% MeOH in DCM, to give the title compound (400 mg, 37.7 %) as an off-white solid. LCMS m / z = 738 [M+H]+Synthesis of JN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin- 4-amine (Intermediate 2)Step 1: Synthesis of7-chloro-8-fluoro-5-isopropoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0067] The title compound was obtained as a white solid, 3 g, 63.7%, from 5,7-dichloro-8- fhioro-2-(mcthylthio)pyndo|4.3-J|pyrimidin-4(3 / / )-one and propan-2-ol, following the procedure described in Intermediate 1, step 1. LCMS m / z = 304 [M+H]+Step 2: Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-ftuoro-5-isopropoxy-2- ( methylthio)pyrido[ 4, 3-d]pyrimidm-4-amine

[0068] Into a stirred solution of 7-chloro-8-fluoro-5-isopropoxy-2-(methylthio)pyndo[4,3- <7]pyrimidin-4-ol (600 mg, 1.97 mmol) in DMA (10 mL) was added DIPEA (1.72 mL, 9,88 mmol) and HATU (1.50 g, 3.95 mmol) at 0 °C and the mixture was stirred at rt for 20 min. 2- ((tert-Butyldimethylsilyl)oxy)ethan-l -amine (693 mg, 3.95 mmol) was added and the reaction mixture stirred for 3 h at rt. The reaction was quenched with ice cold water (20 mL), the precipitated solids were filtered through a Buckner funnel, washed with ice cold water (10 mL) and dried under vacuum to give the title compound (1.0 g, 89%) as an off-white solid. LCMS m / z = 461 [M+H]+Step 3: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-5-isopropoxy-2- ( methylsulfmyl)pyrido [4, 3-d]pyrimidin-4-amine

[0069] The title compound was obtained, 900 mg, 37.7%, from A-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-5-isopropoxy-2-(methylthio)pyrido[4,3- t / |pyrimidin-4-aminc. following the procedure described in Intermediate 1, step 3. LCMS m / z = 477 [M+H]+Step 4: Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4- amine

[0070] The title compound was obtained as an off-white solid, 300 mg, 25.3% ((27?,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(577)-yl)methanol and A-(2-(( / erf- butyldimethylsilyl)oxy)ethyl)-7 -chloro-8-fluoro-5-isopropoxy-2-(methyIsulfinyl)pyrido [4,3 - <7]pyrimidin-4-amine, following the procedure described in Intermediate 1, step 4. LCMS m / z = 572 [M+H]+Synthesis of 7-chIoro-5-cyclopropoxy-8-fIuoro-2-(methylthio)pyrido[4,3-< / ]pyrimidin-4-ol (Intermediate 3)

[0071] Into a stirred solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-<7]pyrirmdin-4(3 / / )-onc (500 mg, 1.79 mmol) and cyclopropanol (259 mg, 4.46 mmol) in THF(12 mL) and DMF (3 ml) was added NaHMDS in THF (4.46 mL, IM, 4.46 mmol) at 0 °C and the reaction mixture was stirred at rt for 2 h. The reaction was quenched with water (2 mL), the mixture concentrated under reduced pressure and the residue acidified with 1 N HC1. The resulting solid was filtered through a Buckner funnel and washed with water (2 xlO mL). The cmde product was purified by silica gel column chromatography using a gradient of 0-100% EtOAc / hexane, to give the title compound (400 mg, 74.3%) as an off white solid. LCMS m / z = 302 [M+H]+Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetraliydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4-ol (Intermediate 4)Step 1: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol

[0072] Into a stirred solution of 7-chloro-8-fluoro-5-isopropoxy-2-(methylthio)pyrido[4,3- t / |pyrimidin-4-ol (Intermediate 2, step 1, 1.5 g, 3.46 mmol) in DMA (40 mL) and water (5 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)naphthalen-l-yl)ethynyl)triisopropylsilane (2.66 g, 5.19 mmol) and K3PO4 (2.20 g, 10.37 mmol). The mixture was purged with N2 for 10 min, XPhos Pd G3 (0.29 g, 0.34 mmol) added and the reaction mixture was heated at 80 °C for 16 h. The cooled mixture was filtered through Celite®, washed with EtOAc (2 x 50 mL) and the filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using agradient of 0-100 % EtOAc in hexane, to give the title compound, (1 g, 90 %) as light yellow solid. LCMS m / z = 654 [M+H]+Step 2: Synthesis of 8-fluoro-7 -(7 -fluoro- 3-(methoxyme thoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2-(methylsulflnyl)pyrido[4,3- d]pyrimidin-4-ol

[0073] The title compound was obtained, 1 g crude, from 8-fluoro-7-(7-fluoro-3- (metlioxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2- (methylthio)pyrido[4,3-<7]pynmidm-4-ol, following the procedure described in Intermediate 1, step 3. LCMS m / z = 670 [M+H]+Step 3: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fl.uorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-dJpyrimidin-4-ol

[0074] Into a stirred solution of ((2R , 7a5)-2 -fluorotetrahydro- lH-pyrrolizin-7a(5F7)- yl)methanol (0.47 g, 2.99 mmol) in THF (10 mL) was added portion wise, NaH (0.11 g, 2.99 mmol) at 0 °C and the mixture stirred at rt for 30 min. 8-Fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2- (methylsulfinyl)pyrido[4,3-d]pyrimidin-4-ol (1 g, 1.49 mmol) in THF (5 mL) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was cooled to 0 °C, quenched with ice cold water and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over NazSOr. filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using a gradient of 0-100 % EtOAc in hexane, to give the title compound (400 mg, 33.3 %) as an off white solid. LCMS m / z = 765 [M+H]+Synthesis of 2-(7-fliioro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (Intermediate 5)Step 1: Synthesis of 7-fluoro-3-(methoxymelhoxy) naphthalen-l-ol

[0075] Into a stirred solution of 7-fluoronaphthalene-l,3-diol (5 g, 28.1 mmol) in anhydrous DCM (50 mL) were added DIPEA (10.88 g, 84 mmol) and chloromethyl methyl ether (2.26 g, 28. 1 mmol) at 0 °C under N2 and the reaction mixture was stirred for 30 min. The reaction mixture was washed with water and extracted with EtOAc (2 x 150 mL). The combined organiclayer was dried over anhydrous NaiSO i and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (1.1 g, 17.7%) as an orange liquid. LCMS m / z = 223 [M+H]+Step 2: Synthesis of 7-fluoro-3-(methoxymethoxy)naphthalen-l-yl tri fluoromethane sulfonate

[0076] Into a solution of 7-fluoro-3 -(methoxymethoxy )naphthalen-l-ol (650 mg, 2.93 mmol) and TEA (0.77 mL, 4.39 mmol) in DCM (10 mL) was added trifluoromethanesulfonic anhydride (0.59 mL, 3.51 mmol) at 0 °C under N2 and the reaction mixture was stirred for 30 min. The reaction mixture was washed with water (2 x 30 mL) and extracted with DCM. The combined organic layer was dried over Na2SOr, filtered, and concentrated under reduced pressure. The crude was purified by neutral alumina column chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (700 mg, 66.2%). LCMS m / z = 353 [M-H]-Step 3: Synthesis of 2-(7-fluoro-3-(melhoxymelhoxy)naphlhalen-l-yl)-4,4,5,5-lelramefhyl-l,3,2- dioxaborolane

[0077] Into a stirred solution of 7-fluoro-3- (methoxymethoxy )naphthalen- 1-yl trifluoromethane sulfonate (560 mg, 1.58 mmol) in dioxane (5 mL) were added bis(pinacolato)diboron (602 mg, 2.38 mmol) and KOAc (776 mg, 7.9 mmol) at rt under N2. The reaction mixture was degassed with N2 for 5 min, Pd(dppf)Ch.DCM (51.9 mg, 0.06 mmol) was added, the reaction mixture was further degassed with N2 and then heated at 100 °C for 6 h. The cooled reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (2 x 20 mL), dried overNaiSOi. filtered and evaporated under reduced pressure to afford the title compound (360 mg, 68.5 %) as a light-yellow liquid.1HNMR (400 MHz, DMSO-d6 ): δ 88 .26 (dd, 1H), 7.95-7.91 (m, 1H), 7.69- 7.65 (m, 2H). 7.43-7.38 (m, 1H). 5.32 (s, 2H), 3.42 (s, 3H), 1.38 (s, 12H)Synthesis of 5,6-dimethyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole (Intermediate 6)Step 1: Synthesis of 4-bromo-5, 6-dimethyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0078] Into a stirred solution of 4-bromo-5-iodo-6-methyl-l-(tetrahydro-2H-pyran-2-yl)- IH-indazole (1 g, 2.37 mmol) in dioxane (20 niL) were added methylboronic acid (0.28 g, 4.75 mmol) and K3PO4 (1.51 g, 7.12 mmol) at rt under N2. The reaction mixture was degassed with N2, Pd(dppf)C12.DCM (0.19 g, 0.23 mmol) was added and the reaction mixture was stirred at 100 °C for 24 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was dried overlMuSOi, filtered and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel, using a gradient of 0-100% EtOAc in hexane, to afford the title compound (630 mg, 66.9 %) as a liquid. LCMS m / z = 311 [M+H]+Step 2: Synthesis of 5,6-dimethyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole

[0079] Into a stirred solution of 4-bromo-5,6-dimethyl-l-(tetrahydro-2H-pyran-2-yl)-lH- indazole (300 mg, 0.97 mmol) in dioxane (5mL) were added bis(pinacolato)diboron (493 mg, 1.94 mmol) and KO Ac (286 mg, 2.91 mmol) at rt under N2. The reaction mixture was degassed with N2 and Pd(dppf)Ch.DCM (79 mg, 0.09 mmol) was added. The reaction mixture was further degassed and then stirred at 100 °C for 6 h. The reaction mixture was diluted EtOAc (30 mL), filtered and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel, using a gradient of 0-100% EtOAc in hexane, to afford the title compound (150 mg, 43.4 %) as a gum. LCMS m / z = 357 [M+H]+Synthesis of 5-cyclopropyl-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyI- l,3,2-dioxaborolan-2-yl)-lH-indazole (Intermediate 7)Step 1: Synthesis of 4-bmmo-5-cyclopropyl-6-methyl-l-(letrahydro-2H-pyran-2-yl)-lH-indazole

[0080] Into a solution of 4-bromo-5-iodo-6-methyl-l -(tetrahydro-2H-pyran-2-yl)- 1H- indazole (1 g, 2.37 mmol) in dioxane (20 mL) and water (6 mL) was added K2CO3 (0.98 g, 7. 12 mmol). The reaction mixture was degassed with N2 and cyclopropylboronic acid (0.26 g, 3.09 mmol) and Pd(dppf)Ch (0.17 g, 0.23 mmol) were added. The reaction mixture was heated to 90°C and stirred for 24 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (2x 20 mL), the organic layer was dried over NazSCh, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica-gel, 25g, using a gradient of 0 % - 100 % of EtOAc in hexane to obtain the title compound (400 mg, 36.9 %) as a colorless gum. LCMS m / z = 337 [M+H]+Step 2: Synthesis of 5-cyclopropyl-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4, 4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)-lH-indazole

[0081] Into a stirred solution of 4-bromo-5-cyclopropyl-6-methyl-l-(tetrahydro-2H-pyran- 2-yl)-lH-indazole (650 mg, 1.93 mmol) in EtOH (20 mL) was added bis(pinacolato)diboron (1.96 g, 7.76 mmol) and K3PO4 (1 64 g, 7.76 mmol). The mixture was degassed with N 2, XPhos (277 mg, 0.58 mmol) and XPhos Pd G3 (246 mg, 0.29 mmol) were added, the reaction mixture was degassed and stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel, using a gradient of 0 %- 30 % of EtOAc in hexane, to obtain the title compound, 310 mg, 32.8 % as a colorless gum. LCMS m / z = 383 [M+H]+Synthesis of Trans rac-2-((tert-butyldimethylsilyl)oxy)cyclopropan-l-amine (Intermediate 8)Step 1: Synthesis of (E)-2-(2-((tert-butyldimethylsilyl)oxy)vinyl)isoindoline-l, 3-dione

[0082] Into a stirred solution of tcrt-butyldimcthylsilyl tnfluoromc thane sulfonate (5.53 g, 20.93 mmol) in DCM (100 mL) was added a solution of 2-(l,3-dioxoisoindolin-2- yl)acetaldehyde (3.6 g, 19.03 mmol) and TEA (5.78 g, 57, 1 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was allowed to stir at rt for 2 h. The reaction mixture was evaporated 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, 1.7 g, 28.9 % as a yellow solid. LCMS m / z = 304 [M+H]+Step 2: Synthesis of trans rac-2-(2-((tert-butyldimethylsilyl)oxy)cyclopropyl)isoindoline-l,3- dione

[0083] Into a stirred solution of diethylzinc 1 M in toluene (11.0 mL, 16.48 mmol) in toluene (10 mL) was added TFA (0.75 g, 6.59 mmol) at 0 °C and the mixture was stirred for 20min. A solution of diiodomethane (4.41 g, 16.48 mmol) in toluene (2 mL) was added drop wise, the mixture stirred for 20 min, then (E)-2-(2-((tert-butyldimethylsilyl)oxy)vinyl)isoindohne-l,3- dione (1.0 g, 3.30 mmol) in toluene (5 mL) was added. The reaction mixture was stirred at 65 °C for 20 h. The reaction mixture was cooled to 0 °C and carefully quenched with ice water, NH4Q solution (100 mL) added drop wise and the mixture extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO+, filtered and evaporated under reduced pressure. The crude was purified by silica-gel chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (0.85 g, 81 % as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.85-7.81 (m, 2H), 7.74-7.71 (m, 2H), 3.96-3.92 (m, 1H), 2.85-2.81 (m, 1H), 1.33-1.21 (m, 2H), 0.95 (s, 9H), 0.24 (d, 6H),Step 3: Synthesis of Trans rac-(2-((tert-butyldimethylsilyl)oxy)cyclopropan-l-amine

[0084] Into a stirred solution of trans rac-2-(2-((tert- butyldimethylsilyl)oxy)cyclopropyl)isoindoline-L3-dione (1.0 g, 3.15 mmol) in DCM (10 mL) and EtOH (2 mL) was added hydrazine hydrate (2.36 g, 47.3 mmol) and the reaction mixture was stirred at rt for 4 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The crude was dissolved in DCM (50 mL), washed with sat.NaHCCh solution (20 mL) and brine (20 mL). The organic layer was dried over Na2SOr, filtered and evaporated under reduced pressure to obtain the title compound (0.55 g, 40.1 %) as a yellow oil.Synthesis of 3-((lS,3R)-3-aminocyclopentyl)isoxazol-5-amine trifluoroacetate (Intermediate 9)Step-1: Synthesis of tert-butyl ((lR,3S)-3-(2-cyanoacetyl)cyclopentyl)carbamate

[0085] Into a stirred solution of methyl (1 S,3R)-3-((tert- butoxycarbonyl)amino)cyclopentane-l -carboxylate (350 mg, 1.43 mmol) in MeCN (118 mg, 2.88 mmol) was added THF (4 mL), then LDA (1.65 mL, 3.31 mmol) was slowly added at -78 °C. The reaction mixture was stirred for 20 min at -78°C, then at 25 °C for 2 h. The reaction mixture was quenched with 2 M HC1 (5 mL), diluted with water (30 mL) and extracted withEtOAc (2 x 50 mL). The combined organic layer was dried over Na2SO i. fdtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc / hexane, to afford the title compound, 195 mg. 53.1 %, as an off-white solid. LCMS m / z = 251 [M+H]+Step 2: Synthesis of tert-butyl (( 1R, 3S)-3-(5-aminoisoxazol-3-yl)cyclopentyl)carbamate

[0086] Into a stirred solution of tert-butyl ((lR,3S)-3-(2-cyanoacetyl)cyclopentyl)carbamate (50 mg, 0. 19 mmol) in NaOH (23.78 mg, 0.59 mmol) in water (0.5 mL) was added hydroxylamine hydrochloride (15.15 mg, 0.21 mmol) in water (0.5 mL) at 25 °C and the reaction mixture was heated at 50 °C for 4 h. The reaction was quenched with water (20 mL) and extracted with DCM (2 x 30 mL). Tire combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (40 mg, 70.5 %, as a colorless gum. LCMS m / z = 268 [M+H]+Step 3: Synthesis of 3-((lS,3R)-3-aminocyclopentyl)isoxazol-5-amine, trifluoroacetate

[0087] Into a stirred solution of tert-butyl ((lR,3S)-3-(5-aminoisoxazol-3- yl)cyclopentyl)carbamate (40 mg, 0.15 mmol) in DCM (5 mL) was added TFA (0.11 mL, 1.49 mmol) at 0 °C and the reaction mixture stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the crude was triturated with MTBE (2 x 5 mL) to give the title compound (40 mg, 85 %) as a light brown gum. LCMS m / z = 168 [M+H]+Synthesis of 7-chloro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Intermediate 10)Step 1 -Synthesis of 5, 7-dichloro-2-thioxo-2, 3-dihydropyrido[4, 3-d]pyrimidin-4(lH)-one

[0088] Into a stirred solution of 4-amino-2,6-di chloronicotinic acid (5 g, 24. 15 mmol) in MeCN (150 mL) was added pyridine (9.55 g, 121 mmol) at rt under N2. The reaction mixture was cooled to 0 °C and O-ethyl carbonisothiocyanatidate (3.80 g, 29.0 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered., theprecipitated solid was washed with MeCN (50 ml) and concentrated under reduced pressure to give the title compound as an off-white solid, (4 g, 65.0 %). LCMS m / z = 248 [M+H]+.Step 2-Synthesis of 5, 7-dichloro-2-(methylthio)pyrido[4, 3-d]pyrimidin-4-ol

[0089] Into a stirred solution of 5,7-dichloro-2-thioxo-2,3-dihydropyrido[4,3-d]pyrimidin- 4(lH)-one (4 g, 16. 12 mmol) in THF (40 mL) and DMF (10 mL) was added TEA (6,44 mL, 48.4 mmol) under N2 at rt. The reaction mixture was cooled at 0 °C and iodomethane (1 .00 mL, 16.12 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h under N2. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over NazSCL, filtered and concentrated under reduced pressure to afford tire title compound, (3.8 g, 87 %) as an off white solid. LCMS m / z = 262 [M+H]+Step 3-Synthesis of7-chloro-5-methoxy-2-(methylthio)pyrido[4,3-dJpyrimidin-4-ol

[0090] Into a stirred solution of 5,7-dichloro-2-(methylthio)pyndo[4,3-d]pyrimidin-4(3H)- one (2 g, 7.63 mmol) in DMF (5 mL) and THF (25 mL) were added MeOH (0.92 mL, 22.89 mmol) followed by NaHMDS (IM in THF, 15.26 mL, 15.26 mmol) dropwise at 0 °C under N2. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with cold water (20 mL) and the resulting mixture was concentrated under reduced pressure. The crude was diluted with water (5 mL) and the pH was adjusted to 3-4 using 1 ,5N HC1. The precipitated solid was filtered and dried to afford the title compound, 1.05 g, 49.5 % as an off-white solid. LCMS m / z = 258 [M+H]Synthesis of 7-chloro-5-isopropoxy-2-(methylthio)pyrido [4, 3-d] pyrimidin-4-ol (Intermediate 11)

[0091] The title compound was obtained as an off-white solid, 1.5 g, 45.5%, from 5,7- dichIoro-2-(methylthio)pyrido[4,3-t / ]pyrimidin-4(377)-one (Intermediate 10, step 2) and 2- propanol, following the procedure described in Intennediate 10, step 3. LCMS m / z = 286 [M+H]+Synthesis of 4-((lS,3R)-3-aminocyclopentyl)-l-methyl-lH-imidazol-2- amine trifluoroacetate (Intermediate 12)Step 1: Synthesis of tert-butyl ((lR,3S)-3-(methoxy(methyl)carbamoyl)cyclopentyl)carbamate

[0092] Into a stirred solution of (lS,3R)-3-((tert-butoxycarbonyl)amino)cyclopentane-l- carboxylic acid (1 g, 4.36 mmol) in THF (10 mL) was added TEA (1.52 mL, 10.9 mmol) followed by ethyl chloroformate (0.49 mL, 5.23 mmol) at -10 °C. The resulting mixture was stirred at -10 °C for 1 h, then N,O-dimethylhydroxylamine hydrochloride (0.51 g, 5.23 mmol) in THF (4 mL) and water (1 mL) was added. Tire reaction mixture was stirred at 25 °C for 16 h, then diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous NarSCh. filtered and concentrated under reduced pressure. Tire crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (1 g, 83 % yield) as off white semi-solid. LCMS m / z = 273 [M+H]+Step 2: Synthesis of tert-butyl ((lR,3S)-3-acetylcyclopentyl)carbamate

[0093] Into a stirred solution of tert-butyl ((lR,3S)-3- (methoxy(methyl)carbamoyl)cyclopentyl)carbamate (1 g, 3.67 mmol) in THF (20 mL) was added mcthylmagncsium bromide (18.36 mL, 18.36 mmol) at 0 °C and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with sat. ammonium chloride solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (30 mL), dncd over anhydrous NazSOr, filtered and evaporated under reduced pressure to afford the title compound (650 mg, 72.4 %) as pale yellow, semi-solid. LCMS m / z = 228 [M+H]+Step 3: Synthesis of tert-butyl ((lR,3S)-3-(2-bromoacetyl)cyclopentyl)carbamate

[0094] Into a stirred solution of tert-butyl ((lR,3S)-3-acetylcyclopentyl)carbamate (550 mg, 2.42 mmol) in MeOH (9 mL) was added a solution of Br> (387 mg, 2.42 mmol) in MeOH (2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 3 h and was then diluted with water(30 mL) and extracted with EtOAc (2 x 30 ml). The combined organic layer was washed with brine (30 mL), dried over anhydrous NazSOr, filtered and concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (360 mg, 48.1 %) as pale yellow, semi-solid. LCMS m / z = 250 [M+H]+Step 4: Synthesis of tert-butyl ((1 R, 3S)-3-(2-amino-] -methyl-lH-imidazol-4- yl) cyclopentyl)carbamate

[0095] Into a stirred solution of tert-butyl ((lR,3S)-3-(2- bromoacetyl)cyclopentyl)carbamate (170 mg, 0.55 mmol) in MeOH (1.7 mL) was added methylamine (33% in MeOH) (0. 13 mL, 1.10 mmol) and the mixture stirred at 25 °C for 30 min. NaOH (3M in water) (0.55 mL, 1.66 mmol) followed by ethyl carbamimidothioate, HBr (154 mg, 0.83 mmol) were added and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude was purified by reverse phase column chromatography (Rcdiscp Rf Gold®rcvcrscd-phasc C18-tclcdync ISCO, 120 g), (Mobile phase A: 0.1M Formic acid; Mobile phase B: MeCN) to give the title compound (50 mg, 19.6 %) as a pale yellow oil. LCMS m / z = 281 [M+H]+Step 5: Synthesis of 4-((lS,3R)-3-aminocyclopentyl)-l-methyl-lH-imidazol-2-amine trifluoroacetate

[0096] TFA (0.13 mL, 1 .78 mmol) was added to a stirred solution of tert-butyl ((lR,3S)-3- (2-amino-l -methyl- lH-imidazol-4-yl)cyclopentyl)carbamate (50 mg, 0.17 mmol) in DCM (5 mL) at 0 °C and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (60 mg, crude) as pale brown oil. LCMS m / z = 181 [M+H]Synthesis of (S)-3-(l-aminoethyl)pyridin-2-amine (Intermediate 13A) and (S)-3-(l- aminoethyl)pyridin-2-amine (Intermediate 13B)Step 1: Synthesis of (E)-l-(2-aminopyridin-3-yl)ethan-l-one oxime

[0097] Into a stirred solution of l-(2-aminopyridin-3-yl)ethan-l-one (2 g. 14.69 mmol) in pyridine (20 mL) was added hydroxylamine hydrochloride (1.53 g, 22.03 mmol) and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was neutralized withNaHCO3 solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried overNa2SO4, filtered and concentrated under reduced pressure to obtain the title compound (2 g, 81 %) as an off white solid. LCMS m / z = 152 [M+H]+Step 2: Synthesis of 3-(l -aminoethyl)pyridin-2-amine

[0098] Into a mixture of (E)-l-(2-aminopyridin-3-yl)ethan-l-one oxime (900 mg, 5,95 mmol) and zinc (1.56 g, 23.81 mmol) was added cone. HC1 (15 mL) slowly at 0 °C. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered, basified with 2 N NaOH solution at 0 °C, and extracted with 10% MeOH in DCM (3 X 100 mL). The combined organic layer was concentrated under reduced pressure and the crude was purified by reverse phase column chromatography (Redisep Rf Gold®reversed-phase C18-teledyne ISCO, 120 g), (Mobile phase A: 10 mM NH4HCO3; Mobile phase B: MeCN) to afford the title compound (300 mg) as a pale yellow gum. LCMS m / z = 138 [M+H]+Step 3: Synthesis of (R)-3-(l-aminoethyl)pyridin-2-amine and (S)-3-(l-aminoethyl)pyridin-2- amine

[0099] Racemic 3-(l-aminoethyl)pyridin-2-amine (300 mg) was purified by chiral SFC purification using an 1 CELLULOSE Z (250*30) mm, 5pm column, Mobile Phase: CO2: 0.5% Isopropylamine in MeOH [90: 10], at 120 mL / min, to give Peak 1, Intermediate 13A, (S)-3-( 1- aminoethyl)pyridin-2-amine, 7.2 mg, as a brown gum. LCMS m / z = 138 [M+H]+.

[0100] Further elution provided Peak 2, Intermediate 13B, (R)-3-(l-aminoethyl)pyridin-2- amine, 7.8 mg, as a brown gum. LCMS m / z = 138 [M+H]+.Synthesis of 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((2R,7aS)-2-fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5- methoxypyrido[4,3-d]pyrimidin-4-ol (Intermediate 14)Step 1 : Synthesis of 7-(7-fluoro-3-( methoxy met hoxy)-8-( ( triisopropylsilyl)ethynyl)naphthalen-l - yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol

[0101] K3PO4 (2.47 g, 11.64 mmol) was added to a stirred solution of 7-chloro-5-methoxy- 2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Intermediate 10, 1 g, 3,88 mmol) in DMA (20 mL) and the mixture was degassed with N2 for 10 min. ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l -yl)ethynyl)triisopropylsilane (2.98 g, 5.82 mmol) followed by Xphos Pd G3 (0,32 g, 0,38 mmol) were added and the reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was diluted with water (2 x 100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over NazSO-i. filtered and concentrated in vacuo. The crude was punfied by silica gel column chromatography (0-100% EtOAc in hexane), to give the title compound (1.2 g, 47.4 %) as a yellow solid. LCMS m / z = 608 [M+H]+Step 2: Synthesis of7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-5-methoxy-2-(methylsulflnyl)pyrido[4,3-dJpyrimidin-4-ol

[0102] The title compound was obtained as a pale yellow solid, 1.1 g, 60%, from 7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4-ol, following the procedure described in Intermediate 1, step 3. LCMS m / z = 624 [M+H]+Step 3: Synthesis of 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-4-ol

[0103] The title compound was obtained as a pale yellow solid, 510 mg, 42%, from 7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- (methylsulfinyl)pyrido[4,3-d]pyrimidin-4-ol (1 g, 1.60 mmol) and ((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol, following a similar procedure to that described in Intermediate 1, step 4. LCMS m / z = 719 [M+H]+Synthesis of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-4-ol (Intermediate 15)Step 1: Synthesis of 4, 7-dichloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidine

[0104] To a solution of POCh (202 g, 1.32 mol) in MeCN (560 mL) was added 7-chloro-8- fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Intermediate 1, step 1, 28.0 g, 101 mmol) and DIEA (65.6 g, 507 mmol) and the reaction mixture was stirred at 80 °C for 1 h. Tire reaction mixture was concentrated under reduced pressure and tire residue was poured slowly into ice-ELO (500 mL) and EtOAc (200 mL). The resulting precipitate was filtered off, and dried to give title compound. The aqueous layer was extracted with EtOAc (200 mL x 2) and the combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (IS CO®; SepaFlash® Silica Column, 0-50% DCM / PE gradient at 150 mL / min) to give the title compound, which was combined with a previous batch to give 37 g, crude. LCMS m / z = 294 [M+H]+Step 2: Synthesis of7-chloro-8-fluoro-5-methoxy-2-(methylthio)-4-(2-( trimethylsilyl)ethoxy)pyrido[4, 3-d]pyrimidine

[0105] To a solution of 2-trimethylsilylethanol (14.1 g, 119 mmol) in THF (320 mL) was added t-BuOK (1 M, 119 mL) under N2, and the mixture was stirred at 0 °C for 1 h. 4,7-Dichloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidine (32.0 g, 108 mmol) in THF (320 mL) was added and the reaction mixture was stirred at 0 °C for 2 h. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (ISCO®;SepaFlash® Silica Column, 0-20% DCM / PE gradient at 30 mL / min) to give the title compound (39.0 g, 85.8%) as a white solid. LCMS m / z = 376 [M+H]+Step 3: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylthio)-4-(2-( trimethylsilyl)ethoxy)pyrido[4, 3-d]pyrimidine

[0106] To a solution of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (52.3 g, 102 mmol), 7-chloro-8- fluoro-5-methoxy-2-(methylthio)-4-(2-(trimethylsilyl)ethoxy)pyrido[4,3-d]pyrimidine (32.0 g, 85.1 mmol) and aq. CS2CO3 (1.5 M, 170 mL) in dioxane (680 mL) was added CatacXium-Pd- G2 (3.64 g, 5.44 mmol). The reaction was stirred at 100 °C for 2 h under N2. The mixture was separated, and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography (ISCO®; SepaFlash® Silica Column, 0-52% PE / EtOAc, gradient at 30 mL / min) to give the title compound as a yellow oil (61.4 g, 89.4%). 1H NMR (400 MHz, CDCI3) δ ppm 7.63 (dd, 1H), 7.36 (d, 1H), 7.22 (d, 1H), 7.18 - 7.13 (m, 1H), 5.16 (s, 2H), 4.60 - 4.50 (m, 2H), 3.88 (s, 3H), 3.38 (s, 3H), 2.48 (s, 3H), 1.15 - 1.08 (m, 2H), 0.74 (t, 19H), 0.45 - 0.39 (m, 2H), 0.00 (s, 8H)Step 4: Synthesis of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylsulfonyl)-4-(2-( trimethylsilyl)ethoxy)pyrido[4, 3-d]pyrimidine

[0107] To a solution of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylthio)-4-(2- (trimethylsilyl)ethoxy)pyrido[4,3-d]pyrimidine (44.0 g, 60.6 mmol) in DCM (500 mL) was added m-CPBA (24.6 g, 121 mmol) and the reaction was stirred at 20 °C for 1 h. The mixture was quenched with 10% Na2SOs (1 L), then extracted with DCM (500 mLx2). The combined organic layer was washed with 10% Na>SO< (500 mL x 2) and concentrated in vacuo. Hie residue was purified by silica gel chromatography (ISCO®; SepaFlash® Silica Column, 15% - 35% EtOAc / PE gradient at 330 mL / min) to give the title compound as a yellow solid (30.8 g, 60.3%) and 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- l-yl)-5-methoxy-2-(methylsulfmyl)-4-(2-(trimethylsilyl)ethoxy)pyndo[4,3-d]pynmidine (17.3 g, 34.6%) as a yellow oil.Step 5: Synthesis of8-fluoro-7-(7-Jhioro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxy-4-(2-(trlmethylsilyl)ethoxy)pyrido[4,3-d]pyrlmidine

[0108] To a solution of ((2R7aS)-2 -fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol (13.6 g, 85.4 mmol), 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trnsopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylsulfonyl)-4-(2- (trimethylsilyl)ethoxy)pyrido[4,3-d]pyrimidine (21.6 g, 28.5 mmol) in THF (216 mL) was added t-BuOLi (2.2 M, 30.4 mL) and the mixture was stirred at 20 °C for 1 h, then concentrated in vacuo.

[0109] To a solution of ((2R7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (9.14 g, 57.4 mmol) and 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylsulfmyl)-4-(2- (trimethylsilyl)ethoxy)pyrido[4,3-d]pyrimidine (14.2 g, 19.1 mmol) in THF (142 mL) was added t-BuOLi (2.2 M, 20.4 mL) and the reaction was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo. The combined residues were purified by silica gel chromatography (ISCO®; SepaFlash® Silica Column, Eluent of 0-26% EtOAc / PE at 50 mL / min) to give the title compound (27.8 g) as a yellow oil.Step 6: Synthesis of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-jluoro-2- (((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4, 3- d]pyrimidin-4-ol

[0110] A solution of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxy-4-(2-(trimethylsilyl)ethoxy)pyrido[4,3-d]pyrimidine (27.8 g, 33.2 mmol) in DMF (278 mL) was added CsF (50.5 g, 332 mmol) and the mixture was stirred at 60 °C for 1 h. The mixture was diluted with H2O (1 L) then acidified to pH 4 using 1 M HC1. The precipitated solid was filtered off, dried, then triturated with DCM (400 mL) for 2 h at rt, to give the title compound as a yellow solid. (15.0 g, 77.0%). 'H NMR: (400 MHz, DMSO-d6) δ ppm 11.40 - 11.17 (m, 1H), 8.11 (dd, 1H), 7.75 (d, 1H), 7.57 (t, 1H), 7.41 (dd, 1H), 5.70 - 5.46 (m, 1H), 5.44 - 5.32 (m, 2H), 4.68 - 4.51 (m, 2H), 4.22 (d, 1H), 4.02 - 3.88 (m, 1H), 3.80 (br s, 1H), 3.86 (d, 6H), 3.48 - 3.42 (m, 3H), 3.30 - 3.16 (m, 1H), 2.65 - 2.54 (m, 1H), 2.46 - 2.24 (m, 2H), 2.20 - 2.00 (m, 3H)Synthesis of 2-(3-chloro-2-cyclopropyl-5-(methoxyniethoxy)phenyl)-4, 4, 5, 5-tetramethyl-l , 3, 2- dioxaborolane (Intermediate 16)Step 1: Synthesis of l-bromo-3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzene

[0111] A solution of l-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)C12 (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 in vacuo. 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 in vacuo. The residue was purified by reverse-phase column chromatography on C18 silica gel, eluting with MeCN : Water, 0% to 100%, to afford the title compound (220 mg, 12.9%) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 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

[0112] The title compound was obtained as a yellow solid, 120 mg, 46.9%, from 1-bromo- 3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzene, following a similar procedure to that described in Intermediate 6, step 2. LCMS: m / z = 339 | M 1 H |Example 1: Synthesis of 4-(4-(cyclopropylamino)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7- yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 105)Step 1: Synthesis of7-chloro-N-cyclopropyl-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-amine

[0113] Into a stirred solution of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol (Intermediate 1, step 1, 300 mg, 1.08 mmol) in MeCN (10 mL) were added DIPEA (0.57 mL, 3.26 mmol) followed by phosphonitrilic chloride trimcr (757 mg, 2.17 mmol) at 0 °C under N2. The resulting mixture was stirred at 25 °C for 1 h, then cyclopropanamine hydrochloride (204 mg, 2.17 mmol) was added. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (15 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was 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 (280 mg, 79%) as an off-white solid. LCMS m / z = 315 [M+H]+Step 2: Synthesis ofN-cyclopropyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((lriisopmpylsilyl)ethynyl)naphthalen-l-yl)-5-melhoxy-2-(melhyllhio)pyrido[4,3-d]pyrimidin-4- amine

[0114] Into a solution of 7-chloro-A-cyclopropyl-8-fhioro-5-methoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4-amine (300 mg, 0.95 mmol) in dioxane (10 mL) and water (3 mL) were added ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (977 mg, 1.90 mmol) and K3PO4 (607 mg, 2.86 mmol) at rt under N2. The reaction mixture was degassed with N2 for 5 min, then cataCXium® A Pd G3 (69.4 mg, 0.09 mmol) was added. The reaction mixture was irradiated in the microwave at 100 °C for 2 h. Tire cooled reaction mixture was diluted with water (5 mL), extracted with EtOAc (2 x 20 mL), the combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica-gel columnchromatography, eluting with 0-100% EtOAc in hexane, to afford the title compound (100 mg, 14.2 %) as a pale yellow solid. LCMS m / z = 665 [M+H]+Step 3: Synthesis ofN-cyclopropyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trilsopropylsllyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylsulfonyl)pyrldo[4,3- d]pyrimidin-4-amine

[0115] Into a stirred solution of / V-cyclopropyl-8-fliioro-7-(7-fluoro-3-(mcthoxymcthoxy)-8-((tnisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylthio)pyrido[4,3-J|pynmidin-4-amine (100 mg, 0.15 mmol) in DCM (5 ml) was added mCPBA (74.2 mg, 0.30 mmol) at 0 °C under N2 and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with sat. sodium sulfite solution (5 111L) and extracted with EtOAc (2 x 15 mL). The combined organic layer was washed with 10% aqueous NaHCOa solution (10 ml), dried over anhydrous NaiSOi and evaporated under reduced pressure, to afford the title compound (100 mg, 53.7 %) as a pale yellow solid. LCMS m / z = 697 [M+H]+Step 4: Synthesis of N-cyclopropyl-8-fluoro-7-(7-fluoro-3-(melhoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido [4,3-d]pyrimidin-4-amine

[0116] Into a stirred solution of / V-cyclopropyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylsulfonyl)pyrido[4,3- <7]pyrimidin-4-amine (100 mg, 0.14 mmol) in toluene (5 mL) was added ((2 / ?.7a.S')-2- fluorotetrahydro-177-pyrrolizin-7a(577)-yl)methanol (45.7 mg, 0.29 mmol) followed by NaOtBu (41.4 mg, 0.43 mmol) at 0 °C under N2 and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (3 x 10 mL) and the combined organic layer was dried over Na2SO+. filtered and evaporated under reduced pressure to give the title compound (130 mg, 54.7 %) as a pale yellow solid. LCMS m / z = 776 [M+H]+Step 5: Synthesis of 4-(4-(cyclopropylamino)-8-fluoro-2-(((2'R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0117] Into a stirred solution of A-cyclopropyl-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((tnisopropylsilyl)cthynyl)naphthalcn- l -yl)-2-(((2 / ?.7aS')-2-fluorotctrahydro-17 / -pyrrolizin- 7a(5 / 7)-yl)methoxy)-5-methoxypyrido[4,3-J]pyrimidin-4-amine (100 mg, 0.13 mmol) in dioxane (5 mL) was added HC1 in MeOH (1.25 M, 0.51 mL, 0.65 mmol) at 0 °C under N2. The reaction mixture was stirred at it for 16 h. The reaction was quenched with TEA (0.4 mL) and the pH of the mixture was adjusted to 7-8. The mixture was concentrated under reducedpressure to afford the title compound (130 mg, crude) as a brown solid. LCMS m / z = 732 [M+H]+Step 6: Synthesis of 4-(4-(cyclopropylamino)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4, 3-d]pyrimidm-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol

[0118] Into a stirred solution of 4-(4-(cyclopropylamino)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-177-pyrrolizin-7a(5 / 7)-yl)methoxy)-5-methoxypyrido[4,3-<7]pyrimidin-7-yl)-6- fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (100 mg, 0,13 mmol) in DMF (3 mL) was added CsF (208 mg, 1.37 mmol) at rt under N2 and the reaction mixture was stirred at 70 °C for 2 h. Tire mixture was filtered and the filtrate was concentrated under reduced pressure. Tire crude was purified by preparative-HPLC Method H, to give the title compound (28 mg, 35.0 %) as an off-white solid. LCMS m / z = 576 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.08 (d, 1H), 7.97 (dd, 1H), 7.47 (t, 1H), 7.38 (d, 1H), 7.18 (d, 1H), 5.29 (d, 1H), 4.18-4.12 (m, 1H), 4.10-4.01 (m, 2H), 3.95 (s, 3H), 3.14-3.09 (m, 4H), 2.85-2.83 (m, 1H), 2.15-2.03 (m, 3H), 1.87-1.78 (m, 3H), 0.94-0.66 (m, 4H)Example 2: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-methoxypyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Compound 106)Step 1-Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-5-methoxy-2- ( methylthio)pyrido[4, 3-d]pyrimidin-4-amine

[0119] The title compound was obtained as a pale brown solid, 320 mg, 45.3%, from 7- chloro-8-fluoro-5-methoxy-2-(methylthio)pyndo[4,3-d]pynmidin-4-ol (Intermediate 1, step 1) and 2-((tert-butyldimethylsilyl)oxy)ethan-l -amine, following the procedure described in Example 1 , step 1 . LCMS m / z = 433 [M+H]+Step 2-Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- ( methylthio)pyrido[4, 3-d]pyrimidin-4-amine

[0120] The title compound was obtained as a solid, from N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-amine and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane, following the sprocedure described in Example 1, step 2. LCMS m / z = 783 [M+H]+Step 3: Synthesis of N-(2-((tert-hutyldimethylsilyl)oxy)ethyl)-8fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- ( methylsulfmyl)pyrido[4, 3-d]pyrimidin-4-amine

[0121] Into a stirred solution N-(2-((tcrt-butyldimcthylsilyl)oxy)cthyl)-8-fluoro-7-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4-amine (5, 150 mg, 0.19 mmol) in DCM (2 mL) was added m-CPBA (51.5 mg, 0.23 mmol) at 0 °C and the reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was quenched with aq. sodium sulfite solution (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure to obtain the title compound (120 mg, 76 %) as a brown solid. LCMS m / z = 799 [M+H]+Step 4: Synthesis of N-(2-((tert-hutyldimethylsilyl)oxy)ethyl)-8fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine

[0122] The title compound was obtained from N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5- methoxy-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-amine and ((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methanol, following the method described in Example 1, step 4.LCMS m / z = 895 [M+H]+Step 4 to 6: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-methoxypyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-ol

[0123] The title compound was obtained as a solid, from N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine, following a similar 2 step procedure to that described in Example 1, steps 5 to 6. The final product was purified by HPLC Method D at 14 mL / min. LCMS m / z = 580 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.41-8.39 (m, 1H), 7.97 (dd, 1H), 7.47 (t, 1H), 7.39 (d, 1H), 7.19 (d, 1H), 5.28 (d, 1H), 4.99 (s, 1H), 4.12-4.08 (m, 2H), 4.03-3.96 (m, 4H), 3.73-3.61 (m, 4H), 3.10-3.02 (m, 3H), 2.86- 2.80 (m, 1H), 2.14-2.01 (m, 3H), 1.89-1.77 (m, 3H) Example 3 and Example 4: Synthesis of Compound 107 and Compound 113

[0124] The compounds in the following table were obtained from the appropriate 7-chloro- 8-fluoro-5-alkoxy-2-(methylthio)pyrido[4,3-<7]pyrimidin-4-ol, protected amine and ((2R,7aS)-2- fluorotetrahydro-17 / -pyrrolizin-7a(5 / 7)-yl)methanol, following a similar 6 step procedure to that described in Example 1.Example 5: Synthesis of 4-(4-((3-aminopropyl)amino)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 109)Steps 1 and 2: Synthesis of tert-butyl (3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-yl)amino)propyl)carbamate

[0125] The title compound was obtained as a pale yellow solid, from 7-chloro-8-fluoro-5- isopropoxy-2-(methylthio)pyrido[4,3-d / ]pyrimidin-4-ol (Intermediate 2, step 1), tert-butyl (3- aminopropyl)carbamate and ((2-fluoro-6-(rnethoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane, following the procedure described in Example 1, steps 1 and 2. LCMS m / z = 810 [M+H]+Step 3: Synthesis of tert-butyl (3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((trnsopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2-(methylsulfinyl)pyrido[4,3- d]pyrimidin-4-yl)amino)propyl)carbamate

[0126] The title compound was obtained as a pale yellow solid, 150 mg, 60.7%, from tertbutyl (3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2-(methylthio)pyrido[4,3-c / ]pyrimidm-4-yl)aniino)propyl)carbamate, following the procedure described in Intermediate 1 step 3. LCMS m / z = 826 [ M 1 111Steps 4 to 6: Synthesis of 4-(4-((3-aminopropyl)amino)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizln-7a(5H)-yl)methoxy)-5-lsopropoxypyndo[4,3-d]pyrimldln-7-yl)- 5-ethynyl-6-fluoronaphthalen-2-ol

[0127] The title compound was obtained as an off-white solid, from / (?r / -butyl (3-((8-fluoro- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy- 2-(methylsulfinyl)pyrido[4,3-J]pyrimidin-4-yl)amino)propyl)carbamate and ((2 / <7aS')-2- fluorotetrahydro- 17L-pyrrolizin-7a(5E7)-yl)methanol, following a similar procedure to that described in Example 1, steps 4 to 6. Tire final compound was purified by prep HPLC Method D, at 14 mL / min. LCMS m / z = 621 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.28-8.22 (m, 1H), 7.97 (dd, 1H), 7.46 (t, 1H), 7.38 (d, 1H), 7.16 (d, 1H), 5.38-5.22 (m, 2H), 4.12-4.09 (m, 2H), 4.03-3.99 (in, 1H), 3.69-3.62 (m, 3H), 3.11-3.02 (in, 3H), 2.84-2.82 (in, 1H), 2.73 (t, 2H), 2.34-2.00 (m, 3H), 1.88-1.71 (m, 6H), 1.40-1.35 (m, 6H)Example 6: Synthesis of 4-(4-((2-aminoethyl)amino)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 110)Step 1: Synthesis of tert-butyl (2-((7-chloro-8fluoro-5-isopropoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-yl)amino)ethyl)carbamate

[0128] Into a stirred solution of 7-chloro-8-fluoro-5-isopropoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol (Intermediate 2, step 1, 500 mg, 1.65 mmol) in MeCN (10 mL) was added DIPEA (1.52 mL, 8.23 mmol) and phosphonitrilic chloride trimer (1.15 g, 3.29 mmol) and the mixture was stirred at rt for 1 h. tert-Butyl (2-aminocthyl)carbamatc (0.31 mL, 1.98 mmol) was added and the resulting mixture was stirred at 25 °C for 16 h. The reaction was poured into ice-water (20 mL), the resulting mixture filtered and washed with MTBE (50 mh) to give the title compound (750 mg, 67.6 %) as a yellow solid. LCMS m / z = 446 [M+H]+Steps 2 to 6: Synthesis of 4-(4-((2-aminoethyl)amino)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro- lH-pyrrolizln-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimldln-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol

[0129] The title compound was obtained as an off-white solid, from tert-butyl (2-((7-chloro- 8-fluoro-5-isopropoxy-2-(inethylthio)pyrido[4,3-c / ]pyriinidin-4-yl)amino)ethyl)carbamate, following a similar procedure to that descnbed in Example 2, steps 2 to 6. The final compound was purified by HPLC Method C. LCMS m / z = 607 [M+H]+;1H-NMR (400 MHz, DMSO-d6): δ 10.05 (br s, 1H), 8.69-8.68 (m, 1H), 7.97 (dd, 1H), 7.46 (t, 1H), 7.38 (d, 1H), 7.16 (d, 1H), 5.38-5.21 (m, 2H), 4.11-4.08 (m, 2H), 4.02-3.98 (m, 1H), 3.58-3.49 (m, 3H), 3.10-3.08 (m, 2H), 3.02 (s, 1H), 2.90-2.82 (m, 3H), 2.14-2.13 (m, 1H), 2.05-2.00 (m, 2H), 1.88-1.77 (m, 4H), 1.41- 1.36 (m, 6H)Example 7: Synthesis of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrroIizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyI)amino)-5-isopropoxypyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Compound 108)Steps 1 to 3: Synthesis of N-(2-((tert-hutyldimethylsilyl)oxy)ethyl)-7-(8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4-amine

[0130] The title compound was obtained as a pale yellow solid, from JV-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-5-isopropoxy-2-(methylthio)pyrido[4,3- r / |pyrimidin-4-aminc (Intermediate 2, step 2), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy )naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane and ((2R .7a.S')-2- fluorotetrahydro- 1 / / -pyrrolizin-7a(5 / H)-yl )methanol, following a similar 3 step procedure to that described in Example 2, steps 2 to 4. LCMS m / z = 771 [M+H]+Step 4: Synthesis of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-isopropoxypyrido [4, 3-d]pyrimidin-7- yl)naphthalen-2-ol

[0131] Into a stirred solution of JV-(2-((tert-butyldimethylsilyl)oxy)ethyl )-7-(8-ethyl-7- fluoro-3-(methoxymethoxy)naphthalen- 1 -y I )-8-fluoro-2-(((2 / ?.7aS')-2-fluorotctrahydro- 1H- pyrrolizin-7a(577)-yl)methoxy)-5-isopropoxypyrido[4,3-J]pyrimidin-4-amine (90 mg, 0.12 mmol) in dioxane (4 mh) was added HC1 in MeOH (1.25 M, 0.46 ml, 0.58 mmol) at 0 °C under N2. The reaction mixture was stirred at rt for 16 h. The reaction was quenched with TEA (0.1 mL), the pH of the mixture was adjusted to 7-8 and concentrated under reduced pressure. The crude compound was purified by preparative HPLC Method C, to afford the title compound (23 mg, 32.1 %) as an off-white solid. LCMS m / z = 612 [M+H]+‘H-NMR (400 MHz, DMSO- d6): δ 9.93 (s, 1H), 8.48 (t, 1H), 7.76 (dd, 1H), 7.37-7.31 (m, 2H), 7.02 (d, 1H), 5.37-5.34 (m, 2H), 5.23-5.19 (d, 1H), 5.07 (t, 1H), 4.13 (d, 1H), 4.03 (d, 1H), 3.71-3.64 (m, 4H), 3.10-3.01 (m, 3H), 2.84-2.82 (m, 1H), 2.34-2.33 (m, 1H), 2.13-2.00 (m, 3H), 1.85-1.76 (m, 3H), 1.38-1.35 (m, 6H), 0.77 (t, 3H)Example 8: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(((lR,3S)-3-(hydroxymethyl)cyclopentyl)amino)-5- methoxypyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Compound 114)Step 1: Synthesis of ((lS,3R)-3-((7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido [4, 3- d]pyrimidin-4-yl)amino)cyclopentyl)methanol

[0132] The title compound was obtained as a colorless solid, 230 mg, 42%, from 7-chloro- 8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Intermediate 1, step 1) and (lR,3S)-3-(hydroxymcthyl)cyclopcntan-l-aminium chloride, following the procedure described in Example 1, step 1. LCMS m / z = 373 [M+H]+Step 2: Synthesis of ((lS,3R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphlhalen-l-yl)-5-melhoxy-2fmelhylthio)pyrido[4,3-d )pyrimidin-4- yl)amino)cyclopentyl)methanol

[0133] Into a solution of ((lS,3R)-3-((7-chloro-8-fluoro-5-methoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)cyclopentyl)methanol (0.2 g, 0.53 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane (0.41 g, 0.80 mmol) in THF (6 mL) and water (1 mL) was added K3PO4 (0.34 g, 1.60 mmol). The mixture was degassed with N2, XPhos Pd G3 (0.04 g, 0.05 mmol) was added and the reaction mixture was stirred at 85 °C under microwave irradiation for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (30 mL), dried over NazSOr. filtered and concentrated under reduced pressure. The crude compound was purified by silica gel columnchromatography using 0-100% EtOAc / hexane as eluent to afford the title compound (0.18 g, 44. 1 %) as a colorless solid. LCMS m / z = 723 [M+H]+Step 3: Synthesis of ((lS,3R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3- d]pyrimidin-4-yl)amino)cyclopentyl)methanol

[0134] Into a stirred solution of ((lS,3R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin- 4-yl)ammo)cyclopentyl)methanol (0.2 g, 0.27 mmol) in DCM (5 mL) under N2 was added mCPBA (0.07 g, 0.41 mmol) at 0 °C and the reaction was stirred at rt for 1 h. The reaction was quenched with sat. sodium sulfite solution (10 mL) and sodium thiosulfate solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with aq. NaHCOa ( 10 mL), brine (10 mL), dried over Na2 SO4 and concentrated under reduced pressure to afford the title compound (0.18 g, 88 %). LCMS m / z = 739 [M+H]+Step 4: Synthesis of ((lS,3R)-3-((8-fluoro-7-(7-fluoro-3-(melhoxymelhoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)amino)cyclopentyl)methanol

[0135] Into a stirred solution of (( 1 S,3R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3- d]pyrimidin-4-yl)amino)cyclopentyl)methanol (0.17 g, 0.20 mmol) and ((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (0.07 g, 0.46 mmol) in toluene (5 mL) under N2 was added KOtBu (0.05 g, 0.46 mmol) at 0 °C and the reaction was stirred at rt for 3 h. The reaction mixture was quenched with aq. NH4Q solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 0-100% EtOAc / Hexane as eluent to afford the desired product, 0.15 g, 77 % as a colorless solid. LCMS m / z = 835 [M+H]+Steps 5 and 6: Synthesis of 5-ethynyl-6-fluoro-4-(8fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-(((lR,3S)-3-(hydroxymethyl)cyclopentyl)ammo)-5- methoxypyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0136] The title compound was obtained as a colorless solid, from ((l S,3R)-3-((8-fluoro-7- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)amino)cyclopentyl)methanol, following a similar procedure to that described in Example 1,steps 5 and 6. The final compound was purified by HPLC Method E. LCMS m / z = 634 [M+H]+1H-NMR (400 MHz,DMSO-d6) δ 10.21 (m, 1H), 8.27 (dd, 1H), 7.97 (q, 1H), 7.46 (t, 1H), 7.38 (d, 1H), 7.18 (d, 1H), 5.39-5.18 (m, 1H), 4.85-4.73 (m, 1H), 4.64-4.53 (m, 1H), 4.13-3.92 (m, 6H), 3.46-3.43 (m, 2H), 3.11-3.02 (m, 3H), 2.83-2.73 (m, 1H), 2.29-2.10 (m, 3H), 2.01-1.91 (m, 3H), 1.89-1.66 (m, 5H), 1.64-1.35 (m, 2H)Example 9: Synthesis of 4-(4-(cyclopropylamino)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol (Compound 102)

[0137] The title compound was obtained as an off-white solid, from 7-chloro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Intermediate 10) and cyclopropanamine, following a similar 6 step procedure to that described in Example 2. The final compound was purified by HPLC Method A. LCMS m / z = 558 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.99 (d, 1H), 7.94 (dd, 1H), 7.44 (t, 1H), 7.32 (d, 1H), 7.13 (d, 1H), 6.97 (s, 1H), 5.22-5.40 (m, 1H), 4.11-4.09 (m, 1H), 4.04-4.02 (m, 2H), 3.94 (s, 3H), 3.11 -3 07 (m, 3H), 3.03 (s, 1H), 2.85-2.83 (m, 1H), 2.16-2.12 (m, 1H), 2.08-2.00 (m, 2H), 1.86-1.78 (m, 3H), 0.88-0.86 (m, 2H), 0.85-0.74 (m, 2H)Example 10: Synthesis of 5-ethynyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-(((lRS,2RS)-2-hydroxycyclopropyl)amino)-5- methoxypyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Compound 115)Step 1: Synthesis of trans rac-N-(2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-7-chloro-5- methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine

[0138] The title compound was obtained as a yellow foam, 330 mg, crude, from 7-chloro-5- methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Intermediate 10) and trans rac-2-((tert- butyldimethylsilyl)oxy)cyclopropan-l -amine (Intermediate 8) following a similar procedure to that described in Example 1, step 1. LCMS m / z = 427 [M+H]+Step 2: Synthesis of trans rac-N-(2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-( methylthio)pyrido[4, 3-d]pyrimidin-4-amine

[0139] Into a stirred solution of trans rac-N-(2-((tert-butyldimethylsilyl)oxy)cyclopropyl)- 7-chloro-5-methoxy-2-(inethylthio)pyrido[4,3-d]pyrimidin-4-amine (400 mg, 0.93 mmol) in dioxane (10 mL) and water (2 mL) were added K3PO4 (400 mg, 2.34 mmol) and ((2-fluoro-6- (methoxymethoxy)- 8-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)naphthalen- 1 - yl)ethynyl)triisopropylsilane (960 mg, 1 87 mmol). The reaction mixture was purged with N2, then CataCXium® A Pd G3 (60 mg, 0.09 mmol) was added and the mixture heated to 100 °C for 2 h. The reaction mixture was filtered through Celite® and washed with EtOAc (80 mL).The filtrate was collected 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 (450 mg, 55,0 %) as a light-yellow foam solid. LCMS m / z = 777 [M+H]+Step 3: Synthesis of trans rac-N-(2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- ( methylsulfmyl)pyrido[4, 3-d]pyrimidin-4-amine

[0140] Into a stirred solution of trans rac-N-(2-((tert-butyldimethylsilyl)oxy)cyclopropyl)- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4-amine (320 mg, 0.41 mmol) in DCM (25 mL) was added mCPBA (107 mg, 0.61 mmol) and tire reaction mixture stirred at 0 °C for 1 h. Tire reaction mixture was quenched with sat. sodium sulfite solution (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with sat. NaHCCh solution ( 20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was azcotropcd with toluene (10 mL) and dried under vacuum to afford the title compound, 300 mg, 70.7 %. LCMS m / z = 793 [M+H]+Step 4: Synthesis ofN-((lRS,2RS)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-7-(7-fluoro-3- (methoxymelhoxy)-8-((triisopropylsilyl)ethynyl)naphlhalen-l-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine

[0141] Into a stirred solution of trans rac-N-(2-((tert-butyldimethylsilyl)oxy)cyclopropyl)- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- (methylsulfinyl)pyrido[4,3-d]pyrimidin-4-amine (250 mg, 0.31 mmol) and ((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (100 mg, 0.63 mmol) in toluene (10 mL) was added NaOtBu (60 mg, 0.69 mmol) and the reaction mixture stirred at 0 °C for 2 h. The reaction mixture was quenched with sat.NaHCCh solution (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over Na^SO-i. filtered and evaporated 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, 150 mg, 40.2 %, as a light brown foam. LCMS m / z = 888 | M+111Step 5: Synthesis of 6fluoro-4-(2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-4-(((lRS,2RS)-2-hydroxycyclopropyl)amino)-5-methoxypyrido[4,3-d]pyrimidin-7- yl) -5-( ( Piisopropylsilyl)ethynyl)naphthalen-2-ol

[0142] Into a stirred solution of N-((lRS,2RS)-2-((tert- butyldimethylsilyl)oxy)cyclopropyl)-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine (125 mg, 0.14 mmol) in dioxane (25 mL) was added HC1 (4 M in dioxane) (51.3 mg, 1.40 mmol) at 0 °C and the reaction mixture stirred at rt for 16 h. The reaction mixture was quenched with TEA (0.4 mL) and the pH of the reaction mixture was adjusted to 7-8. The mixture was concentrated under reduced pressure and the crude was purified by preparative HPLC Method E to afford the title compound, 15 mg, 13.1 % as an off-white solid. LCMS m / z = 729 [M+H]+Step 6: Synthesis of 5-ethynyl-6-fluoro-4-(2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-4-( ((1 RS, 2RS)-2-hydroxycyclopropyl)amino)-5-methoxypyrido[4, 3- d]pyrimidin- 7-yl)naphthalen-2-ol

[0143] Into a stirred solution of 6-£luoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)mcthoxy)-4-((( IRS, 2RS)-2 -hydroxy cyclopropyl )amino)-5-mcthoxypyrido[4, 3- d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (15 mg, 0.02 mmol) in DMF (0.5 mL) was added CsF (15.61 mg, 0.10 mmol) at rt and the reaction mixture stirred for 6 h. The reaction mixture was evaporated under reduced pressure and the crude residue was purified by preparative HPLC Method L to give the title compound (1.8 mg, 14.1 %) as an off-white solid. LCMS m / z = 574 [M+H]+1H-NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.95-7.89 (m, 2H), 7.44 (t, 1H), 7.32 (d, 1H), 7.13 (d, 1H). 6.97-6.95 (m, 1H), 5.61-5.59 (m, 1H), 5.38- 5.25 (m, 1H), 4.19-4.13 (m, 3H), 4.05-4.00 (m, 2H), 3.93 (s, 3H), 3.13-3.11 (m, 3H), 2.89-2.88 (m, 1H), 2.22-2.03 (m, 3H), 1.90-1.79 (m, 3H), 1.03-1.01 (m, 2H)Example 11: Synthesis of 5-ethynyl-6-fhioro-4-(2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-methoxypyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Compound 101)Step 1: Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-5-methoxy-2-( methylthio)pyrido[4, 3-d]pyrimidin-4-amine

[0144] Into a stirred solution of 7-chloro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin- 4-ol (Intermediate 10, 500 mg, 1 .94 mmol) in DMA (5 mL) was added DIPEA (1.6 ml, 9.7 mmol) and HATU (1.4 g, 3.88 mmol) and the mixture stirred at rt for 30 min. 2-((tert- Butyldimethylsilyl)oxy)ethan- 1 -amine (408 mg, 2.32 mmol) was added and the reaction mixture stirred at rt for 4 h. Tire reaction mixture was suspended in water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried overNa2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography, using a gradient of 0-100 % EtOAc / n-hexane to obtain the title compound, 450mg, 54.8 %, as an off-white solid. LCMS m / z = 415 | M+H |Step 2: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4- amine

[0145] The title compound was obtained as an off-white solid, 350 mg, 39.5%, from N-(2- ((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin- 4-amine and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl)ethynyl)triisopropylsilane, following a similar procedure to that described in Example 1, step 2. LCMS m / z = 765 [M+H]+Step 3: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyi)naphthalen-l-yl)-5-methoxy-2-(methylsulfmyl)pyrido[4,3- d]pyrimidin-4-amine

[0146] Into a stirred solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine (340 mg, 0.44 mmol) in DCM (15 mL) was added mCPBA (124 mg, 0.55 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 30 min. Tire reaction mixture was quenched with sat. Nal IC’CL solution (10 111L) and extracted with DCM (2 x 20 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SC>4, and concentrated under reduced pressure at low temperature to afford the title compound, 300 mg, 76 % as a white foam. LCMS m / z = 781 [M+H]+Step 4: Synthesis of N-(2-((tert-hutyldimethylsilyl)oxy)ethyl)-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrirnidin-4-amine

[0147] Into a stirred solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(7-fluoro-3- (metlioxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- (mcthylsulfinyl)pyrido[4,3-d]pyrimidin-4-aminc (150 mg, 0.19 mmol) and ((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (61.1 mg, 0.38 mmol) in toluene (5 mL) was added NaOtBu (36.9 mg, 0.38 mmol) at 0 °C under N2 and the reaction mixture was stirred at rt for 6 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over NazSOr, fdtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 0-100 % EtOAc / n-hexane to afford the title compound, 170 mg, 57.6 % as a colorless gum. LCMS m / z = 876 [M+H]+Steps 5 and 6: Synthesis of 5-ethynyl-6-fluoro-4-(2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-methoxypyrido[4, 3-d]pyrimidin-7- yl)naphthalen-2-ol

[0148] The title compound was obtained as an off-white solid, from N-(2-((tert- butyldimethylsilyl)oxy)ethyl) -7 -(7-fluoro -3 -(methoxymethoxy )- 8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)inethoxy)-5-metlioxypyrido[4,3-d]pyriinidin-4-amine, following die procedure described in Example 1, steps 5 and 6. The final product was purified by HPLC Method G. LCMS m / z = 562 [M+H]+1H-NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.32-8.30 (m, 1H), 7.94 (dd, 1H), 7.44 (t, 1H), 7.33 (d, 1H), 7.14 (d, 1H), 6.96 (s, 1H), 5.40-5.22 (m, 1H), 4.98 (t, 1H), 4.08-4.06 (m, 2H), 4.00-3.96 (m, 4H), 3.70-3.59 (m, 4H), 3.11-3.02 (m, 3H), 2.84-2.83 (m, 1H), 2.14-2.00 (m, 3H), 1.86-1.77 (m, 3H)Example 12: Synthesis of 5-ethynyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-(3-hydroxypropyl)-5-isopropoxypyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol (Compound 103)

[0149] The title compound was obtained as an off-white solid, from Intermediate 11, 2-((tert-butyldimethylsilyl)oxy)ethan-l -amine, ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane and ((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol, following a similar 6 step procedure to that described in Example 11. LCMS m / z = 590 [M+H]+1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 8.44 (t, 1H), 7.93 (dd, 1H), 7.44 (t, 1H), 7.32 (d, 1H), 7.11 (d, 1H), 6.93 (s, 1H),5.36-5.21 (m, 2H), 5.06 (t, 1H), 4.08-3.96 (m, 3H), 3.70-3.59 (m, 4H), 3.11-3.02 (m, 4H), 2.84- 2.82 (m, 1H), 2.13-2.00 (m, 3H), 1.86-1.76 (m, 3H), 1.37 (t, 6H)Example 13: Synthesis of 5-ethynyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-lH- py rrolizin-7 a(5H)-yl)meth oxy)-4-(((S)-2-hydroxypropyl)amino)-5-isop rop oxypyrido [4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Compound 104)Step 1: Synthesis of (S)-2-((tert-butyldimethylsilyl)oxy)propan-l-amine

[0150] Into a stirred solution of (S)-l-aminopropan-2-ol (500 mg, 6.66 mmol) in DCM (10 mL) was added imidazole (680 mg, 9.99 mmol) followed by TBDMS-C1 (1.154 g, 7.66 mmol) in DCM (5 mL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound, 800 mg, 42.0 %, as a colorless liquid. LCMS m / z = 190 [M+H]Step 2: Synthesis of (S)-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-7-chloro-5-isopropoxy-2- ( methylthio)pyrido[4, 3-d]pyrimidin-4-amine

[0151] The title compound was obtained as an off-white solid, 450 mg, 56.3%, from 7- chloro-5-isopropoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Intermediate 11) and (S)-2- ((tert-butyldimethylsilyl)oxy)propan-l-amine, following the procedure described in Example 11, step 1. LCMS m / z = 457 [M+H]"Step 3: Synthesis of (S)-N-(2-((tert-butyldimethylsilyl)oxy)propyl)-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2-( methylthio)pyrido[ 4, 3-d]pyrimidin-4-amine

[0152] The title compound was obtained as an off-white foam, 350 mg. 44.2%, from (S)-N- (2-((tert-butyldimethylsilyl)oxy)propyl)-7-chloro-5-isopropoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-amine and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-I,3,2-dioxaborolan-2-yl)naphtlialen-l-yl)ethynyl)triisopropylsilane, following the procedure descnbed in Example 1, step 2. LCMS m / z = 807 [M+H]+Step 4: Synthesis ofN-((S)-2-((tert-butyldimethylsilyl)oxy)propyl)-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2- ( methylsulfinytypyrido [4, 3-d]pyrimidin-4-amine

[0153] The title compound was obtained as a white foam, 190 mg, 86%, from (S)-N-(2- ((tert-butyldimethylsilyl)oxy)propyl)-7-(7-fluoro-3-(methoxymetlioxy)-8- ((tnisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2-(methylthio)pyndo[4,3- d]pyrimidin-4-amine, following the method described in Example 11, step 3. LCMS m / z = 823 [M+H]+Steps 5 to 7: Synthesis of 5-ethynyl-6-Jl.uoro-4-(2-(((2R,7aS)-2-Jl.uorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-4-(((S)-2-hydroxypropyl)amino)-5-isopropoxypyrido[4,3-dJpyrimidin-7- yl)naphthalen-2-ol

[0154] The title compound was obtained as a white solid, from (S)-N-(2-((tert- butyldimetliylsilyl)oxy)propyl)-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-isopropoxy-2-(methylsulfonyl)pyndo[4,3- d]pyrimidin-4-amine and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol, following a similar 3 step process to that described in Example 1, steps 4 to 6. The final compound was purified by HPLC Method G. LCMS m / z = 604 [M+H]+1H-NMR (400 MHz, DMSO-d6): δ 10.14 (br s, 1H), 8.48-8.44 (m, 1H), 7.92 (dd, 1H), 7.43 (t, 1H), 7.32 (d, 1H), 7.11 (s, 1H), 6.93 (s, 1H), 5.36-5.33 (m, 1H), 5.15 (d, 1H), 4.07-4.05 (m, 2H), 3.98-3.95 (m, 2H), 3.73-3.61 (m, 2H), 3.28-3.20 (m, 1H), 3.10-3.01 (m, 3H), 2.83-2.82 (m, 1H), 2.13-1.99 (m, 3H), 1.85-1.76 (m, 3H), 1.36 (t, 6H), 1.19 (t, 3H)Example 14: Synthesis of 4-(5-cyclopropoxy-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol (Compound 112)Step I : Synthesis of N-(2-( ( tert-butyldimethylsilyl)oxy)ethyl)- 7-chloro-5-cyclopropoxy-8-fluoro- 2-( methylthio) pyrido[ 4, 3-d]pyrimidin-4-amine

[0155] Into a stirred solution of 7-chloro-5-cyclopropoxy-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-ol (Intermediate 3, 400 mg, 1.32 mmol) in DMA (10 mL) were added DIPEA (0.69 mL, 3.98 mmol) and HATU (1512 mg, 3.98 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h, 2-((tert-hutyldimethylsilyl)oxy)ethan-l -amine (302 mg, 1.73 mmol) added and the reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with ice-cold water (15 mL), the precipitated solid was filtered through a Buckner funnel, washed with water (2 x 10 mL), and dried. Tire crude product was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (260 mg, 43%) as a white solid. LCMS m / z = 459 [M+H]+Steps 2 to 6: Synthesis of 4-(5-cyclopropoxy-8-fluoro-2-(((2R,7aS)-2-fluomtetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)pyrido[4, 3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol

[0156] The title compound was obtained as an off-white solid, from N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-chloro-5-cyclopropoxy-8-fluoro-2-(methylthio)pyrido[4,3- <7]pyrimidm-4-amine and ((2-fhioro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalcn-l-yl)cthynyl)tnisopropylsilanc, following a similar procedure tothat described in Example 2, steps 2 to 6. The final compound was purified by HPLC Method A. LCMS m / z = 606 [M+H]+Tl-NMRHOO MHz, DMSO-d6): δ 10.14 (s, 1H), 8.19-8.18 (m, 1H), 7.97 (dd, 1H), 7.47 (t, 1H), 7.39 (d, 1H), 7.20 (d, 1H), 5.21 (d, 1H), 5.08 (t, 1H), 4.42-4.41 (m, 1H), 4.12-4.09 (m, 2H), 4.03-4.00 (m, 1H), 3.69-3.60 (m, 4H), 3.10-3.02 (m, 3H), 2.86-2.82 (m, 1H), 2.14-2.00 (m, 3H), 1.80-1.77 (m, 3H), 0.87-0.86 (m, 2H), 0.75-0.73 (m, 2H)Example 15: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-isopropoxypyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Compound 117)Steps 1 to 3: Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-2-(((2R, 7aS)-2-jluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4-amine

[0157] The title compound was obtained as a foam, from N-(2-((tert- butyldimcthylsilyl)oxy)cthyl)-7-chloro-8-fluoro-5-isopropoxy-2-(mcthylthio)pyndo[4,3- t / |pyrimidin-4-aminc (Intermediate 2, step 2) and 2-(7-fluoro-3-(m ethoxymethoxy )naphthalen-1-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 5), following a similar procedure to that dcscnbcd in Example 2, steps 2 to 4. LCMS m / z = 742 [ M+H JStep 4: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-4-((2-hydroxyethyl)amino)-5-isopropoxypyrido[4,3-d]pyrimidm-7-yl)naphthalen-2- ol

[0158] The title compound was obtained as an off-white solid, 24 mg, 13.5%, from N-(2- ((ter / -butyldimethylsilyl)oxy)ethyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-2-(((27?,7ari)-2-fluorotetrahydro-17T-pyrrolizin-7a(577)-yl)methoxy)-5-isopropoxypyrido[4,3-t / |pyrimidin-4-aminc following a similar procedure to that described in Example 7, step 4. The compound was purified by HPLC Method K. LCMS m / z = 584 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10.02 (br s, 1H), 8.48 (t, 1H), 8.18 (s, 1H), 7.92-7.88 (m, 1H), 7.40-7.28 (m, 3H), 5.41-5.36 (m, 2H), 5.22 (s, 1H), 4.14 (d, 1H), 4.04 (d, 1H), 3.69-3.65 (m, 5H), 3.12-3.09 (m, 2H), 2.84-2.83 (m, 1H), 2.15-2.01 (m, 3H), 1.86-1.76 (m, 3H), 1.44-1.41 (m, 6H)Example 16: Synthesis of 4-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-4-yl)amino)butanamide (Compound 111)Steps 1 to 3: Synthesis of methyl 4-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-( (triisopropylsilyl) ethynyl)naphthalen-l -yl)-5-methoxy-2-(methylsulfmyl)pyrido[ 4, 3- d]pyrimidin-4-yl)amino)butanoate

[0159] The title compound was obtained as an off white solid, from 7-chloro-8-fluoro-5- methoxy-2-(methylthio)pyrido[4,3-J]pyrimidin-4-ol (Intermediate 1, step 1) and methyl 4- aminobutanoate hydrochloride, following a similar 3 step procedure to that described in Example 2, steps 1 to 3. LCMS m / z = 741 | M+H |Step 4: Synthesis of sodium 4-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)amino)butanoate

[0160] Into a stirred solution of methyl 4-((8-fhioro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylsulfinyl)pyrido[4,3- t / |pyriniidni-4-yl)amino)biitanoatc (260 mg, 0.35 mmol) and ((2 / ?.7a.S')-2-fliiorotctraliydro- l / 7- pyrrolizin-7a(577)-yl)methanol (112 mg, 0,70 mmol) in toluene (10 mL) was added NaOtBu (101 mg, 1.05 mmol) at 0 °C and the reaction mixture was allowed to stir at rt for 1 h. The reaction mixture was concentrated under reduced pressure and triturated with hexane to give the title compound, 240 mg, crude, as a pale yellow solid. LCMS m / z = 822 [M+H]+Step 5: Synthesis of 4-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)amino)butanamide

[0161] Into a stirred solution of sodium 4-((8-fhioro-7-(7-fhioro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen- 1 -yl )-2-(((2 / ?.7aS)-2-fluorotctrahydro- 177-pyrrolizin- 7a(577)-yl)methoxy)-5-methoxypyrido[4,3-J]pyrimidin-4-yl)amino)butanoate (220 mg, 0.26 mmol) in DMF (0.5 mL) were added DIPEA (0.23 mL, 1.34 mmol) and HATU (173 mg, 0.46 mmol) at 0 °C and the mixture stirred for 10 minutes. NH+Cl (129 mg, 2.41 mmol) was added and the reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2x 30 mL). The organic layer was dried over NazSOi. filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using a gradient of 0-20 % of MeOH in DCM, to afford the title compound (150 mg, 35.4 %) as a pale yellow solid. LCMS m / z = 821 [M+H]+Steps 6 and 7: Synthesis of 4-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2- (((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-4-yl)ammo)butananiide

[0162] The title compound was obtained as an off-white solid, from 4-((8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido [4,3-d]pyrimidin-4- yl)amino)butanamide, following a similar 2 step procedure to that described in Example 1 , steps 5 and 6. The final compound was purified by preparative -HPLC Method D, at 14 mL / min. LCMS m / z = 621 [M+H]+. 1H (N40M0R MHz, DMSO-d6)δ101.4 (s, 1H), 8.46 (t, 1H), 7.97 (dd, 1H), 7.47 (t, 1H), 7.39-7.35 (m, 2H), 7.18 (d, 1H), 6.80 (s, 1H), 5.29 (d, 1H), 4.13-4.09 (m,2H), 4.04-3.97 (m, 4H), 3.65-3.51 (m, 2H), 3.12-3.02 (m, 3H), 2.84-2.83 (m, 1H), 2.23-1.73 (m, 10H)Example 17: Synthesis of (lS,3R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5- methoxypyrido [4,3-d]pyrimidin-4-yl)amino)cyclopentane-l-carboxamide (Compound 116)Step 1: Synthesis of methyl (lS,3R)-3-((7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-yl)amino)cyclopentane-l -carboxylate

[0163] The title compound was obtained as a pale yellow solid, 210 mg, 98%, from 7- chloro-8-fluoro-5-inethoxy-2-(methylthio)pyrido[4,3-<7]pyrimidin-4-ol (Intermediate 1, step 1) and methyl (lS,3R)-3-aminocyclopcntanc-l-carboxylatc hydrochloride, following the procedure described in Example 1, step 1. LCMS m / z = 401 [M+H]+Step 2: Synthesis of methyl (lS,3R)-3-((8fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((lriisopropylsilyl)elhynyl)naphlhalen-l-yl)-5-melhoxy-2-(melhyllhio)pyrido[4,3-d]pyrimidin-4- yl)amino)cyclopentane-l-carboxylate

[0164] Into a solution of methyl ( I.S'.3 / ?)-3-((7-chloro-8-fluoro-5-mcthoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)cyclopentane-l-carboxylate (225 mg, 0.56 mmol) in dioxane (6 mb) and water (1.5 ml) were added ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (575 mg, 1.12 mmol) and K3PO4 (293 mg, 1.68 mmol) at rt under Nz. The mixture was degassed with N2, cataCXium® A Pd G3 (40.9 mg, 0.06 mmol) was added and the reaction mixture wasirradiated at 100 °C for 2 h. The reaction mixture was fdtered through a pad of Celite®, dried over NazSCh 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 (250 mg, 56.3 %) as a brown gum. LCMS m / z = 752 [M+H]+Step 3: Synthesis of methyl (lS,3R)-3-((8fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2-(methylsulfonyl)pyrido[4,3- d]pyrimidin-4-yl)amino)cyclopentane-l -carboxylate

[0165] Into a stirred solution of methyl (lS,3R)-3-((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-5-methoxy-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)cyclopentane-l-carboxylate (150 mg, 0.20 mmol) in DCM (10 mL) was added mCPBA (73.9 mg, 0.30 mmol) at 0 °C and the reaction mixture was stirred at rt for 1 h. The reaction was quenched with aq. sodium sulfite solution (10 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was dried over NaiSOi. filtered and concentrated under reduced pressure to give the title compound, 150 mg, 58.6%.LCMS m / z = 784 [M+H]+.Step 4: Synthesis of methyl (lS,3R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluomtetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)amino)cyclopentane-l-carboxylate

[0166] The title compound was obtained as a brown liquid, 220 mg, 29.4%, from methyl (lS,37?)-3-((8-fluoro-7-(7-fluoro-3-methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- l-yl)-5-methoxy-2-(methylsulfmyl)pyrido[4,3-J]pyrimidin-4-yl)amino)cyclopentane-l- carboxylate and ((27?,7aA)-2-fluorotetrahydro-lH-pyrrolizin-7a(577)-yl)methanol, following the procedure described in Example 1, step 4. LCMS m / z = 863 [M+H]Step 5: Synthesis of sodium (lS,3R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido [4, 3-d]pyrimidin-4-yl)amino)cyclopentane-l -carboxylate

[0167] Into a stirred solution of methyl (LS',37?)-3-((8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((27?,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5 / 7)-yl)methoxy)-5-methoxypyrido[4,3-<7]pyrimidin-4- yl)amino)cyclopentane-l -carboxylate (170 mg, 0.20 mmol) in EtOH (10 mL) and water (0.5 mL) was added NaOH (8.68 mg, 0.22 mmol) at 0 °C and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 X 10 mL). The combined organic layer was dried over NazSOr. filtered and concentrated underreduced pressure to give the title compound (120 mg, 57.4 %) as a brown solid. LCMS m / z = 849 [M+H]+Step 6: Synthesis of (lS,3R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido [4, 3-d]pyrimidin-4-yl)ammo)cyclopentane-l -carboxamide

[0168] Into a stirred solution of sodium (lS,3. / ?)-3-((8-fhioro-7-(7-fhioro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((27?,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5 / 7)-yl)methoxy)-5-methoxypyrido[4,3-<7]pyrimidin-4- yl)amino)cyclopentane-l-carboxylate (120 mg, 0.14 mmol), BOP (81 mg, 0.18 mmol) and DIPEA (0.07 mL, 0.43 mmol) in THF (5 mL) was added ammonium chloride (22.71 mg, 0.42 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried overNa2SO4, filtered and concentrated under reduced pressure to give the title compound (110 mg, 60.6 %) as a brown liquid. LCMS m / z = 848 [M+H]+Steps 7 and 8: Synthesis of (lS,3R)-3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoro-2-( ( (2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5- melhoxypyrido[4,3-d]pyrimidin-4-yl)amino)cyclopenlane-l-carboxamide formate

[0169] The title compound was obtained as an off-white solid, from (lS,3R)-3-((8-fluoro-7- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)amino)cyclopentane-l-carboxamide, following a similar 2 step procedure to that described in Example 1, steps 5 and 6. The final compound was purified by HPLC Method J. LCMS m / z = 647 [M+H]1. ' H-NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 8.97-8.88 (m, 1H), 7.97 (dd, 1H), 7.51-7.47 (m, 2H), 7.38 (s, 1H), 7.18 (s, 1H), 6.93 (d, 1H), 5.33 (d, 1H), 4.77-4.73 (m, 1H), 4.19-4.07 (m, 2H), 4.00 (s, 3H), 3.28-3.03 (m, 3H), 2.94-2.84 (m, 2H), 2.20-1.78 (m, 13H)Example 18: Synthesis of 4-(5-(difluoromethoxy)-8-fluoro-2-(((2R,7aS)-2- fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 118)Step 1: Synthesis of 5-(allyloxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidm-4-ol

[0170] The title compound was obtained as a solid, 510 mg, crude, from 5,7-dichloro-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(4aH)-one and allyl alcohol, following the procedure described in Intermediate 1, step 1. LCMS m / z = 302 [M+H]+Step 2: Synthesis of 5-(allyloxy)-N-(2-((tert-hutyldiphenylsilyl)oxy)ethyl)-7-chloro-8-fluoro-2- ( methylthio)pyrido[4, 3-d]pyrimidin-4-amine

[0171] The title compound was obtained as an off-white solid, 330 mg, 79%, from 5- (allyloxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-J]pyrimidin-4-ol and 2-(ftert- butyldiphenylsilyl)oxy)ethan-l -amine, following the procedure described in Example 1, step 1. LCMS m / z = 583 [M+H]+Step 3: Synthesis of 4-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-7-chloro-8-fluoro-2- ( methylthio)pyrido[4, 3-d]pyrimidin-5-ol

[0172] Into a stirred solution of 5-(allyloxy)-2V-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-7- chloro-8-fluoro-2-(methylthio)pyrido[4,3-i7]pyrimidin-4-amine (330 mg, 0.61 mmol) in DCM (10 mL) were added phenylsilane (0.22 mL, 1.85 mmol) at 0 °C under N2. The mixture was degassed with N2, then Pd(PPh3)4 (71.3 mg, 0.06 mmol) was added at 0 °C and the reaction mixture was stirred at it for 1 h. The reaction was concentrated under reduced pressure and the crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc inhexane to afford the title compound (210 mg, 62.7%) as an off-white solid. LCMS m / z = 543 [M+H]+Step 4: Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-5-(difluoromethoxy)-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine

[0173] Into a stirred solution of 4-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-7-chloro- 8-fluoro-2-(methylthio)pyrido[4,3-t / ]pyrimidin-5-ol (120 mg, 0.22 mmol) in MeCN (5 mL) were added NazCCh (117 mg, 1.10 mmol) at rt under Nz, the mixture was stirred at 60 °C for 15 mm and (bromodifluoromethyl)trimethylsilane (90 mg, 0.44 mmol) was added at rt. The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexane, to afford the title compound (90 mg, 85 %) as an off- white solid. LCMS m / z = 593 [M+H]+Steps 5 to 9: Synthesis of 4-(4-((2-((tert-butyldiphenylsilyl)oxy)ethyl)amino)-5- (difluoromelhoxy)-8-fluoro-2-(((2R, 7aS)-2-fluorolelrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0174] The title compound was obtained as an off-white solid, from JV-(2-((tert- butyldiphenylsilyl)oxy)ethyl)-7-chloro-5-(difluoromethoxy)-8-fluoro-2-(methyltliio)pyrido[4,3- i / |pyrimidin-4-aminc and ((2-fhioro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane, following a similar 5 step procedure to that described in Example 2, steps 2 to 6. The final compound was purified by HPLC Method N. LCMS m / z = 616 [M+H] 1H (4N00M MRHz, DMSO-d6): δ 10.75 (br s, 1H), 10.24 (s, 1H), 8.14-8.06 (m, 1H), 8.02-7.62 (m, 2H), 7.49 (t, 1H), 7.42 (d, 1H), 7.23 (d, 1H), 5.48 (d, 1H), 5.10-5.09 (m, 1H), 4.47 (br s, 3H), 4.14 (s, 1H), 3.77-3.66 (m, 6H), 3.17-3.12 (m, 1H), 2.42-2.38 (m, 1H), 2.29-1.99 (m, 4H)Example 19: Synthesis of 5-ethynyI-6-fhioro-4-(8-fhioro-2-(((27?,7aS)-2-fluorotetrahydro- lZZ-pyrrolizin-7a(5Z / )-yl)inethoxy)-4-((2-hydioxy-2-methylpropyl)amino)-5- isopropoxypyrido[4,3-i / ]pyriinidin-7-yl)naphthalen-2-ol (Compound 123)Step 1: Synthesis of l-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4-yl)amino)-2-methylpropan-2-ol

[0175] Into a stirred solution of 8-fhroro-7-(7-fhioro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2 / ?,7aS)-2-fluorotetrahydro-l / 7-pyrrolizin- 7a(577)-yl)methoxy)-5-isopropoxypyrido[4,3-<7]pyrimidin-4-ol (Intermediate 4, 90 mg, 0.15 mmol) in MeCN (5 mL) were added DIPEA (96 mg, 0.73 mmol) and phosphonitrilic chloride trimer (77 mg, 0.22 mmol) at 0 °C under Nz. The mixture was stirred at rt for 1 h, then 1-aniino- 2-methylpropan-2-ol (26.4 mg, 0.29 mmol) in MeCN (0.2 mL) was added and the reaction mixture stirred at rt for 1 h. The mixture was suspended in water (10 mL) and extracted with EtOAc (2 x 15 mL). Tire combined organic layer was washed with brine (30 mL), dried over NazSCh, filtered and the filtrate was evaporated under reduced pressure to afford the title compound (110 mg, 74.2 %) as brown foam. LCMS m / z = 836 | M+H |Step 2: Synthesis of 6-fluoro-4-(8fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-4-((2-hydroxy-2-methylpropyl)amirio)-5-isopropoxypyrido[4,3-d]pyrimidin-7-yl)-5- (triisopropylsilyl)ethynyl)naphthalen-2-ol

[0176] Into a stirred solution of l-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2A,7aS)-2-fluorotetrahydro-127-pyrrolizin- 7a(5J7)-yl)methoxy)-5-isopropoxypyrido[4,3-<7]pyrimidin-4-yl)amino)-2-methylpropan-2-ol (100 mg, 0.12 mmol) in dioxane (10 mL) was added HC1 in McOH (1.25 M, 0.29 mL, 0.36 mmol) at 0 °C under N2. The reaction mixture was stirred at 26 °C for 16 h. The reaction mixture was quenched with TEA (0.4 mL) and the pH adjusted to 7~8. The mixture was evaporated under reduced pressure to afford the title compound, (82 mg, 62.4 %) as an off- white solid. LCMS m / z = 792 [M+H]Step 3: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2fhiorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxy-2-methylpropyl)amino)-5-isopropoxypyrido[4,3- d]pyrimidin- 7-yl)naphthalen-2-ol

[0177] Into a solution of 6-fluoro-4-(8-fluoro-2-(2R,7a6)-2-fluorotetrahydro-l / 7-pyrrolizin-7a( 577)-yl)methoxy)-4-((2 -hydroxy-2 -methylpropyl)amino)-5-isopropoxypyrido[4, 3- c / ]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (80 mg, 0.10 mmol) in DMF (2 mL) was added CsF (123 mg, 0,81 mmol) at rt under N2. The reaction mixture was stirred at 70 °C for 6 h. The reaction mixture was fdtered and the fdtrate evaporated under reduced pressure. The crude was purified by prep HPLC Method E to afford the title compound (18 mg, 27.6 %) as an off-white solid. LCMS m / z = 636 [M+H]+ XH-NMR (400 MHz, DMSO-tfo): d 10.23 (m, 1H), 8.56 (t, 1H), 7.96 (dd, 1H), 7.46 (t, 1H), 7.37 (d, 1H), 7.17 (d, 1H), 5.37-5.21 (m, 2H), 5.00 (s, 1H), 4.10-4.08 (m, 2H), 3.98 (dd, 1H), 3.39-3.38 (m, 2H), 3.09-3.01 (m, 3H), 2.86-2.78 (m, 1H), 2.12-1.99 (m, 3H), 1.85-1.75 (m, 3H), 1.36 (dd, 6H), 1.24 (d, 6H)Example 20: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((27?,7a<S)-2-fluorotetrahydro- 177-pyrrolizin-7a(517)-yl)methoxy)-4-((3-hydroxypropyl)amino)-5-isopropoxypyrido[4,3- < / ]pyrimidin-7-yl)naphthalen-2-ol (Compound 120)Step 1: Synthesis of 3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2Rf7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4-yl)amino)propan-l-ol

[0178] Into a stirred solution of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen- 1 -yl)-2-(((2R,7aS)-2-fluorotetrahydro-177-pyrrolizin- 7a(5 / 7)-yl)mcthoxy)-5-isopropoxypyndo[4,3-<7]pynmidin-4-ol (Intermediate d, 110 mg, 0.14 mmol) in MeCN (5 mL) was added DIPEA (0.13 mL, 0.71 mmol) and phosphonitrilic chloride trimer (75.0 mg, 0.22 mmol) at 0 °C . The reaction mixture was stirred at rt for 1 h then 3- aminopropan-l-ol (16.20 mg, 0.22 mmol) was added and the reaction stirred for a further 3 h.The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layer was dried over NazSCh, filtered and concentrated under reduced pressure to give the title compound (130 mg, crude). LCMS m / z = 822 [M+H]+Step 2: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-4-((3-hydroxypropyl)amino)-5-isopropoxypyrido[4,3-d]pyrimidin-7-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0179] Into a stirred solution of3-((8-fluoro-7-(7-fhioro-3-(methoxymethoxy)-8- ((tnisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2A,7aS)-2-fluorotetrahydro-l / 7-pyrrohzin- 7a(577)-yl)methoxy)-5-isopropoxypyrido[4,3-<7]pyrimidin-4-yl)amino)propan-l-ol (130 mg, 0.16 mmol) in dioxane (5 mL) was added HC1 in MeOH (0.63 mL, 0.79 mmol) at 0 °C. Tire reaction mixture was stirred for 16 h at rt, then quenched with TEA (0.4 mL) and the pH of the reaction mixture adjusted to 7-8. The reaction mixture was evaporated under reduced pressure to afford the title compound (130 mg, crude). LCMS m / z = 778 [M+H]+Step 3: Synthesis of 5-elhynyl-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorolelrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((3-hydroxypropyl)amino)-5-isopropoxypyrido[4,3- d ]pyrimidin- 7-yl)naphthalen-2-ol

[0180] Into a stirred solution of 6-fluoro-4-(8-fhioro-2-(((2 / ?.7aS')-2-fluorotctrahydro- 1 / 7- pyrrolizin-7a(577)-yl)methoxy)-4-((3-hydroxypropyl)amino)-5-isopropoxypyrido[4,3- <7]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (130 mg, 0.17 mmol) in DMF (7 mL) was added CsF (381 mg, 2.50 mmol) at rt and the reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was filtered through a sintered funnel and the filtrate concentrated under reduced pressure. The crude was purified by prep-HPLC Method E to give the title compound (15 mg, 14.0 %) as an off-white solid. LCMS m / z = 622 [M+H]11H-NMR (400 MHz, DMSO-<7>): d 10.14 (s, 1H), 8.35 (t, 1H), 7.97 (dd, 1H), 7.46 (t, 1H), 7.38 (d, 1H), 7.17 (d, 1H), 5.39-5.22 (m, 2H), 4.80 (t, 1H), 4.13-4.10 (m, 2H), 4.04-4.00 (m, 1H), 3.72-3.61 (m, 4H), 3.12-3.03 (m, 3H), 2.85-2.83 (m, 1H), 2.14-2.01 (m, 3H), 1.86-1.77 (m, 5H), 1.39-1.35 (m, 6H)Example 21: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(((lr,3S)-3-hydroxycyclobutyl)amino)-5- isopropoxypyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Compound 119)

[0181] The title compound was obtained as an off-white solid, 29 mg, 20%, over 3 steps, from 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)- 2-(((2R,7a5)-2-fluorotetrahydro-177-pyrrolizin-7a(5 / 7)-yl)methoxy)-5-isopropoxypyrido[4,3- c / |pyriniidin-4-ol (Intermediate 4) and (lr,3r)-3-aminocyclobutan-l-ol hydrochloride, following a similar procedure to those described in Example 20. The title compound was purified by HPLC Method D. LCMS m / z = 634 [M-HJ ^-NMR (400 MHz, DMSO-rf,): 3 10.14 (s, 1H), 8.25 (d, 1H), 7.96 (q, 1H), 7.46 (t, 1H), 7.38 (d, 1H), 7.16 (d, 1H), 5.34-5.21 (m, 3H), 4.68-4.60 (m, 1H), 4.40-4.38 (m, 1H), 4.10 (t, 2H), 4.03-3.98 (m, 1H), 3.10-3.01 (m, 3H), 2.85-2.79 (m, 1H), 2.38-2.26 (m, 4H), 2.12 (s, 1H), 2.06-1.98 (m, 2H), 1.85-1.76 (m, 3H), 1.40 (dd, 6H)Example 22: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-4-(((ls,3R)-3-hydroxycyclobutyl)amino)-5- isopropoxypyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Compound 121)

[0182] The title compound was obtained as an off-white solid, 28 mg, 7.6%, from 8-fluoro- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2 / ?,7aS)-2- fluorotetrahydro- 17 / -pyrrolizin-7a(5H)-yl )methoxy )-5-isopropoxypyrido|4.3-J|pynmidin-4-ol (Intermediate 4) and (lx,3x)-3-aminocyclobutan-l-ol hydrochloride, following a similar 3 step procedure to that described in Example 20, except HPLC Method I was used. LCMS m / z = 634 [M+H]+1H NMR (400 MHz, DMSO-t / d): 3 10.15 (s, 1H), 8.20-8.18 (m, 1H), 7.97 (dd, 1H), 7.47 (t, 1H), 7.38 (d, 1H), 7.17 (d, 1H), 5.36-5.24 (m, 3H), 4.18-3.98 (m, 5H), 3.13-3.05 (m, 3H), 2.88-2.78 (m, 3H), 2.14-2.02 (m, 3H), 1 .88-1.79 (m, 5H), 1 .41 (dd, 6H)Example 23: Synthesis of 5-ethynyl-6-fhioro-4-(8-fluoro-2-(((27?,7aiS)-2-fluorotetrahydro- l / / -pyrrolizin-7a(5 / / )-yl)mcthoxy)-4-(((l-hydroxycyclopropyl)mcthyl)amino)-5- isopropoxypyrido[4,3-iZ]pyriinidin-7-yl)naphthalen-2-ol (Compound 122)Step 1: Synthesis of l-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4-yl)amino)methyl)cyclopropan-l-ol

[0183] Into a stirred solution of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen- 1 -yl)-2-(((2 / ?.7aS)-2-fluorotctrahydro- 177-pyrrolizin- 7a(577)-yl)methoxy)-5-isopropoxypyrido[4,3-<7]pyrimidin-4-ol (Intermediate 4, 100 mg, 0.13 mmol) in DMA (5 mL) was added DIPEA (84 mg, 0.65 mmol) and HATU (99 mg, 026 mmol) and the mixture stirred at rt for 1 h. l-(Aminomethyl)cyclopropan-l-ol (56.9 mg, 0.65 mmol) was added and the reaction mixture stirred at rt for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL), tire combined organic phase was washed with brine, dried over NazSCh and concentrated in vacuo. The crude was purified by silica gel column chromatography using a gradient of 0-15 % MeOH / DCM, to give the title compound (30 mg, 27.2 %). LCMS m / z = 834 [M+H]+Step 2: Synthesis of 6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)~ yl) methoxy)-4-( ((1 -hydroxycyclopropyl) methyl)amino)-5-isopropoxypyrido[4, 3-d]pyrimidin-7- yl)-5-((tnisopropylsilyl)ethynyl)naphthalen-2-ol

[0184] Into a stirred solution of l-(((8-fhioro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2A,7a5)-2-fluorotetrahydro-177-pyrrolizin- 7a(5 / 7)-yl)methoxy)-5-isopropoxypyrido[4,3-fr]pyrimidin-4-yl)amino)methyl)cyclopropan-l-ol (30 mg, 0.04 mmol) in MeCN (3 ml) was added HC1 in IPA (0,02 mL, 0,11 mmol) at 0 °C and the reaction mixture stirred at rt for 1 h. The reaction mixture was quenched with TEA (0.4 mL) and the pH of the reaction mixture was adjusted to 7-8. The mixture was concentrated under reduced pressure to afford the title compound (26 mg, 82%). LCMS m / z = 790 [M+H]+Step 3: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-(((l-hydroxycyclopropyl)methyl)amino)-5- isopropoxypyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0185] The title compound was obtained as an off-white solid, 3.88 mg, 21.5%, from 6- fluoro-4-(8-fluoro-2-(((2 / ?.7aS)-2-fluorotctrahydro-l / / -pyrrolizin-7a(5 / / )-yl)mcthoxy)-4-((( I- hydroxy cyclopropyl)methyl)amino)-5-isopropoxypyrido[4,3-fr]pyrimidin-7-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol, following a similar procedure to that described in Example 20, step 3, except HPLC Method D was used. LCMS m / z = 634 [M I H] 1H NMR (400 MHz, DMSO-dfi): J 10.18 (br s, 1H), 8.57 (t, 1H), 7.97 (dd, 1H), 7.47 (t, 1H), 7.38 (d, 1H), 7.17 (d, 1H), 5.64 (s, 1H), 5.35-5.21 (m, 2H), 4.12-4.08 (m, 2H), 4.01-3.98 (m, 1H), 3.67-3.56 (m, 2H), 3.10-3.02 (m, 3H), 2.84-2.82 (m, 1H), 2.13-2.00 (m, 3H), 1.85-1.76 (m, 3H), 1.41-1.36 (m, 6H), 0.73-0.64 (m, 4H)Example 24: Synthesis of 4-(4-((l-(2-aminopyridin-3-yl)ethyl)amino)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 129)

[0186] The title compound was obtained as an off-white solid, from 8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5 / 7)-yl)methoxy)-5-isopropoxypyrido[4,3-< / ]pyrimidin-4-ol (Intermediate 4) and 3-(l-aminoethyl)pyridin-2-amine, following a similar procedure to that described in Example 20, steps 1 to 3. LCMS m / z = 684 [M+H]+. 1H-NMR (400 MHz, DMSO-c / s): <5 10.15 (s, 1H), 8.34 (t, 1H), 8.00-7 86 (m, 2H), 7.54-741 (m, 2H), 7.38 (d, 1H), 7.16 (d, 1H), 6.63-6.53 (m, 1H), 6.01-5.99 (m, 2H), 5.36-5.31 (m, 3H), 4.15-3.98 (m, 3H), 3.08- 2.95 (m, 3H), 2.82-2.78 (m, 1H), 2.01-1.91 (m, 3H), 1.84-1.73 (m, 3H), 1.57 (t, 3H), 1.39-1.31 (m, 6H)Example 25: Synthesis of 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-methoxypyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Compound 131)Step 1: Synthesis ofN-(2-((tert-butyldimethylsifyl)oxy)ethyl)-7-chloro-8-fluoro-5-methoxy-2- (methylsulfmyl)pyrido[4,3-d]pyrimidin-4-amine

[0187] Into a stirred solution of A-(2-((tert-butyldimethylsilyl)oxy)etlryl)-7-chloro-8-fluoro- 5-methoxy-2-(methylthio)pyrido[4,3-J]pyrimidin-4-amine (470 mg, 1.08 mmol) in DCM (10 mL) was added mCPBA (365 mg, 1.63 mmol) at 0 °C under N2 and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with sat. sodium sulfite solution (10 mL) and extracted with EtOAc (2x 30 mL). The combined organic layer was washed with 10% aqueous NaHCCh solution (10 mL), dried over anhydrous Na2SOr and concentrated under reduced pressure to afford the title compound, (400 mg, 82 %) as an off-white solid. LCMS m / z = 449 [M+H]+Step 2: Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4, 3-d]pyrimidin-4-amine

[0188] Into a stirred solution of A-(2-((terr-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro- 5-methoxy-2-(methylsulfinyl)pyrido[4,3-c / ]pyrimidin-4-amine (400 mg, 0.89 mmol) in toluene (10 mL) were added ((27?.7aS')-2-fluorotetrahydro- l7 / -pyrrolizin-7a(5 / / )-yl)mcthanol (284 mg, 1.78 mmol) and NaOtBu (257 mg, 2.67 mmol) at 0 °C under N2 and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (5 mL), extracted with EtOAc (3 x 10 mL), the combined organic layer w as dried over Na2SOr, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in DCM, to afford the title compound (260 mg, 45.3 %) as an off -white solid. LCMS m / z = 545 [M+H]+Step 3: Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(8-chloro-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine

[0189] Into a solution of A-(2-((tert-butyldimethylsilyl )oxy )ethyl )-7-chloro-8-fluoro-2- ( ( ( 27? .7 aS) -2 -fluorotetrahydro- 177-pyrrolizin-7a(577)-yl)methoxy) -5 -methoxypyrido [4,3 - i / |pyrimidin-4-aminc (40 mg, 0.073 mmol) in dioxane (1.6 mL) and water (0.4 mL) were added 2-(8-chloro-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3-dioxolane (24 4 mg, 0.06 mmol) and K3PO4 (28.1 mg, 0.13 mmol) at rt under N2. Tire reaction mixture was degassed with N2, then cataCXium® A Pd G3 (3.24 pl, 4.41 umol) was added. The reaction mixture was irradiated in a micro wave reactor at 100 °C for 2 h. The cooled mixture was diluted with water (5 mL), extracted with EtOAc (2 x 20 mL), the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel columnchromatography using a gradient of 0-100% MeOH in DCM, to afford the title compound (30 mg, 62.6 %) as a pale yellow solid. LCMS m / z = 748 [M+H]+Step 4: Synthesis of 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-methoxypyrido[4, 3-d]pyrimidin-7- yl)naphthalen-2-ol

[0190] Into a stirred solution of A-(2-((torr-butyldimethylsilyl)oxy)ethyl)-7-(8-chloro-7- fluoro-3-(methoxymethoxy)naphthalen- 1 -y 1 )-8 -fl uoro-2-(((2 / ?.7a.S')-2-fl uorotetrahyd ro- IH- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyndo[4,3-<7]pyrimidin-4-amine (30.0 mg, 0.04 mmol) in dioxane (3 mL) was added 1.25 M HC1 in MeOH (0.54 mL, 0.67 mmol) at rt under N2. The reaction mixture was stirred at 25 °C for 12 h. Hie reaction was quenched with TEA (0.3 mL) and the pH of the mixture was adjusted to 7-8, then concentrated under reduced pressure. The crude was purified by prep-HPLC Method D to give the title compound (5.7 mg, 24.0 %) as an off-white solid. LCMS m / z = 590 [M+H]+1H-NMR (400 MHz, DMSO-tL) <5 10.27 (s, 1H), 8.41 (s, 1H), 7.94 (dd, 1H), 7.57 (t, 1H), 7.43 (d, 1H), 7.22 (d, 1H), 5.28 (d, 1H), 4.98-4.95 (m, 1H), 4.11 (dd, 1H), 4.03-4.01 (m, 1H), 3.97 (s, 3H), 3.67 (s, 4H), 3.14-3.08 (m, 2H), 3.02 (s, 1H), 2.86-2.80 (m, 1H) 2.14-2.01 (m, 3H), 1.91-1.77 (m, 3H)Example 26: Synthesis of 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-isopropoxypyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-ol (Compound 124)Step 1: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(8-chloro-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-isopropoxypyrido[4, 3-d ]pyrimidin-4-amine

[0191] The title compound was obtained as a brown gum, 70 mg, 89%, from N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4-amine (Intermediate 2) and 2-(8- chloro-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane, following the procedure described in Example 17, step 2. LCMS m / z = 776 [M+H]+Step 2: Synthesis of 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)-5-isopropoxypyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-ol

[0192] The title compound was obtained, 25.3 mg, from JV-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-(8-chloro-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- fliioro-2-(((2 / ?.7a.S')-2-fliiorotctrahydro- l / V-pyrrolizin-7a(5H)-yl)mcthoxy)-5- isopropoxypyndo|4.3-J|pynmidin-4-aminc. following a similar procedure to that described in Example 25, step 4, except HPLC Method E was used. LCMS m / z = 618 [M+H]+'H-NMR (400 MHz, DMSO-c / fi): <5 10.26 (s, 1H), 8.48 (t, 1H), 7.94 (dd, 1H), 7.57 (t, 1H), 7.42 (d, 1H), 7.21 (d, 1H), 5.34-5.31 (m, 2H), 5.06 (t, 1H), 4.13-4.10 (m, 1H), 4.03-4.01 (m, 1H), 3.70-3.63 (m, 4H), 3.11-3.02 (m, 3H), 2.87-2.81 (m, 1H), 2.13-2.00 (m, 3H), 1.85-1.77 (m, 3H), 1.42-1.35 (m, 6H)Example 27: Synthesis of 2-((7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin- 4-yl)amino)ethan-l-ol (Compound 133)Step I : Synthesis of N-(2-(tert-butyldimethylsilyl)oxy)ethyl)- 7-chloro-5-cyclopropoxy-8-ftuoro- 2-(methylsulfinyl)pyrido[4, 3-d]pyrimidin-4-amine

[0193] The title compound was obtained, 200 mg, 89%, from N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-chloro-5-cyclopropoxy-8-fluoro-2-(methylthio)pyrido[4,3- t / |pvrimidin-4-aminc. following the procedure described in Intermediate 1, step 3. LCMS m / z =475 |M+H|Steps 2 to 4: Synthesis of 2-((7-(5f -dimethyl- lH-indazol-4-yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4- yl)amlno)ethan-l-ol

[0194] The title compound was obtained as an off-white solid, from ((2 / ?.7aS)-2- fluorotetrahydro- 177-pyrrolizin-7a(5 / 7)-yl)methanol and N-(2-(ftert- butyldimethylsilyl)oxy)ethyl)-7-chloro-5-cyclopropoxy-8-fluoro-2-(methylsulfinyl)pyrido[4,3- J|pynnndin-4-aminc. following a similar 3 step procedure to that described in Example 25, steps 2 to 4. The title compound was purified by HPLC Method F. LCMS m / z = 616 [M+H]+1H NMR (400 MHz, DMSO-ck): δ 10.28 (s, 1H), 8.16 (t, 1H), 7.94 (dd, 1H), 7.57 (t, 1H), 7.43 (d, 1H), 7.24 (d, 1H), 5.28 (d, 1H), 5.07 (t, 1H), 4.43-4.41 (m, 1H), 4.13-4.10 (m, 1H), 4.03-4.00 (m, 1H), 3.68-3.61 (m, 4H), 3.10-3.08 (m, 2H), 3.01 (s, 1H), 2.86-2.80 (m, 1H), 2.12-2.12 (m, 1H), 2.05-2.00 (m, 2H), 1.79-1.76 (m, 3H), 0.89-0.86 (m, 2H), 0.75-0.72 (m, 2H)Example 28: Synthesis of 4-(5-cyclopropoxy-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)pyrido[4,3-d]pyrimidin-7-yl)-6- fluoronaphthalen-2-ol (Compound 132)Step 1: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-cyclopropoxy-8-fluoro-7-(7- fluoro-3-(methoxymethoxy)naphthalen-l-yl)-2-( ( (2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4.3-d]pyrimidin-4-amine

[0195] The title compound was obtained as an off-white foam, 60 mg, 72.4%, from N-(2- ((tcrt-butyldimcthylsilyl)oxy)cthyl)-7-chloro-5-cyclopropoxy-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine (Example 27, step 3) and 2-(7-fhioro-3-(rnethoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetrarnethyl-l,3,2- dioxaborolane (Intermediate 5), following the procedure described in Example 1, step 2.LCMS m / z = 740 [M+H]+Step 2: Synthesis of 4-(5-cy>clopropoxy-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-4-((2-hydroxyethyl)amino)pyrido[4,3-d]pyrimidin-7-yl)-6- fluoronaphthalen-2-ol

[0196] The title compound was obtained as an off-white solid, 18 mg, 34.7%, from JV-(2- ((tert-butyldimethylsilyl)oxy)ethyl)-5-cyclopropoxy-8-fluoro-7-(7-fluoro-3-(methoxymethoxy )naphthalen- 1 -yl )-2-(((2 / ?,7a5)-2-fluorotetrahydro- 17 / -pyrrolizin-7a(5 / / )- yl)methoxy)pyrido[4,3-d]pyrimidin-4-amine, following a similar procedure to that described in Example 25, step 2, except HPLC Method E was used. LCMS m / z = 582 [M+EI]+1H-NMR (400 MHz, DMS0-<4): d 10.00 (s, 1H), 8.16 (t, 1H), 7.90 (dd, 1H), 7.54 (d, 1H), 7.41-7.34 (m. 3H), 5.28 (d, 1H), 5.08 (t, 1H), 4.46-4.44 (m, 1H), 4.14 (d, 1H), 4.04 (d, 1H), 3.67-3.63 (m, 4H), 3.11-3.08 (m, 2H), 3.02 (s, 1H), 2.85-2.80 (m, 1H), 2.14-2.13 (m, 1H), 2.06-2.01 (m, 2H), 1.86-1.77 (m, 3H), 0.96-0.92 (m, 2H), 0.80-0.78 (m, 2H)Example 29: Synthesis of 2-((7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-(((27?,7aA)-2- fluorotetrahydro-l / / -pyrrolizin-7a(5 / / )-yl)methoxy)-5-methoxypyrido[4,3-< / |pyrimidin-4- yl)amino)ethan-l-ol (Compound 125)

[0197] The title compound was obtained as an off-white solid, 24 mg, 32.7%, from N-(2- (( / er / -butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-2-(((27?,7aS)-2-fluorotetrahydro-lH- pyrrolizm-7a(5 / / )-yl)mcthoxy)-5-mcthoxypyndo[4,3-c / ]pynmidin-4-aminc (Example 25, step 2) and 5,6-dimethyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)- 1 / / -indazole (Intermediate 6) following a similar 2 step procedure to that described in Example 25, steps 3 and 4, except the final compound was purified by prep-HPLC Method D. LCMS m / z = 540 [M+H]+1H-NMR (400 MHz, DMSO-J<s): δ 12.95 (s, 1H), 8.42-8.40 (m, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 5.28 (d, 1H), 4.97 (t, 1H), 4.13 (dd, 1H), 4.05-4.01 (m, 4H), 3.67 (s, 4H), 3.11-3.02 (m, 3H), 2.86-2.80 (m, 1H), 2.44 (s, 3H), 2.16-2.13 (m, 4H), 2.06-2.01 (m, 2H), 1.86-1.80 (m, 3H).Example 30: Synthesis of 2-((7-(5-cyclopropyl-6-methyl-lH-indazol-4-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-4-yl)amino)ethan-l-ol (Compound 130)Step 1: Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(5-cyclopropyl-6-methyl-l- ( tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4, 3-d]pyrimidin-4-amine

[0198] Into a stirred solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-4-amine (Example 25, step 2, 45 mg, 0.08 mmol) in dioxane (2 mL) and water (0.5 mL) was added 5-cyclopropyl-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetrametliyl- L3,2-dioxaborolan-2-yl)-lH-indazole (Intermediate 7, 47.4 mg, 0.12 mmol) and K3PO4 (43.9 mg, 0.207 mmol). The mixture was degassed with N2 and cataCXium® A Pd G3 (6.02 mg, 8.27 pmol) was added. The reaction mixture was irradiated under microwave at 110 °C for 1 h. The reaction mixture was diluted with EtOAc (20 mL), filtered through Celite®, washing through with EtOAc (20 mL). The combined filtrate was washed with water (2 x 20 mL), dried over NazSOr. filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 3 - 5 % of MeOH in DCM to obtain the title compound (30 mg, 16.0 %) as a yellow gum. LCMS m / z = 764 [M+H]+Step 2: Synthesis of 2-((7-(5-cyclopropyl-6-methyl-lH-indazol-4-yl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)amino)ethan-l-ol

[0199] The title compound was obtained as a white solid, 15.3 mg, 29.2%, from N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7 -(5-cyclopropyl-6-methyl- 1 -(tetrahydro-2H-pyran-2-yl)- 1H- indazol-4-yl)-8-fhroro-2-(((2R,7aS)-2-fhrorotetrahydro-lH-pyrrolizin-7a(5EI)-yl)methoxy)-5- methoxypyrido[4,3-d]pyrimidin-4-amine, following the procedure described in Example 25, step 4. The title compound was purified by HPLC method E. LCMS m / z = 577 [M+H]+1H- NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.43 (s, 1H), 7.78 (s, 1H), 7.45 (s, 1H), 5.28 (d,1H), 4.99 (s, 1H), 4.14-4.10 (m, 1H), 4.05-4.02 (m, 4H), 3.68-3.67 (m, 4H), 3.11-3.02 (m, 3H), 2.84-2.82 (m, 1H), 2.60 (s, 3H), 2.18-1.74 (m, 7H), 0.80-0.78 (m, 1H), 0.59-0.51 (m, 1H), 0.09- 0.08 (m, 1H). 0.01-0,01 (m, 1H)Example 31: Synthesis of 2-((7-(5,6-dimethyl-lH-indazol-4-yl)-8-fliioro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin- 4-yl)amino)ethan-l-ol (Compound 127)Step 1: Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(5, 6-dimethyl-l -(tetrahydro-2H- pyran-2-yl)-lH-indazol-4-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4-amine

[0200] Into a stirred solution of / V-(2-(( / c77-butyldimcth\ lsilyl)oxy)cthyl)-7-chloro-8-fliioro- 2-(((27?,7aS)-2-fluorotetraliydro-l / f-pyrrolizin-7a(5 / / )-yl)methoxy)-5-isopropoxypyrido[4,3- <7]pynmidin-4-aminc (Intermediate 2, 70 mg, 0.12 mmol) in dioxane (6 mL) and water (1.5 mL) were added 5,6-dimethyl- l-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaboroIan-2-yl)-177-indazole (Intermediate 6, 65.4 mg, 0.18 mmol) and K3PO4 (78 mg, 0.36 mmol). The reaction mixture was purged with N2 for 10 min, then cataCXium® A Pd G3 (8.9 mg, 0.01 pmol) was added and the reaction heated at 100 °C for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure to give the title compound (98 mg, crude). LCMS m / z = 766 [M+H]+Step 2: Synthesis of 2-((7-(5,6-dimethyl-lH-indazol-4-yl)-8-fluoro-2-(((2R, 7aS)-2- fhiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4- yl)amino)ethan-l-ol

[0201] The title compound was obtained as an off-white solid, 10.7 mg, 14.6%, from N-(2- ((tert-buty Idimethyl silyl)oxy)ethyl)-7-(5,6-dimethyl- 1 -(tctrahydro-2 / / -pyran-2-yl )- 1 / / -indazol- 4-yl)-8-fluoro-2-(((27?,7a5)-2 -fluorotetrahydro- lH-pyrrolizin-7a(527)-yl)methoxy)-5- isopropoxypyrido|4.3-i / |pyrimidin-4-aminc. following a similar procedure to that described in Example 25, step 4, except HPLC Method M was used. LCMS m / z = 569 [M+H]+'I I-NMR (400 MHz, DMS0-<4): d 12.99 (br s, 1H), 10.78 (br s, 1H), 8.63-8.62 (m. 1H), 7.63 (s, 1H), 7.48 (s, 2H), 5.58 (d, 1H), 5.41-5.36 (m, 1H), 4.60 (q, 2H), 3.88-3.67 (m, 7H), 3.32-3.30 (m, 2H), 2.58-2.57 (m, 1H), 2.45 (s, 3H), 2.34-2.32 (m, 1H), 2.20-2.14 (m, 4H), 2.10-2.01 (m, 1H), 1.43-1.39 (m, 6H)Example 32: Synthesis of 2-((7-(5-cyclopropyl-6-methyl-lH-indazol-4-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3- d]pyrimidin-4-yl)amino)ethan-l-ol (Compound 126)Step 1: Synthesis ofN-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(5-cyclopropyl-6-methyl-l-( tetrahydro-2H-pyran-2-yl)-lH-indazol-4-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyrido[4,3-d]pyrimidin-4-amine

[0202] Into a stirred solution of JV-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8- fluoro-2-(((2 / ?.7aS)-2 -fluorotetrahydro- lH-pyrrolizin-7a(577)-yl)methoxy)-5- isopropoxypyrido[4.3-<7]pyrimidin-4-amine (Intermediate 2, 60 mg, 0. 10 mmol) in dioxane (3 mb) and water (0.5 mL) was added 5-cyclopropyl-6-methyl-l-(tetrahydro-277-pyran-2-yl)-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole (Intermediate 7, 80 mg, 0.15 mmol). Tire mixture was degassed with N2 for 5 min, then K3PO4 (111 mg, 0.52 mmol) and S-Phos-Pd- G3 (16.36 mg, 0.02 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 4 h. The reaction mixture was diluted with EtOAc (20 mL), filtered through Celite®, and washed with EtOAc (20 mL). The combined filtrate was washed with water (2 x 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, using a gradient of 0- 8 %of MeOH in DCM, to obtain the title compound (40 mg, 25.3 %) as a yellow gum. LCMS m / z = 793 |M 1 11|Step 2: Synthesis of 2-((7-(5-cyclopropyl-6-methyl-lH-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxypyndo[4, 3-d]pyrimidin-4- yl)amino)ethan-l-ol

[0203] The title compound was obtained, 3.3 mg, 10.5%, from N-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-(5-cyclopropyl-6-methyl- 1 -(tetrahydro-2H-pyran-2-yl)-lH- indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5- isopropoxypyrido[4,3-d]pyrimidin-4-amine, following the a similar procedure to that described in Example 25, step 4. LCMS m / z = 594 [M+H]+1H-NMR (400 MHz, DMSO-d6): 3 12.98 (s, 1H), 8.50 (t, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 5.40-5.36 (m, 2H), 5.07 (t, 1H), 4.13-4.11 (m, 1H), 4.05-4.04 (m, 1H), 3.71-3.65 (m, 4H), 3.11-3.08 (m, 2H), 3.02 (s, 1H), 2.86-2.80 (m, 1H), 2.60 (s, 3H), 2.15-1.74 (m, 7H), 1.44 (d, 3H), 1.37 (d, 3H), 0.79-0.74 (m, 1H), 0.60-0.55 (m, 1H), 0.14-0.08 (m, 1H), 0.05-0.02 (m, 1H)Example 33: Synthesis of 2-((8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-isopropoxy-7-(6-methyl-5-(trifluoromethyl)-lH-indazol-4- yl)pyrido[4,3-d]pyrimidin-4-yl)amino)ethan-l-ol (Compound 128)Step 1: Synthesis of 2-bromo-6-fluoro-3-iodo-4-methylbenzaldehyde

[0204] Into a stirred solution of l-bromo-5-fluoro-2-iodo-3 -methylbenzene (5 g, 15.88 mmol) in THF (10 mL) was added LDA (9.53 mL, 19.05 mmol) drop wise at -78 °C and the mixture stirred for 30 min. Ethyl formate (1.29 g, 17.46 mmol) was added and the reaction mixture was stirred at -78 °C for 15 min. The reaction was quenched with aq. NHrCl (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over NaiSOi.filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 0-30% EtOAc in n-hexane, to afford the title compound (4.8 g, 86 %). 1H-NMR (400 MHz, DMSO-t / e): b 10.04 (s, 1H), 7.52 (d, 1H), 2.58 (s, 3H),Step 2: Synthesis of bromo-5-lodo-6-methyl-lH-tndazole

[0205] Into a stirred solution of 2-bromo-6-fluoro-3-iodo-4-methylbenzaldehyde (4 g, 11.66 mmol) in DMSO (20 mb) was added hydrazine monohydrate (5.83 mL, 70 mmol) at 25 °C and the reaction mixture was heated to 60 °C and stirred for 16 h. Ice cold water was added to the reaction, the mixture stirred for 10 mm, the precipitated solids were filtered and dried under high vacuum to obtain the title compound (3.2 g, 81 %) as a white solid. LCMS m / z = 339 [M+H]+Step 3: Synthesis of 4-bromo-5-iodo-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole

[0206] Into a stirred solution of 4-bromo-5-iodo-6-methyl-lH-indazole (1.5 g, 4.45 mmol) in THF (15 mL) was added 4-methylbenzenesulfonic acid (0.15 g, 0.89 mmol) and 3,4-dihydro- 2H-pyran (0.74 g, 8.90 mmol) at rt. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The cmde was purified by silica gel column chromatography using a gradient of 0-30% EtOAc in n-Hexane, to alford the title compound (1.9 g, 93 %) as an off-white solid. LCMS m / z = 423 [M+H]+Step 4: Synthesis of 4-bromo-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-lH- indazole

[0207] Into a solution of 4-bromo-5-iodo-6-methyl-l -(tetrahydro-2H-pyran-2-yl)- 1H- indazole (1 g, 2.37 mmol) in NMP (6 mL) was added copper(I) iodide (1.35 g, 7.12 mmol) and methyl 2,2-difluoro-2-(fluorosulfbnyl) acetate (2.28 g, 11.87 mmol) under N2 and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 100 mL). Hie combined organic layer was dried overNa AOi and concentrated under reduced pressure. The cmde was purified by silica gel column chromatography using a gradient of 0-30% EtOAc in n-hexane, to afford the title compound (550 mg, 32.5 %) as colorless liquid. LCMS m / z = 363 [M+H]+Step 5: Synthesis of 6-methyl- l-(tetrahydro-2H-pyran-2-yl)-4-(4, 4,5 , 5-tetram.ethyl-l ,3 ,2- dioxaborolan-2-yl)-5-(trifluoromethyl)-lH-indazole

[0208] Into a stirred solution of 4-bromo-6-methyl-l-(tetrahydro-2H-pyran-2-yl)-5-( trifl uoromethy 1 )- 177-indazolc (400 mg, 1.10 mmol) in dioxane (8 mL) was added bis(pinacolato)diboron (418 mg, 1 65 mmol) and KOAc (270 mg, 2.75 mmol) at rt. The reactionmixture was purged with N2 for 10 min, PdC12(dppf).DCM (161 mg, 0.22 mmol) was added and the reaction stirred at 90 °C for 16 h. The cooled reaction mixture was concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 0-30% EtOAc in n-Hexane, to afford the title compound (250 mg, 33.2 %) as sticky solid. LCMS m / z = 411 [M+H]+Step 6: Synthesis ofN-(2-((tert-hutyldimethylsilyl)oxy)ethyl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-isopropoxy-7-(6-methyl-l-(tetrahydro- 2H-pyran-2-yl)-5-(trifluoromethyl)-lH-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-amine

[0209] Into a stirred solution of 6-mcthyl-l -(tctrahydro-2 / / -pyran-2-yl)-4-(4.4,5,5- tctramcthyl- 1 .3.2-dioxaborolan-2-yl)-5-(trifluoromcthyl)-l / 7-indazolc (35.8 mg, 0.08 mmol) and jV-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-8-fluoro-2-(((2A,7a5)-2- fluorotetrahydro-177-pyrrolizin-7a(577)-yl)methoxy)-5-isopropoxypyrido[4,3-<7]pyrimidin-4- amine (Intermediate 2, 50 mg, 0.08 mmol) in dioxane (0.8 mL) and water (0.1 mL) was added K3PO4 (18.55 mg, 0.08 mmol). The mixture was purged with N2 for 5 min and SPhos Pd G3 ( 14.79 mg, 0.02 mmol) was added. The reaction mixture was stirred for 16 h at 100 °C. The cooled reaction mixture was filtered through Celite®, washed with DCM and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel column chromatography using a gradient of 0-20% MeOH in DCM, to afford the title compound (30 mg, 12.1 %) as light brown solid. LCMS m / z = 820 [M+H]"Step 7: Synthesis of 2-((8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-isopropoxy-7-(6-methyl-5-(trifluoromethyl)-lH-indazol-4-yl)pyrido[4,3- d ]pyrimidin-4-yl)amino)ethan-l -ol

[0210] Into a stirred solution of / V-(2-(( / m-butyldmicthylsilyl)oxy)ethyl)-8-fluoro-2- (((27?,7aS)-2-fluorotetrahydro-177-pyrrolizin-7a(577)-yl)methoxy)-5-isopropoxy-7-(6-methyl-l- (to trahydro-2 / / -pyran-2-yl)-5-(tri fluoromethyl)- 1 / / -indazol-4-yl)pyrido|4.3-c / |pyrimidin-4- amine (25 mg, 0.03 mmol) in dioxane (1.5 mL) was added HC1 in MeOH (1.25 M, 0.12 mL, 0.15 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 6 h. The reaction mixture was concentrated under reduced pressure and the crude was purified by preparative HPLC Method E to give the title compound, as off-white solid. LCMS m / z = 622 [M+H]+. 1H-NMR (400 MHz, DMSO-tfe): d 13.51 (s, 1H), 8.48 (t, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 5.31-5.28 (m, 2H), 5.09 (t, 1H), 4.12 (d, 1H), 4.03 (d, 1H), 3.70-3.67 (m, 3H), 3.10-3.08 (m, 2H), 3.01 (s, 1H), 2.83-2 82 (m, 1H), 2.65-2.65 (m, 3H), 2.13-1.99 (m, 4H), 1.85-1.76 (m, 3H), 1.37 (d, 6H)Example 34: Synthesis of 4-(4-(((lR,3S)-3-(5-aminoisoxazol-3-yl)cyclopentyl)amino)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5- methoxypyrido [4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 134)Step 1: Synthesis of 3-((lS,3R)-3-((8-fl.uoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)amino)cyclopentyl)isoxazol-5- amine

[0211] Into a stirred solution of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)cthynyl)naphthalcn-l-yl)-2-(((2R,7aS)-2-fluorotctrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-dlpyrimidin-4-ol (Intermediate 1, 50 mg, 0.05 mmol) in MeCN (3 mL) was added DIPEA (0.04 mL, 0.27 mmol) followed by phosphonitrilic chloride trimer (37.7 mg, 0.10 mmol) at 0 °C. The reaction mixture was allowed to stir at 25 °C for 1 h. 3-((lS,3R)-3-aminocyclopentyl)isoxazol-5-amine (Intermediate 9, 30.4 mg, 0.10 mmol) dissolved in MeCN (0.5 mL) was added at 0 °C. The resulting reaction mixture was stirred at 25 °C for 3 h. the reaction mixture was concentrated under reduced pressure and the crude was purified by silica gel chromatography using a gradient of 0-20% MeOH / DCM, to afford the title compound, 60 mg, 92 % as a light brown gum. LCMS m / z = 884 |M-H|Step 2: Synthesis of 4-(4-(((lR,3S)-3-(5-aminoisoxazol-3-yl)cyclopentyl)amino)-8-fluoro-2- (((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0212] Into a stirred solution of 3-((lS,3R)-3-((8-fluoro-7-(7-fhioro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)amino)cyclopentyl)isoxazol-5-amine (30 mg, 0.03 mmol) in DCM (2 mL) was added TFA (0.02 ml, 0.33 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 6 h. The reaction mixture was quenched with TEA (0.4 mL) and the pH of the reaction mixture was adjusted to 7-8. The reaction mixture was concentrated under reduced pressure to afford the title compound (80 mg, 61.7 %) as a brown gum. LCMS m / z = 842 [M+H]+Step 3: Synthesis of 4-(4-(((lR,3S)-3-(5-aminoisoxazol-3-yl)cyclopentyl)amino)-8-fluoro-2- (((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4, 3- djpyrimidin- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0213] Into a stirred solution of 4-(4-(((lR,3S)-3-(5-aminoisoxazol-3- yl)cyclopentyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (150 mg, 0.04 mmol) in DMF (3 mL) was added CsF (211 mg, 1.38 mmol) and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through Cclitc® and washed with McCN (10 mL). The filtrate was concentrated under reduced pressure and the crude was purified by preparative HPLC Method D to give the title compound, 0.9 mg, 2.71 % as an off-white solid. LCMS m / z = 686 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): S 10. 19 (s, 1H), 8.39-8.33 (m, 1H), 7.99-7.94 (m, 1H), 7.46 (t, 1H), 7.38 (d, 1H), 7.18 (s, 1H), 6.57 (d, 2H), 5.75 (s, 1H), 5.36-5.23 (m, 1H), 4.92 (d, 1H), 4.78-4.73 (m, 1H), 4.12-4.00 (m, 5H), 3.12-3.06 (m, 4H), 2.86-2.82 (m, 1H), 2.42-2.37 (m, 1H), 2.22-1.75 (m, 11H).Example 35: Synthesis of 4-(4-(((lR,3S)-3-(difluoromethyl)cyclopentyl)amino)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 135)Step I: Synthesis of ((1 S,3R)-3-aminocyclopentyl)methanol hydrochloride

[0214] Into a stirred solution of tert-butyl (( 17?,3>.S)-3- (hydroxymethyl)cyclopentyl)carbamate (100 mg, 0.46 mmol) in DCM (8 mL) was added 4 M HC1 in dioxane (0.58 mL, 2.32 mmol) dropwise at 0 °C under N2 and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was washed with hexane to afford the title compound, 69 mg, 98 %, as a colorless solid. LCMS m / z = 117 [M+H]+Step 2: Synthesis of ((lS,3R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-dJpyrimidin-4-yl)amino)cyclopentyl)methanol

[0215] Into a stirred solution of 8-fhioro-7-(7-fhioro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2A,7aS)-2-fluorotetrahydro-177-pyrrolizin- 7a(577)-yl)methoxy)-5-methoxypyrido[4,3-J]pyrimidin-4-ol (Intermediate 1, 70 mg, 0.09 mmol) in MeCN (8 mL) were added phosphonitrilic chloride trimer (49.5 mg, 0. 14 mmol) followed by DIPEA (123 mg, 0.95 mmol) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 1 h, then ((lS,3R)-3-aminocyclopentyl)methanol hydrochloride (16.41 mg, 0.14 mmol) was added. Hie reaction mixture was diluted with water (8 mL), extracted into EtOAc (2 x 20 mL), the combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel using a gradient of 0-20% MeOH in DCM, to afford the title compound, 78 mg, 73.8 % as an off-brown solid. LCMS m / z = 834 [M+H]+Step 3: Synthesis of (lS,3R)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)ammo)cyclopentane-l- carbaldehyde

[0216] Into a stirred solution of ((LS',3 / ?)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ctliynyl)naplitlialcn- l -yl)-2-(((2 / <7aS)-2-fluorotctrahydro- l / / -pyrrolizin- 7a(5 / 7)-yl)methoxy)-5-methoxypyrido[4,3-J]pyrimidin-4-yl)amino)cyclopentyl)methanol (78 mg, 0.09 mmol) in DCM (10 mL) was added Dess-Martin periodinane (198 mg, 0.46 mmol) at 0 °C. The resulting reaction mixture was allowed to stir for 16 h at 25 °C. The reaction mixture was filtered through Celite®, the filtrate was washed with 10%NaHCC>3 solution (2 x 10 mL), dried over NazSO-i and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel, using a gradient of 0-20% McOH in DCM, to afford the title compound (70 mg, 58.5 %) as a brown solid. LCMS m / z = 832 [M+H]+Step 4: Synthesis ofN-((lR)-3-(difluoromethyl)cyclopentyl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine

[0217] Into a stirred solution of (37?)-3-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2A,7a5)-2-fluorotetrahydro-l / / -pyrrolizin- 7 a(5 / / )-y 1 )m ethoxy ) -5 -methoxypyrido [ 4, 3 -d ] pyrimidin-4-yl)amino)cyclopentane- 1 - carbaldehyde (70 mg, 0.08 mmol) in DCM (6 mL) was added deoxofluor (0.2 mL, 0.54 mmol) dropwise at -78 °C under N2. The reaction mixture was stirred at this temperature for 30 min and was then quenched with water (5 mL), extracted with DCM (2 x 10 mL), the organic layer was dried over Na2SO4 filtered and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel using a gradient of 0-20% MeOH / DCM, to afford the title compound, 60 mg, 50. 1 % as a brown solid. LCMS m / z = 854 [M+H]+Steps 5 and 6: Synthesis of 4-(4-(((lR3S)-3-(difluoromethyl) cyclopentyl)amino)-8-fluoro-2- (((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4, 3- d Jpyrimidin- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol

[0218] The title compound was obtained as an off-white solid, from 7V-((lA,3S)-3- (difluoromethyl)cyclopentyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((tri isopropylsilyl )ethynyl)naphthalen- 1 -yl)-2-(((2 / ?, 7aS)-2 -fluorotetrahydro- 1 / / -pyrrol izin-7a(5 / 7)-yl)methoxy)-5-methoxypyrido[4,3-J]pyrimidin-4-amine, following a similar 2 step procedure to that described in Example 1, steps 5 and 6. The title compound was purified by prep-HPLC Method B. LCMS m / z = 654 [M+H]+1H NMR (400 MHz, DMSO-d6) δ 10. 16 (s, 1H), 8.08-7.96 (m, 2H), 7.47 (t, 1H), 7.39 (d, 1H), 7.18 (d, 1H), 6.13-6.12 (m, 1H), 5.28-5.18 (m, 1H), 4.63-4.60 (m, 1H), 4.13-4.09 (m, 2H), 4.04-3.97 (m, 4H), 3.10-3.08 (m, 2H), 3.02 (s,1H), 2.84-2.83 (m, 1H), 2.31-2.25 (m, 1H), 2.13-2.01 (m, 4H), 1.92-1.73 (m, 8H)Example 36: Synthesis of Additional Compounds

[0219] The compounds in the following table were prepared by analogy to the methods previously described in the Intermediates and Examples sections above.Example 37: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-4-(((5-methylisoxazol-4- yl)methyl)ainino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Compound 168)Step 1: Synthesis of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2- (((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-N-((5- methylisoxazol-4-yl)methyl)pyrido[4,3-d]pyrimidin-4-amine:

[0220] To a vial containing a solution of 7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrohzin- 7a(5H)-yl)mcthoxy)-5-mcthoxypyrido[4,3-dJpynmidin-4-ol (Intermediate 15, 174 mg, 0.30 mmol) in MeCN (2.50 mL) and DCM (0.5 mL) was added Mukaiyama’s reagent (115 mg, 0.45 mmol) and N-ethyl-N-isopropylpropan-2-amine (58.1 mg, 0.45 mmol) and the reaction mixture was stirred at 30 °C for 4 h. (5-Methylisoxazol-4-yl)methanamine hydrochloride (88.8 mg, 0.60 mmol) and N-ethyl-N-isopropylpropan-2-amine (58.1 mg, 0.45 mmol) were added, the vial capped and the reaction mixture was stirred at 30 °C for 16 h. The reaction mixture wasconcentrated by N2 flow and the residue was purified by prep-HPLC (WePure Biotech XP tC18 150*40mm*7pm; gradient 19% - 49% MeCN : water (0.225% FA) over 10 mins) to give the title compound, as a white solid. LCMS m / z = 675 [M+H]+Step 2: Synthesis of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-4-(((5-methylisoxcizol-4-yl)methyl)amino)pyrido[4, 3- d]pyrimidin- 7-yl)naphthalen-2-ol:

[0221] To a solution of 7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-N-((5- methylisoxazol-4-yl)methyl)pyrido[4,3-d]pyrimidin-4-amine (0.10 mmol) in MeCN (1.0 mL) was added 2,2'-bipyridme (46.8 mg, 0.30 mmol) and the solution cooled to 0 °C. TMSOTf (44.4 mg, 0.20 mmol) was added and the resulting mixture was stirred at 25 °C for 2 h. H2O (0.2 mL) was added and the reaction stirred at 25 °C for 2 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (Boston Prime C18 150* 30mm* 5um column and gradient of 35% - 75% MeCN in water (0.05% NHsHzO+lOmM NH4HCO3) over 10 mins at 30 mL / min) to give the title compound (25.2 mg, 13.3%) as a white solid. LCMS m / z = 631 [M+H]+, RT (LCMS gradient 25%-100%, acidic) = 1.828 minExample 38: Synthesis of 3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-4-yl)amino)-2-methylpropanenitrile (Compound 180)Step 1: Synthesis of 3-((7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2- (((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4, 3- d]pyrimidin-4-yl)amino)-2-methylpropanenitrile:

[0222] The title compound was obtained as a white solid, from 7-(8-ethynyl-7-fluoro-3- (mcthoxyrncthoxy)naphthalcn-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotctrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-ol (Intermediate 15) and 3-amino-2- methylpropanenitrile, following a similar procedure to that described in Example 37, step 1. The crude product was punfied by prep-HPLC (Phcnomcncx Gcmmi C18 l 50-30mm*5um.gradient 45% - 85% MeCN in water (0.05% NHsffcO+lOmM NH4HCO3 over 10 mins at 30 mL / min). LCMS m / z = 647 [M+H]+Step 2: Synthesis of 3-((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)~ 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4, 3-d]pyrimidin-4- yl)amino)-2-methylpropanenitrile :

[0223] The title compound was obtained as a white solid, 23.4 mg, 12.9%, from 3-((7-(8- ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4- yl)amino)-2 -methylpropanenitrile, following a similar procedure to that described in Example 37, step 2. LCMS m / z = 603 [M+H]+RT (LCMS gradient 10%-100%, acidic) = 2.303 mmExample 39: Synthesis of 3-(((7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fhioro- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-4-yl)amino)methyl)cyclobutane-l-carbonitrile (Compound 182)

[0224] Tire title compound was obtained as a white solid, from 7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-ol (Intermediate 15) and 3- (aminomethyl)cyclobutane- 1 -carbonitrile hydrochloride, following a similar 2 step procedure to that described in Example 38. LCMS m / z = 629 [M+HJ+RT (LCMS gradient 10%- 100%, acidic) = 2.349 minExample 40: Synthesis of 4-(4-(((S)-l-(2-aminopyridin-3-yl)ethyl)amino)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 149)Step 1: Synthesis ofN-((S)-l-(2-aminopyridin-3-yl)ethyl)-8-fluoro-7-(7-fluoro-3- (methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidm-4-amine

[0225] Into a stirred solution of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-ol (Intermediate 1, 200 mg, 0.27 mmol) in DMF (4 mL) were added N-ethyl-N-isopropylpropan-2-amine (0.47 mL, 2.71 mmol) and BOP (300 mg, 0.68 mmol) under N2 at 0 °C and the solution stirred for 10 min. (S)-3-( 1 - aminoethyl)pyridin-2-amine (Intermediate 13A, 186 mg, 1.36 mmol) was added and the reaction mixture stirred at 25 °C for 16 h. The mixture was concentrated in vacuo and water (25 mL) added. The aqueous layer was extracted with 10% MeOH / DCM (3 x 25mL). The combined organic layer was dried over Na2SOr and concentrated to afford the title compound (230 mg, 94 %) as a brown gum. LCMS m / z = 857 [M+H]+Step 2: Synthesis of 4-(4-(((S)-l-(2-aminopyridin-3-yl)ethyl)amino)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-6- fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0226] HC1 (1 .2 M in MeOH, 1 .08 mL, 1 .34 mmol) was added to a solution of N-((S)-l-(2- aminopyridin-3 -yl)ethyl)- 8-fluoro-7 -(7 -fluoro-3 -(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine (230 mg, 0.27 mmol) in dioxane (1 .5 mL) at 0 °C under N2 and the reaction mixture was stirred at 25 °C for 16 h. TEA was added to basify the solution to pH 9 and the mixture evaporated under reduced pressure to give the title compound (195 mg, 89 %) as brown gum. LCMS m / z 812 [M+H]+Step 3: Synthesis of 4-(4-(((S)-l-(2-aminopyridin-3-yl)ethyl)amino)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5- e thynyl- 6-fluoronaphthalen-2-ol

[0227] CsF (0.36 g, 2,34 mmol) was added to a solution of 4-(4-(((S)-l-(2-aminopyridin-3- yl)ethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5- methoxypyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (0.19 g, 0.24 mmol) in DMF (3 mL) and the reaction mixture was stirred at 80 °C for 2 h. The reaction was diluted with water (2 mL) and evaporated under reduced pressure. The crude product was purified by prep. HPLC (Method N, gradient 0 to 100% MeCN) The pure fractions were collected and lyophilized under neutral media to afford the title compound (44.2 mg, 28.7 %) as a light brown solid. LCMS m / z = 656 [M+H]+ 1H-NMR (400 MHz, DMSO-de): 3 10.19 (m, 1H), 8.36-8.32 (m, 1H), 7.99-7.95 (m, 1H), 7.90-7.86 (m, 1H), 7.58-7.47 (m, 2H), 7.39 (d, 1H), 7.18 (d, 1H), 6.62-6.54 (m, 1H), 6.01-5.98 (m, 2H), 5.42 (t, 1H), 5.29-5.15 (m, 1H), 4.12-3.97 (m, 6H), 3.07-3.01 (m, 3H), 2.83-2.79 (m, 1H), 2.08-1.92 (m, 3H), 1.84-1.73 (m, 3H), 1.59 (d, 3H).Example 41: Synthesis of N-((R)-l-(2-aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-7-(6-methyl-5- (trifluoromethyl)-lH-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-amine trifluoroacetate (Compound 173)Step 1: Synthesis of (R)-N-(l-(2-aminopyridin-3-yl)ethyl)-7-chloro-8-fluoro-5-methoxy-2- ( methylthio)pyrido[ 4, 3-d]pyrimidin-4-amine

[0228] Into a stirred solution of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3- d]pyrimidin-4-ol (Intermediate 1, step 1, 1 g, 3.63 mmol) in THF (15 mL) at 0 °C, were added DIPEA (3.16 mL, 18.14 mmol) and PyBOP (2.83 g, 5.44 mmol) and the solution stirred for Ih. (R)-3-(l-aminoethyl)pyndm-2-amine (Intermediate 13B, 995 mg, 7.25 mmol) was added and the reaction mixture stirred for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na^SOr, filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (0%-100% EtOAc in hexane) to obtain the title compound (1 g, 56.5 %) as an off-white solid. LCMS m / z = 395 [M+H]+Step 2: Synthesis of tert-butyl (R)-(3-(l-((7-chloro-8fhioro-5-melhoxy-2- (methylthio)pyrido [4, 3-dJpyrimidm-4-yl)amino)ethyl)pyridin-2-yl)carbamate

[0229] Boc-anhydride (0.9 mL, 3.80 mmol) was added to a stirred suspension of (R)-N-(l-(2-aminopyridin-3 -yl) ethyl) -7 -chloro- 8 -fluoro-5 -m e thoxy-2 -(me th yl th i o )pyrido [4,3- d]pyrimidin-4-amine (1 g, 2.53 mmol) in t-BuOH (5 mL) and the reaction mixture was heatedto 90 °C and stirred for 5 h. The reaction mixture was concentrated in vacuo, the residue triturated with hexane, the solid was filtered and dried under vacuum to obtain the title compound (1 g, 65.2 %) as an off-white solid. LCMS m / z = 495 [M+H]+Step 3: Synthesis ofN-((R)-l-(2-aminopyridin-3-yl)ethyl)-8-fluoro-5-methoxy-7-(6-methyl-l- ( te trahydro-2H-pyran-2-yl)-5-( trifluoromethyl) -lH-indazol-4-yl)-2-(methylthio)pyrido[ 4,3- d]pyrimidin-4-amine

[0230] The title compound was obtained as a pale yellow solid, 110 mg, 56.5%, from tertbutyl (R)-(3-(l-((7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyndo[4,3-d]pyrimidin-4- yl)amino)ethyl)pyridin-2-yl)carbamate and 6-methyl-l-(tetrahydro-2H-pyran-2-yl)-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-lH-indazole (Example 33, step 5), following a similar procedure to that described in Example 1, step 2. LCMS m / z = 643 [M+H]+Step 4: Synthesis ofN-((R)-l-(2-aminopyridin-3-yl)ethyl)-8-fluoro-5-methoxy-7-(6-methyl-l- (tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-lH-indazol-4-yl)-2-(methylsulfmyl)pyrido[4,3- d]pyri midi n-4-a mine

[0231] The title compound was obtained as a pale yellow solid, 105 mg, 46.8%, from N- ((R)-l-(2-aminopyridin-3-yl)ethyl)-8-fluoro-5-methoxy-7-(6-methyl-l-(tetrahydro-2H-pyran-2- yl)-5-(trifluoromethyl)-lH-indazol-4-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-amine, following a similar procedure to that described in Example 1, step 3. LCMS m / z = 659 [M+H]+Step 5: Synthesis ofN-((R)-l-(2-aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxy-7-(6-methyl-l-(tetrahydro-2H- pyran-2-yl)-5-(trifluoromethyl)-lH-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-amine

[0232] A solution of N-((R)-l-(2-aminopyridin-3-yl)ethyl)-8-fluoro-5-methoxy-7-(6- methyl-l-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-lH-indazol-4-yl)-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-amine (100 mg, 0. 15 mmol) and ((2 / ?,7a.S')-2- fluorotetrahydro-177-pyrrolizin-7a(5J7)-yl)methanol (72.5 mg, 0.45 mmol) in toluene (3 mL) was heated to 80 °C and stirred for 16 h. The cooled reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over Na2SC>4, filtered and evaporated under reduced pressure to obtain the title compound (110 mg, crude) as a pale yellow gum. LCMS m / z = 754 [M+H]+Step 6: Synthesis ofN-((R)-l-(2-aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R, 7aS)-2- fl.uorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-m.ethoxy-7-(6-m.ethyl-5-(trifluorom.ethyl)- lH-indazol-4-yl)pyrido [ 4, 3-d ]pyrimidin-4-amine trifluoroacetate

[0233] TFA (151 mg, 1.33 mmol) was added to a stirred solution N-((R)-l-(2- aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5 -methoxy -7 -(6-methyl- 1 -(tetrahydro-2H-pyran-2-yl)-5 -(trifluoromethyl)- 1H- indazol-4-yl)pyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.13 mmol) in DCM (2 mL) at 0 °C and the reaction mixture was stirred at rt for 16 h. Tire reaction was quenched with aq. Nal ICCL solution (10 mL, pH adjusted to ~9) and extracted with DCM (3 x 20 mL). The combined organic layer was dried over NaiSOi, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: SHIMPACK Cl 8(250 xl 9mm)5p, MeCN: 0.1 % TFA in water, using gradient 0 to 100 % MeCN, at 15 mL / min). The pure product containing fractions were combined and lyophilized to obtain the title compound (17.2 mg, 18.6 %) as an off-white solid. LCMS m / z = 670 [M+H]+(400 MH1zH, DNMMSRO-d6): 8 13.56 (s, 1H), 10.79 (s, 1H), 8.64 (d, 1H), 8.31-8.05 (m, 3H), 7.97 (d, 1H), 7.80 (d, 1H), 7.74 (s, 1H), 6.96-6.89 (m, 1H), 5.67-5.41 (m, 2H), 4.54 (d, 1H), 4.41 (d, 1H), 4.07 (s, 3H), 3.91- 3.65 (m, 2H), 3.29-3.21 (m, 1H), 2.67 (d, 3H), 2.49-2.36 (m, 2H), 2.31-1.97 (m, 4H), 1.66 (d, 3H)Example 42: Synthesis of 3-(4-(((R)-l-(2-aminopyridin-3-yl)ethyl)amino)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol (Compound 174)Step 1: Synthesis of (R)-N-(l-(2-ammopyridin-3-yl)ethyl)-7-(3-chloro-2-cyclopropyl-5- (methoxymethoxy)phenyl)-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidm-4-amine

[0234] K3PO4 (188 mg, 0.88 mmol) and 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (Intennediate 16, 100 mg, 0.29 mmol) were added to a solution of tert-butyl (R)-(3-(l-((7-chloro-8-fluoro-5-m ethoxy-2 - (methylthio)pyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)pyridin-2-yl)carbamate (Example 41, step2, 73.1 mg, 0.14 mmol) in dioxane (2.5 mL) and water (0.5 mL) under N2 and the mixture was purged with N2 for 5 min. CataCXium A Pd G3 (21.51 mg, 0.03 mmol) was added and the reaction mixture was irradiated at 80 °C in a microwave for 1.5 h. The mixture was passed through a Celite® pad and washed with EtOAc (3 x 20 mL). The filtrate was concentrated in vacuo and the crude compound was purified by reverse phase column chromatography (Redisep Rf Gold® reverse-phase C18-Teledyne ISCO, MeCN: 10 mm aq. NH4CO3). The combined pure fractions were lyophilized to afford the title compound (50 mg, 25.9 %) as a white solid. LCMS m / z = 571 [M+H]+Step 2: Synthesis ofN-((R)-l-(2-aminopyridin-3-yl)ethyl)-7-(3-chloro-2-cyclopropyl-5- (methoxymethoxy)phenyl)-8-fluoro-5-methoxy-2-(methylsulflnyl)pyrido[4, 3-d] pyrimidineamine

[0235] The title compound was obtained as a yellow solid, 60 mg, 33.7%, from (R)-N-(l- (2-aminopyridin-3-yl)efhyl)-7-(3-cliloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro- 5-mcthoxy-2-(mcthylthio)pyrido[4,3-d]pyrimidin-4-aminc, following a similar procedure to that described in Example 10, step 3. LCMS m / z = 587 [M+H]+Step 3: Synthesis ofN-((R)-l-(2-aminopyridin-3-yl)ethyl)-7-(3-chloro-2-cyclopropyl-5- (methoxymethoxy)phenyl)-8-fluoro-2-(((2R, 7aS)-2-fluoroletrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-methoxypyrido[4, 3-d]pyrimidin-4-amine

[0236] The title compound was obtained as a brown gum 55 mg, crude, from N-((R)-l-(2- aminopyridin-3-yl)ethyl)-7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-5- methoxy-2-(methylsulfmyl)pyrido[4,3-d]pyrimidin-4-amine and ((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methanol, following a similar procedure to that described in Example 41, step 5. LCMS m / z = 682 [M+H]Step 4: Synthesis of 3-(4-(((R)-l-(2-aminopyridin-3-yl)ethyl)amino)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5- chloro-4-cyclopropylphenol

[0237] TFA (0.3 mL, 4.03 mmol) was added to a solution of N-((R)-l -(2-aminopyridin-3- yl)ethyl)-7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine (55 mg, 0.08 mmol) in DCM (5.0 mL) at 0 °C and the reaction mixture was stirred at rt for 1 h. The mixture was concentrated in vacuo and the crude compound was purified by prep-HPLC (Method A, gradient 0%to 100% MeCN). The combined pure fractions were lyophilized to afford the title compound (7.65 mg, 14.4 %) as an off-white solid. LCMS m / z = 638 [M+H]+1H-NMR (400 MHz, DMSO-d6): 6 9.98 (s, 1H), 8.30 (d, 1H), 7.88-7.86 (m, 1H), 7.52 (d, 1H), 6.94 (d, 1H), 6.79 (d, 1H), 6.56 (dd, 1H), 5.96 (s, 2H), 5.41 (t, 1H), 5.32-5.19 (m, 1H), 4.07 (s, 3H), 4.04-3.98 (m, 2H), 3.07-3.03 (m, 2H), 2.96 (s, 1H), 2.82-2.80 (m, 1H), 2.09-2.05 (m, 1H), 1.99-1.94 (m, 2H), 1.81-1.74 (m, 4H), 1.58 (d, 3H), 0.72-0.60 (m, 2H), 0.06-0.05 (m, 2H).Example 43: Synthesis of 7-(6-amino-2-methyl-3-(trifhioromethyl)pyridin-4-yl)-N-((R)-l- (2-aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine (Compound 175)Steps 1 and 2: Synthesis ofN-((R)-l-(2-aminopyridin-3-yl)ethyl)-7-(6-(bis(4- methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-8-fluoro-5-methoxy-2-( methylsulfinyl)pyrido[4, 3-d]pyrimidin-4-amine

[0238] The title compound was obtained from 2-(3-chloro-2-cyclopropyl-5- (metlioxymethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 16) and tertbutyl (R)-(3-(l-((7-chloro-8-fluoro-5-mcthoxy-2-(mcthylthio)pyrido[4,3-d]pyrimidin-4- yl)amino)ethyl)pyridin-2-yl)carbamate (Example 41, step 2), following a similar 2 step procedure to that described in Example 1, steps 2 and 3. LCMS m / z = 791 [M+H]+Step 3: Synthesis of N-( (R)-l-(2-aminopyridin-3-yl)ethyl)-7-( 6-(bis(4-methoxybenzyl)amino)-2- methyl-3-( trifluoromethyl)pyridin-4-yl)-8-fluoro-2-(( (2R, 7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidm-4-amine

[0239] The title compound was obtained, from N-((R)-l-(2-aminopyridin-3-yl)ethyl)-7-(6- (bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-8-fluoro-5-methoxy-2- (methylsulfinyl)pyrido[4,3-d]pyrimidin-4-amine and ((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol, following a similar procedure to that described in Example 41, step 5. LCMS m / z = 886 [M+H]+Step 4: Synthesis of7-(6-amino-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-N-((R)-l-(2- aminopyridin-3-yl)ethyl)-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-methoxypyndo[4, 3-d]pyrimidin-4-amine

[0240] Triflic acid (0.06 mL, 0.67 mmol) was added to a stirred solution of N-((R)-l-(2- aminopyridin-3-yl)ethyl)-7-(6-(bis(4-methoxybenzyl)amino)-2-methyl-3- (trifluoromethyl)pyridin-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine (60 mg, 0.06 mmol) in TFA (2 mL) at 0 °C and the reaction mixture was stirred for 1 h at 25 °C. The reaction was diluted with DCM (20 mL) and concentrated in vacuo. The crude compound was purified by prep-HPLC (Method H, gradient 0% to 100% MeCN). The combined pure fractions were lyophilized to afford the title compound (5 mg, 11.4 %) as an off-white solid. LCMS m / z = 646 [M+H]+. 'H-NMR (400 MHz, DMSO-d6) δ 8.30 (d, 1H), 8.16 (s, 1H), 7.86 (d, 1H), 7.50 (d, 1H), 6.84 (s, 2H), 6.55 (dd, 1H), 6.29 (s, 1H), 5.94 (s, 2H), 5.40 (t, 1H), 5.32-5.18 (m, 1H), 4.08-3.98 (m, 5H), 3.24-3.16 (m, 2H), 3.07-2.97 (m, 3H), 2.82-2.80 (m, 1H), 1.98-1.74 (m, 6H), 1.56 (d, 3H).Example 44: Synthesis of 4-(4-(((R)-l-(2-aminopyridin-3-yl)ethyl)amino)-8-fhioro-2- (((2R,7aS)-2-fliiorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 150)Step 1: Synthesis ofN-((R)-l-(2-aminopyridin-3-yl)ethyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidm-4-amine

[0241] N-Ethyl-N-isopropylpropan-2-amine (193.8 mg, 1.5 mmol) and HATU (142 mg, 0.375 mmol) were added to a stirred solution of 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-ol (Intermediate 1, 110 mg, 0.15 mmol) in DMF (2 mL) at 0 °C under N2. The solution was stirred at 0 °C for 15 min then (R)- 3 -(1 -aminoethyl )pyridin-2 -amine (Intermediate 13B, 102 mg, 0,75 mmol) was added and the reaction mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo to afford the title compound, crude, 130 mg. LCMS m / z = 855 [M+H]+Step 2: Synthesis of 4-(4-(((R)-l-(2-aminopyridin-3-yl)ethyl)amino)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4, 3-d]pyrimidin-7-yl)-6- fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol

[0242] The title compound was obtained as a yellow solid, 118 mg, 33.5%, from N-((R)-1- (2-aminopyridin-3-yl)ethyl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-amine, following a similar procedure to that described in Example 40, step 2. LCMS m / z = 810 [M+H]+Step 3: Synthesis of 4-(4-(((R)-l-(2-aminopyridin-3-yl)elhyl)amino)-8-fluoro-2-(((2R, 7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol

[0243] CsF (193 mg, 1.45 mmol) was added to a stirred solution of 4-(4-(((S)-l-(2- aminopyridin-3-yl)ethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5- ((triisopropylsilyl)ethynyl)naphthalen-2-ol (118 mg, 0.15 mmol) in DMF (2 mL) and the reaction mixture was stirred at 80 °C for 2 h. The reaction was concentrated in vacuo and the crude product purified by HPLC (Method A, gradient 0 to 100% MeCN) to afford the title compound (18.5 mg, 19.3 %) as an off white solid. LCMS m / z = 656 [M+H]1.1H-NMR (400 MHz, DMSO-de): 8 10.16 (s, 1H), 8.36-8.32 (m, 1H), 7.99-7.90 (m, 1H), 7.89-7.86 (m, 1H), 7.59-7.47 (m, 2H), 7.39 (d, 1H), 7.19 (s, 1H), 6.63-6.54 (m, 1H), 6.00-5.97 (m, 2H), 5.45-5.40 (m, 1H), 5.34-5.18 (m, 1H), 4.12-3.96 (m, 6H), 3.07-2.95 (m, 3H), 2.85-2.78 (m, 1H), 2.11-1.98 (m, 3H), 1.84-1.72 (m, 3H), 1.59 (d, 3H).Example 45: Synthesis of Additional Compounds

[0244] The compounds in the following table were prepared from 7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-ol (Intermediate 15) and the appropriate amine, by analogy to the methods described section above.Example 46: Active KRAS G12D / CRAF RBD TR-FRET Binding Assay

[0245] The ability of compounds to inhibit activation of KRAS G12D (GMPPNP loaded) and its interaction with effector protein, CRAF, was measured using a TR-FRET assay. In a 10- pl final assay volume, 2.5 pL of biotinylated KRAS G12D and 2.5 pL FLAG-tagged CRAF- RBD were added to pre-dispensed compounds. The assay buffer consisted of 25 mM HEPES, pH 7.4, 0.002% Tween20, 0.1 % BS A, 100 mM NaCl and 5 mM MgC12. Then, 1 nM Tb-anti- FLAG and 5 nM SA-XL665 were added to detect the interaction. After a 60-minute incubation at room temperature, the reaction was measured in a plate reader using excitation and emissionwavelengths of 340 nm and 620 / 665 nm, respectively. IC50 values were established using a four-parameter fit model. The results are shown in Table 2, where A is < 10 nM; B is > 10 nm and < 100 nM; C is > 100 nM and < 1000 nM; and D is > 1000 nM. Example 47: KRAS G12D SOSl-mediated TR-FRET Assay

[0246] The ability of compounds to inhibit SOSl-mediated nucleotide exchange was measured using a TR-FRET assay. In a 10-pil final assay volume, 5 pL of GST-tagged KRAS G12D and 1 nM anti-GST-Tb were added to pre-dispensed compounds. The assay buffer consisted of 10 mM HEPES, pH 7.4, 150 mM NaCl, 0.05% BSA, 0.0025% Tgepal and 5 mM MgC12. Then, 5 pL of S0S1 and 10 nM EDA-GTP-DY-647P1 were added to initiate the nucleotide exchange reaction. After a 60-minute incubation at room temperature, the reaction was measured in a plate reader using excitation and emission wavelengths of 337 nm and 615 / 665 nm, respectively. IC50 (nM) values were established using a four-parameter fit model. The results are shown in Table 2, where A is < 10 nM; B is > 10 nm and < 100 nM; C is > 100 nM and < 1000 nM; and D is > 1000 nM.Table 2.Example 48: p-ERK HTRF Assay

[0247] The potency of test compounds in inhibiting phosphorylation of ERK was determined by p-ERK HTRF assay in human cancer cell lines expressing either mutant or wild- type KRAS. Cells (8000 cells per well) were plated in 384-well cell culture plates. After overnight incubation at 37 °C and 5% CO2, cells were treated with a 3-fold, 10 points dilution of indicated compounds or DMSO (0. 1% DMSO final) for 3 hours. Cells were then lysed, and the lysates transferred to assay plates and incubated with phospho-ERK HTRF detection reagents according to the manufacturer’s protocol. The HTRF signal was measured using an EnVision multimode plate reader. Curves were fitted and IC50 values calculated using a four- parameter logistic model (XEFit; equation 201). IC50 (nM) values were established using a four-parameter fit model. The results are shown in Table 3, where A is < 10 nM; B is > 10 nM and < 100 nM; C is > 100 nM and < 1000 nM; and D is > 1000 nM.Table 3.Example 49: Cell Proliferation Assay

[0248] The anti-proliferative activity of compounds was assessed by CellTiter-Glo (CTG) assay in human cancer cell lines expressing either mutant or wild-type KRAS. Cells were seeded into 384-well plates at densities of 500-3000 cells per well in complete growth medium. After overnight incubation at 37 °C and 5% CO2, cells were treated with a 3-fold, 10 points dilution of indicated compounds or DMSO (0.1% DMSO final) and cell viability was assessed 3 days post-treatment according to the manufacturer’s protocol. The luminescent signal was measured using an EnVision multimode plate reader. Curves were fitted and IC50 (nM) values calculated using a four-parameter logistic model (XLFit; equation 201) The results are shown in Table 4, where A is < 100 nM; B is > 100 nM and < 1000 nM; C is > 1000 nM and < 3000 nM; and D is > 3000 nM.Table 4.INCORPORATION BY REFERENCE

[0249] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS AND SCOPE

[0250] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary' or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, morethan one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0251] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, eg. in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising’’ and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges arc given, endpoints arc included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0252] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0253] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:Ring A is selected from the group consisting of naphthyl, 8-10 membered bicyclic heteroaryl phenyl, and 5-6 membered monocyclic heteroaryl;RAis independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkcnyl. C2-C6alkynyl. C1-C6alkoxy, Cs-Cecycloalkyl, 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)OCi- Cealkyl, -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;Ring B is a 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, Ci -Coalkyl, and Ci -Coalkoxy:R1is selected from the group consisting of hydrogen, C1 -C6alkyl. C2-Cealkenyl, C2- Cealkynyl, -(CRcRd)m-(C3-C6Cycloalkyl), -(CRcRd)m-(phenyl), -(CRcRd)m-(4-7 membered heterocyclyl), -(CRcRd)m-(5-6 membered heteroaryl), and (C3-Cecycloalkyl)-(5-6 membered heteroaryl); wherein alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, and heteroaryl may optionally be substituted with one or more substituents each independently selected from R11;R11is independently selected for each occurrence from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, Ci-Coalkyl, Ci -Coalkoxy. Ci-Cocycloalkyl. 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, -SCi-Cealkyl, -S(O)C1-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl; wherein C i -Coal kyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, and C1-C6alkoxy;R1is selected for each occurrence from the group consisting of hydrogen and Ci- Csalkyl;R2is selected from the group consisting of C1-C6alkyl, C2-Cgalkenyl, C2-Cealkynyl, C3- Cecycloalkyl, and 4-7 membered monocyclic heterocyclyl; wherein R2may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy;R3is selected from the group consisting of hydrogen, deuterium, halogen, and Ci- Csalkyl;RaandRbare each independently selected from the group consisting of hydrogen and Ci- Cealkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci- Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci- Cealkyl, and C1-C6alkoxy;Rcand Rdare each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and C1-C6alkyl; m is 0, 1, 2, 3, or 4; p is 0, 1 , 2, 3, or 4; q is 0, 1, 2, 3, or 4; and t is 1 or 0.

2. The compound of claim 1, wherein A is selected from the group consisting of naphthyl, indazolyl, quinolinyl, isoqumohnyl, phenyl, and pyridyl.

3. The compound of claim 1 or 2, wherein RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NRaRb, -CN, C1-C6alkyl, C2-Cr,alkvnyl. and C3- Cecycloalkyl, wherein C1-C6alkyl may optionally be substituted with one, two, or three halogens.

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

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

6. The compound of any one of claims 1-5, wherein R1' is hydrogen or -CI Is.

7. The compound of any one of claims 1-6, wherein R1is C1-C6alkyl substituted with one, two, or three R11.

8. The compound of any one of claims 1-7, wherein R1is C1-C6alkyl substituted with one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, -C(O)NRaRb, and C1-C6alkoxy.

9. The compound of any one of claims 1 -8, wherein R1is selected from the group consisting of - CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH3, -CH2C(CH3)2OH, -CH2CH2CH2NH2, - CH2CH2NH2, -CH2CH2CH2C(O)NH2, -CH(CH3)C(CH3)2OH, -CH2CHF2, -CH2CH(CH3)-OCH3, -CH(CH3)-C(O)N(CH3)2, -CH2CHFCH2OH, -CH(-cyclopropyl)-CH2OH, -CH(CH3)C(O)NH2, - CH2CH(CH3)CN, -CH(-isopropyl)CH2OH, and -CH(CH3)CH(OH)CH(CH3)2.

10. The compound of any one of claims 1-6, wherein R1is selected from the group consisting of C3-C6cycloalkyl, (C3-C6Cycloalkyl)-(5-6 membered heteroaryl), -CH2-(C3-C6cycloalkyl), and - CH2-CH2-(C3-C6cycloalkyl), wherein cycloalkyl and heteroaryl may optionally be substituted with one, two, or three R11.

11. The compound of any one of claims 1-6 and 10 wherein R1is selected from the group consisting of Cs-Cocycloalkyl, (C3-C6Cycloalkyl)-(5-6 membered heteroaryl), and CH2-(C3- Cecycloalkyl), wherein cycloalkyl and heteroaiyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, - CH3, -CH2OH, -CHF2, -CH2CF3, -CH2CN, -CN, -NH2, and -CONH2.

12. The compound of any one of claims 1-6 and 10-11, wherein R1is selected from the group consisting of13. The compound of any one of claims 1-6, wherein R1is selected from the group consisting of 4-7 membered heterocyclyl, -CH2-(4-7 membered heterocyclyl), -CH(CH3)-(5-6 membered heterocyclyl), -CH2-(5-6 membered heteroaryl), -CH(CFb)-(5-6 membered heteroaryl), and - CH2-CH2-(5-6 membered heteroaryl), wherein heterocyclyl and heteroaryl may optionally be substituted with one, two, or three R11.

14. The compound of any one of claims 1-6 and 13, wherein R1is selected from the group consisting of 4-7 membered heterocyclyl, -CH2-(4-7 membered heterocyclyl), -CH(CH<)-(5-6 membered heterocyclyl), -CH2-(5-6 membered heteroaryl), -CH(CH3)-(5-6 membered heteroaryl), and -CH2-CH2-(5-6 membered heteroaryl), wherein heterocyclyl and heteroaryl may optionally be substituted with one, two, or three substituents independently selected from the group consisting of halogen, hydroxyl, oxo, -CH3, -CF3, -CN, -NH2, and -CONH2.

15. The compound of any one of claims 1-6 and 13-14, wherein R1is selected from the group consisting of16. The compound of any one of claims 1-15, wherein R2is selected from the group consisting of C1-C6alkyl, Cs-Cecycloalkyl, and 4-7 membered monocyclic heterocyclyl, wherein alkyl, cycloalkyl, and heterocyclyl may optionally be substituted with one, two, or three substituents each independently selected from halogen and hydroxyl.

17. The compound of any one of claims 1-16, wherein R2is selected from the group consisting of -CH3, -CHF2, -CF3, -CH(CH3)2, -CH2CH2OH, -CH(CH2CH2OH)2, cyclopropyl, and oxetanyl.

18. The The compound of any one of claims 1-17, wherein m is 0, 1, or 2.

19. The compound of any one of claims 1-18, wherein R3is selected from the group consisting of hydrogen, halogen, and -CH3.

20. The compound of any one of claims 1 -19, wherein R3is hydrogen or fluoro.

21. Tire compound of any one of claims 1 -20, wherein ring B is22. The compound of any one of claims 1 -21 , wherein p is 1 .

23. The compound of any one of claims 1-22, wherein ring B is24. The compound of any one of claims 1-23, wherein RBis halogen.

25. The compound of any one of claims 1-24, wherein RBis fluoro.

26. The compound of any one of claims 1-25, wherein n is 1.

27. The compound of claim 1, wherein the compound is represented by Formula II:

28. A compound selected from the group consisting of:

29. A pharmaceutical composition comprising a compound of any one of claims 1-28, or a pharmacally acceptable salt and / or a stereoisomer thereof, and a pharmacally acceptable excipient.

30. 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 1-29.

31. The method of claim 30, wherein the disease or disorder is characterized by aberrant Ras activity in the patient due to a Ras mutation.

32. The method of claim 30 or 31, wherein the Ras mutation is a K-Ras mutation, a H-Ras mutation, or aN-Ras mutation.

33. Tire method of any one of claims 30-32, wherein the disease or disorder is a cancer.

34. 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 1-28.

35. The method of claim 34, wherein the cancer is a Ras-mutated cancer.

36. The method of claim 34, wherein the cancer is a KRas-mutated cancer.

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