KRAS inhibitors

Abstract

A compound having the following structure of Formula (I): or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein R1, R2, L, X, Y, A, and B are as defined herein. Pharmaceutical composition comprising the compounds, and their use in methods of treating diseases are also described.

Description

[0001] KRAS INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No.63 / 564,090, filed March 12, 2024; U.S. Provisional Patent Application No. 63 / 669,038, filed July 09, 2024; U.S. Provisional Patent Application No.63 / 709,182, filed October 18, 2024; the disclosure of each of which is hereby incorporated by reference in its entirety for all purposes. TECHNICAL FIELD The disclosure relates to substituted pyridopyrimidine compounds that act as Kirsten rat sarcoma virus (KRAS) inhibitors. The disclosure also provides compounds of formula (I), stereoisomers of the compounds, and tautomers of the compounds, and pharmaceutically acceptable salts thereof and uses of the compounds, stereoisomers, tautomers, and salts for the treatment of abnormal cell growth, such as cancer, in a subject. BACKGROUND Kirsten rat sarcoma virus (KRAS) is a GTPase, a class of enzymes that convert nucleotide guanosine triphosphate (GTP) into guanosine diphosphate (GDP). KRAS plays an important role in the signal transduction cascade in biochemical pathways responsible for cell growth and differentiation. While current kinase inhibitors can be effective treatments for cancer, their use may be limited by poor selectivity for KRAS. There remains a need to identify potent KRAS inhibitors for the treatment of patients with cancer or other proliferative diseases or conditions driven by KRAS alterations. BRIEF SUMMARY In brief, the present disclosure provides compounds, including stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, which can be used alone or in combination with other therapeutic agents. In one embodiment, a compound having a structure of Formula (I) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein R1, R2, L, X, Y, A, and B are as defined herein. In some embodiments, a compound having a structure of Formula (IA) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (IA-2) is provided: . (IA-2) or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (IA-3) is provided: , or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (III) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (IIIA) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (IIIB) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (IIIC) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (III-1) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (III-1A) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (III-1B) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (III-1C) is provided: (III-1C) or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (IV) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. In some embodiments, a compound having a structure of Formula (IVA) is provided: or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein the variables are as defined herein. Pharmaceutical compositions comprising one or more of the foregoing compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) and an additional therapeutic agent are also provided. In other embodiments, methods of treatment by administering the foregoing compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) or the pharmaceutical compositions comprising a compound of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA), to a subject in need thereof to treat a disease are provided. Various aspects and embodiments now will be described more fully hereinafter. Such aspects and embodiments may take many different forms, and the exemplary ones disclosed herein should not be construed as limiting; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art. DETAILED DESCRIPTION I. Definitions For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Where a range of values is provided, it is intended that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. For example, if a range of 1 mM to 8 mM is stated, it is intended that 2 mM, 3 mM, 4 mM, 5 mM, 6 mM, and 7 mM are also explicitly disclosed, as well as the range of non-integer values greater than or equal to 1 mM and the range of non-integer values less than or equal to 8 mM. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "polymer" includes a single polymer as well as two or more of the same or different polymers, reference to an "excipient" includes a single excipient as well as two or more of the same or different excipients, and the like. The term “about”, particularly in reference to a given quantity, is meant to encompass deviations of plus or minus five percent. The compositions of the present disclosure can comprise, consist essentially of, or consist of, the components disclosed. All percentages, parts and ratios are based upon the total weight of the compositions and all measurements made are at about 25 ºC., unless otherwise specified. As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated: "Amino" refers to the -NH2, -NHR, or -NR2radical, "Cyano" refers to the -CN radical, "Hydroxyl" refers to the -OH radical, "Imino" refers to the =NH or =NR substituent, "Nitro" refers to the -NO2 radical, "Oxo" refers to the =O substituent, "Thio" refers to the -S substituent, "Trifluoromethyl" refers to the -CF3radical, Hydrazido or hydrazino refers to N-N substituent, wherein each R of “amino” or “imino” is a compatible substituent as described in this disclosure and wherein an R group is chiral, isomers are contemplated and included herein. "Alkyl" refers to a linear, saturated, acyclic, monovalent hydrocarbon radical or branched, saturated, acyclic, monovalent hydrocarbon radical, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1- methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2- methylhexyl and the like. An optionally substituted alkyl radical is an alkyl radical that is optionally substituted, valence permitting, by one, two, three, four, or five substituents independently selected from the group consisting of halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilyl, -OR′, -OC(O)R′, -N(R′)2, C(O)R′′, -C(O)OR′, - C(O)N(R′)2, -N(R′)C(O)OR′′′, N(R′)C(O)R′′′, -N(R′)S(O)tR′′′ (where t is 1 or 2), -S(O)tOR′′′ (where t is 1 or 2), -S(O)pR′′′ (where p is 0, 1, or 2) and -S(O)tN(R′)2(where t is 1 or 2), where each R′is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl; each R′′ is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl; and each R′′′ is independently alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. “Alkylene” refers to a divalent radical of an alkyl group. “Deuteroalkylene” refers to a divalent radical of a deuteroalkyl group. “Alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C2–20 alkenyl”). “Alkenylene” refers to a divalent radical of an alkenyl group. “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds), and optionally one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C2–20 alkynyl”). “Alkynylene” refers to a divalent radical of an alkynyl group. “Alkylalcohol” refers to an alkyl group substituted with an alcohol (-OH) group. "Alkoxy" refers to a radical of the formula -ORawhere Rais an alkyl radical as defined above containing one to twelve carbon atoms. The alkyl part of the optionally substituted alkoxy radical is optionally substituted as defined above for an alkyl radical. "Alkoxyalkyl" refers to a radical of the formula -Ra-O-Rbwhere Rais alkylene and Rbis alkyl as defined above. Alkyl and alkylene parts of the optionally substituted alkoxyalkyl radical are optionally substituted as defined above for an alkyl radical and alkylene chain, respectively. “Aralkyl” refers to a radical of the formula -Ra-Rb, where Rais alkylene and Rbis aryl as described herein. Alkylene and aryl portions of optionally substituted aralkyl are optionally substituted as described herein for alkylene and aryl, respectively. "Aryl" refers to an aromatic monocyclic or multicyclic hydrocarbon ring system radical containing from 6 to 18 carbon atoms, where the multicyclic aryl ring system is a bicyclic, tricyclic, or tetracyclic ring system. Aryl radicals include, but are not limited to, groups such as fluorenyl, phenyl and naphthyl. An optionally substituted aryl is an aryl radical that is optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, akenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, heteroaryl, heteroarylalkyl, -R′′-OR′, -R′′-OC(O)-R′, - R′′-N(R′)2, -R′′-C(O)R′, -R′′-C(O)OR′, -R′′-C(O)N(R′)2, -R′′-N(R′)C(O)OR′′′, - R′′-N(R′)C(O)R′′′, -R′′-N(R′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), - R′′-S(O)pR′′′ (where p is 0, 1, or 2), and -R′′-S(O)tN(R′)2(where t is 1 or 2), where each R′is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R′′ is independently a direct bond or a linear or branched alkylene or alkenylene chain; and each R′′′ is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, or heteroaryl. “Arylene” refers to a divalent radical of an aryl group. “Arylalkoxy” refers to a group of formula –O-R, where R is aralkyl. An optionally substituted arylalkoxy is an arylalkoxy that is optionally substituted as described herein for aralkyl. In some embodiments, arylalkoxy is benzyloxy. "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, and which is saturated or unsaturated, and which attaches to the rest of the molecule by a single bond. A polycyclic hydrocarbon radical is bicyclic, tricyclic, or tetracyclic ring system. An unsaturated cycloalkyl contains one, two, or three carbon-carbon double bonds and / or one carbon-carbon triple bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, and the like. An optionally substituted cycloalkyl is a cycloalkyl radical that is optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R′′-OR′, -R′′-OC(O)-R′, -R′′-N(R′)2, -R′′-C(O)R′, - R′′-C(O)OR′, -R′′-C(O)N(R′)2, -R′′-N(R′)C(O)OR′′′, -R′′-N(R′)C(O)R′′′, -R′′-N(R′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), -R′′-S(O)pR′′′ (where p is 0, 1, or 2) and -R′′-S(O)tN(R′)2(where t is 1 or 2) where each R′is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R′′ is independently a direct bond or a linear or branched alkylene or alkenylene chain; and each R′′′ is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl. “Deuterated compounds” are compounds where one or more hydrogen atoms have been replaced with a deuterium atom. Deuterated drugs may be derivatives of an active compound. Deuterated drugs may be prodrugs. Deuteration may alter the physical properties, metabolic properties, activity or safety of a drug. “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium. “Derivatives” are related chemical species that can be derived from a similar compound via chemical reactions. They may encompass slight chemical modifications, substitution of atoms with deuterated atoms, substitution of atoms with stable or radioactive isotopes or other modifications that imbue a compound with desirable properties. "Fused" refers to any ring system described herein which is fused to an existing ring structure in the compounds of the invention. When the fused ring system is a heterocyclyl or a heteroaryl, any carbon atom on the existing ring structure which becomes part of the fused ring system may be replaced with a nitrogen atom. "Halo" refers to the halogen substituents: bromo, chloro, fluoro, and iodo. "Haloalkyl" refers to an alkyl radical, as defined above, that is further substituted by one or more halogen substituents. The number of halo substituents included in haloalkyl is from one and up to the total number of the hydrogen atoms available for replacement with the halo substituents (e.g., perfluoroalkyl). Non-limiting examples of haloalkyl include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl, 2- fluoroethyl, 3-bromo 2-fluoropropyl, 1-bromomethyl, 2-bromoethyl and the like. For an optionally substituted haloalkyl, the hydrogen atoms bonded to the carbon atoms of the alkyl part of the haloalkyl radical may be optionally replaced with substituents as defined above for an optionally substituted alkyl. "Haloalkenyl" refers to an alkenyl radical, as defined above, that is further substituted by one or more halo substituents. The number of halo substituents included in haloalkenyl is from one and up to the total number of the hydrogen atoms available for replacement with the halo substituents (e.g., perfluoroalkenyl). Non-limiting examples of haloalkenyl include 2,2- difluoroethenyl, 3-chloroprop-1-enyl, and the like. For an optionally substituted haloalkenyl, the hydrogen atoms bonded to the carbon atoms of the alkenyl part of the haloalkenyl radical may be optionally replaced with substituents as defined above for an optionally substituted alkenyl group. "Haloalkynyl" refers to an alkynyl radical, as defined above, that is further substituted by one or more halo substituents. The number of halo substituents included in haloalkynyl is from one and up to the total number of the hydrogen atoms available for replacement with the halo substituents (e.g., perfluoroalkynyl). Non-limiting examples of haloalkynyl include 3-chloroprop-1-ynyl and the like. The alkynyl part of the haloalkynyl radical may be additionally optionally substituted as defined above for an alkynyl group. “Heteroalkyl” refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2- NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2- S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O- CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. “Heteroalkylene” refers to a divalent radical of a heteroalkyl. “Heteroarylalkyl” refers to a radical of the formula -Ra-Rb, where Rais alkylene and Rbis heteroaryl as described herein. Alkylene and heteroaryl portions of optionally substituted heteroarylalkyl are optionally substituted as described herein for alkylene and heteroaryl, respectively. "Heterocyclyl" refers to a stable 3- to 18-membered nonaromatic ring system radical having the carbon count of two to twelve and containing a total of one to six heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. A heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. A bicyclic, tricyclic, or tetracyclic heterocyclyl is a fused, spiro, and / or bridged ring system. The heterocyclyl radical may be saturated or unsaturated. Heterocyclyl includes ring systems wherein the heterocyclyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring. An unsaturated heterocyclyl contains one, two, or three carbon-carbon double bonds and / or one carbon-carbon triple bond. An optionally substituted heterocyclyl is a heterocyclyl radical that is optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, heterocyclyl-, heteroaryl, -R′′-OR′, -R′′-OC(O)-R′, -R′′-N(R′)2, - R′′-C(O)R′, -R′′-C(O)OR′, -R′′-C(O)N(R′)2, -R′′-N(R′)C(O)OR′′′, -R′′-N(R′)C(O)R′′′, - R′′-N(R′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), -R′′-S(O)pR′′′ (where p is 0, 1, or 2), and -R′′-S(O)tN(R′)2(where t is 1 or 2), where each R′is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R′′ is independently a direct bond or a linear or branched alkylene or alkenylene chain; and each R′′′ is independently alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized (when the substituent is oxo and is present on the heteroatom); the nitrogen atom may be optionally quaternized (when the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R′′-OR′, -R′′-OC(O)-R′, -R′′-N(R′)2, -R′′-C(O)R′, -R′′-C(O)OR′, - R′′-C(O)N(R′)2, -R′′-N(R′)C(O)OR′′′, -R′′-N(R′)C(O)R′′′, -R′′-N(R′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), -R′′-S(O)pR′′′ (where p is 0, 1, or 2), and - R′′-S(O)tN(R′)2(where t is 1 or 2), where R′′ is a linear or branched alkylene or alkenylene chain, and R′and R′′′ are as defined above). Examples of optionally substituted heterocyclyl radicals include, but are not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl-, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1---oxothiomorpholinyl, and 1,1---dioxo-thiomorpholinyl. “Heterocyclylene” refers to a heterocyclyl in which one hydrogen atom is replaced with a valency. An optionally substituted heterocyclylene is optionally substituted as described herein for heterocyclyl. "Heteroaryl" refers to a 5- to 18-membered ring system radical containing at least one aromatic ring, having the carbon count of one to seventeen carbon atoms, and containing a total of one to ten heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. The bicyclic, tricyclic, or tetracyclic heteroaryl radical is a fused and / or bridged ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring. An optionally substituted heteroaryl is a heteroaryl radical that is optionally substituted by one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, or heteroarylalkyl-, -R′′-OR′, - R′′-OC(O)-R′, -R′′-N(R′)2, -R′′-C(O)R′, -R′′-C(O)OR′, -R′′-C(O)N(R′)2, - R′′-N(R′)C(O)OR′′′, -R′′-N(R′)C(O)R′′′, -R′′-N(R′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), -R′′-S(O)tR′′′ (where p is 0, 1, or 2), and -R′′-S(O)tN(R′)2(where t is 1 or 2), where each R′is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; each R′′ is independently a direct bond or a linear or branched alkylene or alkenylene chain; and each R′′′ is alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized (when the substituent is oxo and is present on the heteroatom), provided that at least one ring in heteroaryl remains aromatic; the nitrogen atom may be optionally quaternized (when the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R′′-OR′, -R′′-OC(O)-R′, -R′′-N(R′)2, -R′′-C(O)R′, -R′′-C(O)OR′, - R′′-C(O)N(R′)2, -R′′-N(R′)C(O)OR′′′, -R′′-N(R′)C(O)R′′′, -R′′-N(R′)S(O)tR′′′ (where t is 1 or 2), -R′′-S(O)tOR′′′ (where t is 1 or 2), -R′′-S(O)pR′′′ (where p is 0, 1, or 2), and - R′′-S(O)tN(R′)2(where t is 1 or 2), where R′′ is a linear or branched alkylene or alkenylene chain, and R′and R′′′ are as defined above), provided that at least one ring in heteroaryl remains aromatic. Examples of optionally substituted heteroaryl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo-[1,2a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyl, naphthyridinyl, oxadiazolyl-, 2oxoazepinyl, oxazolyl, oxiranyl-, 1-phenyl-1Hpyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl- (i.e., thienyl). “Heteroarylene” is a divalent radical of a heteroaryl group. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, salts, compositions, dosage forms, etc., which are--within the scope of sound medical judgment--suitable for use in contact with the tissues of human beings and / or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals (e.g., mammals), and more particularly, in humans. “Prodrugs” are compounds that after administration are metabolized or otherwise chemically transformed into an active moiety. Prodrugs may be derivatives of an active compound. Prodrugs may or may not be active prior to conversion into an active form in vivo. The term "treating" is used herein, for instance, in reference, for example, to methods of treating inflammatory diseases or to a gastrointestinal disease, and generally includes the administration of a compound or composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition (e.g., autoimmune disease, inflammatory disorder, gastrointestinal disorder) in a subject relative to a subject not receiving the compound or composition. This can include reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject's condition (e.g., regression of symptoms of an autoimmune or inflammatory disease such as improvement in the MAYO score in the treatment of ulcerative colitis). In the case of oncology, “treating” can be ameliorative (slowing or reducing symptoms) or curative (reversing or eliminating symptoms). The embodiments disclosed herein encompass all pharmaceutically acceptable compounds of the compound of (I), (II), (IA)-(IE), or (IA-1)-(IE-1) being isotopically- labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically-labelled compounds of (I)-(IL), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of (I)-(IL) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Preparations and Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. The term “cyclyl” refers to any cyclic group. In some embodiments, the term “cyclyl”includes aryl, heteroaryl, carbocyclyl, cycloalkyl, and heterocyclyl, as defined herein. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group. When a functional group is “optionally substituted,” there may be more than one (e.g., 1, 2, 3, or 4) optional substituent regardless of whether it is indicated that the functional group is optionally substituted with “one or more substituents” and each optional substituent may be the same or different. In some embodiments, the term “one or more substituents” refers to 1, 2, 3, or 4 substituents. Combinations of substituents envisioned under this invention are preferably those that result in the formation of stable or chemically feasible compounds. Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group (such as an alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene or the carbon atom of a carbocyclyl, aryl, heterocyclyl or heteroaryl) are independently, for example,halogen; -(CH2)0-4R ; -(CH2)0-4OR ; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR )2; -(CH2)0-4SR; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-4O(CH2)0-1Ph, which may be substituted with R°; -CH=CHPh, which may be substitutedwith -NO2; -CN; -N3; - (CH2)0-4N(R )2;-(CH2)0-4N(R )C(O)R ; -N(R )C(S)R ; -(CH2)0-4N(R ) C(O)NR 2; -N(R )C(S)NR 2;-(CH2)0-4N(R )C(O)OR ; -N(R )N(R )C(O)R ; -N(R )N(R )C(O)NR 2; -N(R )N(R )C(O)OR ;-(CH2)0-4C(O)R ; -C(S)R ; -(CH2)0-4C(O)OR ; -(CH2)0-4C(O)SR ; -(CH2)0-4C(O)OSiR 3;-(CH2)0-4OC(O)R ; -OC(O)(CH2)0-4SR -, SC(S)SR°; -(CH2)0-4SC(O)R ; -(CH2)0-4C(O)NR 2;-C(S)NR 2; -C(S)SR°; -(CH2)0-4OC(O)NR 2; -C(O)N(OR )R ; -C(O)C(O)R ; -C(O)CH2C(O)R ;-C(NOR )R ; -(CH2)0-4SSR ; -(CH2)0-4S(O)2R ; -(CH2)0-4S(O)2OR ; -(CH2)0-4OS(O)2R ;-S(O)2NR 2; -(CH2)0-4S(O)R ; -N(R )S(O)2NR 2; -N(R )S(O)2R ; -N(OR )R ; -C(NH)NR 2;-P(O)2R ; -P(O)R 2; -OP(O)R 2; -OP(O)(OR )2; -SiR3; -(C1-4 straight or branchedalkylene)O-N(R )2; or -(C1-4 straight or branched alkylene)C(O)O-N(R )2, where each Rmay be substituted as defined below and is independently hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R , taken together withtheir intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.Suitable monovalent substituents on R (or the ring formed by taking two independentoccurrences of R together with their intervening atoms), are independently, for example,deuterium, halogen, -(CH2)0-2R , -(haloR ), -(CH2)0-2OH, -(CH2)0-2OR ,-(CH2)0-2CH(OR )2; -O(haloR ), -CN, -N3, -(CH2)0-2C(O)R , -(CH2)0-2C(O)OH,-(CH2)0-2C(O)OR , -(CH2)0-2SR , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR , -(CH2)0-2NR 2,-NO2, -SiR 3, -OSiR 3, -C(O)SR , -(C1-4 straight or branched alkylene)C(O)OR , or -SSR ,where each R is unsubstituted or where preceded by “halo” is substituted only with one ormore halogens, and is independently selected from C1-4alkyl, C1-4alkenyl, C1-4alkynyl, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalentsubstituents on a saturated carbon atom of R include =O and =S.Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, where each independent occurrence of R*is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, and carbocyclyl, which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(C(R*)2)2-3O-, where each independent occurrence of R*is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6 alkynyl, and carbocyclyl, which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable substituents on the alkyl, alkenyl, alkynyl, or carbocyclyl group of R*includehalogen, -R , -(haloR ), -OH, -OR , -O(haloR ), -CN, -C(O)OH, -C(O)OR ,-NH2, -NHR , -NR 2, or -NO2, where each R is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independently C1-6alkyl, C1-6alkenyl, C1-6alkynyl, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, -C(S)NR†2, -C(NH)NR†2, or -N(R†)S(O)2R†; where each R†is independently hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, it should be understood that a substitutable nitrogen can be substituted with four substituents (or have four bonds to less than four substituents) such that the nitrogen atom will be positively charged or its cation, i.e., N+. Such substitution of a substitutable nitrogen can be of a ring nitrogen, for example, a ring nitrogen of a heterocyclic group containing nitrogen as a ring atom. In particular embodiments, where one of the substituents of a cationic nitrogen atom is a hydroxyl group, the hydroxyl group can be deprotonated and represented by a negatively charged oxygen atom, i.e., O-. In such cases, a general formula for the substitution can be represented by RN+(O-)(R’)R’’, where R, R’ and R’’ represent carbon or other atoms, groups and / or moieties to which the nitrogen atom is bound. Suitable substituents on the alkyl, alkenyl, alkynyl, or carbocyclyl group of R†are independently, for example,halogen, -R , -(haloR ), -OH, -OR , -O(haloR ), -CN, -C(O)OH,-C(O)OR , -NH2, -NHR , -NR 2, or -NO2, where each R is unsubstituted or where precededby “halo” is substituted only with one or more halogens, and is independently C1-6alkyl, C1-6alkenyl, C1-6alkynyl, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The embodiments disclosed herein encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples. "Pharmaceutically acceptable salt" includes both acid and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5- disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid (TFA), undecylenic acid, and the like. "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. A "pharmaceutical composition" refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents and excipients therefor. "Effective amount" or "therapeutically effective amount" refers to that amount of a compound of the disclosure which, when administered to a mammal, preferably a human, is sufficient to effect treatment in the mammal, preferably a human. The amount of a compound which constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure. A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another. The present disclosure also contemplates "diastereomers", which refers to non-mirror image of non-identical stereoisomers. Diastereomers occur when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other. A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any said compounds. “Abnormal cell growth”, as used herein, unless otherwise indicated, means cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous) or malignant (cancerous). By reserving the right to proviso out or exclude any individual members of any such group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, less than the full measure of this disclosure can be claimed for any reason. Further, by reserving the right to proviso out or exclude any individual substituents, analogs, compounds, ligands, structures, or groups thereof, or any members of a claimed group, less than the full measure of this disclosure can be claimed for any reason. Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure. II. Compounds The compounds described herein are KRAS inhibitors. In one embodiment, a compound having a structure of Formula (I), or a stereoisomer of the compound, tautomer of the compound, or a pharmaceutically acceptable salt thereof is provided: wherein A is 4-11 membered heterocyclylene, wherein the 4-11 membered heterocyclylene is optionally substituted; B is an arylene or 5-14 membered heteroarylene, wherein the arylene or 5-14 membered heteroarylene is optionally substituted, wherein the 5- 14 membered heteroarylene is not indazolylene; R1is a hydrogen or C1-C3alkyl; R2is a hydrogen, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, -(C1-C3alkylene)-heteroaryl, aryl fused to 4-8 membered heterocyclyl, or amine, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, 4-8 membered heterocyclyl, or amine is optionally substituted; L is C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1-C8heteroalkylene, wherein the C1-C8alkylene, C1-C8alkenylene, C1-C8alkynylene, or C1-C8heteroalkylene is optionally substituted; X is -O-, -NR3-, or a direct bond, wherein R3is a hydrogen or C1-C3alkyl; and Y is C1-C5alkylene, C1-C5deuteroalkylene, or a direct bond, wherein the C1-C5alkylene or C1-C5deuteroalkylene is optionally substituted, wherein: when B is not C2 alkylene, wherein * indicates the location ofa bond to L and indicates the location of a bond to the pyridine group. In some embodiments, A is 4-10 membered heterocyclylene. In some other embodiments, A is 5-8 membered heterocyclylene. In some other embodiments, A is 5-10 membered heterocyclylene. In some other embodiments, A is 6-8 membered heterocyclylene. In some embodiments, the 4-11 membered heterocyclylene of A is pyrrolidinylene, piperidinylene, morpholinylene, azepanylene, oxazepanylene, or diazepanylene. In some embodiments, wherein the 4-11 membered heterocyclylene of A is azepanylene, piperidinylene, or oxazepanylene. In some embodiments, the 4-11 membered heterocyclylene of A is pyrrolidinylene. In some embodiments, the 4-11 membered heterocyclylene of A is piperidinylene. In some embodiments, the 4-11 membered heterocyclylene of A is morpholinylene. In some embodiments, the 4-11 membered heterocyclylene of A is azepanylene. In some embodiments, the 4-11 membered heterocyclylene of A is oxazepanylene. In some embodiments, the 4-11 membered heterocyclylene of A is or diazepanylene. In some embodiments, the 4-11 membered heterocyclylene of A has one of the following structures: ,wherein * indicates the location of a bond to the carbamate group, and indicates the location of a bond to the pyrimidine group. In some embodiments, the 4-11 membered heterocyclyleneof A is . In the 4-11 membered heterocyclylene In some embodiments, the 4-11 membered heterocyclylene of A has one of the following structures: , wherein * indicates the location of a bond to the carbamate group and indicates the location of a bond to the pyrimidine group, wherein the 4-11 membered heterocycloalkylene is optionally substituted. In some embodiments, the 4-11 membered heterocyclylene of A is a fused bicyclic heterocyclylene or a bridged bicyclic heterocyclylene. In some embodiments, A is a fused bicyclic heterocyclylene. In some embodiments, the fused bicyclic heterocyclylene has one wherein * indicates the location of a bond to the carbamate group, and indicates thelocation of a bond to the pyrimidine group. In some embodiments, A is . In someembodiments, A is . In some embodiments, some embodiments, In some embodiments, A is a bridged bicyclic heterocyclylene. In some embodiments, the bridged bicyclic hetrocyclylene has one of the following structures: , wherein m is 1 or 2 and * indicates the location of a bond to a carbamate group and indicates the location ofa bond to the pyrimidine group. In some embodiments, someembodiments, some embodiments, some embodiments, some embodiments, In some embodiments, when A is a bridged bicyclic heterocyclylene, m is 1. In some embodiments, when A is a bridged bicyclic heterocyclylene, m is 2. In some embodiments, the 4-11 membered heterocyclylene of A is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from C1-C4alkyl, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, C1-C4alkylene-CN, halo, amine, hydroxyl, and -C(=O)CH3. In some embodiments, the 4-11 membered heterocyclylene of A is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, and -C(=O)CH3. In some embodiments, the 4-11 membered heterocyclylene of A is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from - CH3, -CD3, -D, -F, -CN, -CH3CN, -NH2, -CH2OCH3, -OCH3, -CF2H, -CF3, -OH, -C1-C3alkylalcohol, and C1-C3alkoxyl.. In some embodiments, the 4-11 membered heterocyclylene of A is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from -CH3, -F, -CN, -NH2, -CH2OCH3, -OCH3, -CF2H, -CF3, -OH, - C1-C3alkylalcohol, and C1-C3alkoxyl. In some embodiments, C1-C3alkylalcohol is C1alkylalcohol. In some embodiments, C1-C3alkylalcohol is C2alkylalcohol. In some embodiments, C1-C3alkylalcohol is C3alkylalcohol. In some embodiments, C1-C3 alkylalcohol is -CH2OH, -(CH2)2OH, -CH(CH3)OH, -(CH2)3OH, or -C(CH3)2OH. In some embodiments, C1-C3alkoxyl is C1alkoxyl. In some embodiments, C1-C3alkoxyl is C2alkoxyl. In some embodiments, C1-C3alkoxyl is C3alkoxyl. In some embodiments, C1-C3alkoxyl is -OCH3, -CH2OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2OCH2CH3, or -(CH2)2OCH3. In some embodiments, the 4-11 membered heterocyclylene of A is substituted with one or more substituents each independently selected from from -CH3, -F, -OH, -CH2CN, and -CH2OH. In some embodiments, the 4-11 membered heterocyclylene of A is substituted with one or more substituents each independently selected from -C1-C4alkyl, -OH, -halo and -CN. In some embodiments, the A is selected from the group consisting of: group and indicates the location of a bond to the pyrimidine group. In some embodiments, the A is selected from the group consisting of: group. In some embodiments, A is a 6-11 membered bicyclic heterocyclylene. In some embodiments, A is a 7-11 membered bicyclic heterocyclylene. In some embodiments, A is a 6-10 membered bicyclic heterocyclylene. In some embodiments, A is a 7-10 membered bicyclic heterocyclylene. In some embodiments, A is a 6 membered bicyclic heterocyclylene. In some embodiments, A is a 7 membered bicyclic heterocyclylene. In some embodiments, A is an 8 membered bicyclic heterocyclylene. In some embodiments, A is a 9 membered bicyclic heterocyclylene. In some embodiments, A is a 10 membered bicyclic heterocyclylene. In some embodiments, A is an 11 membered bicyclic heterocyclylene. In some embodiments, some embodiments, A is .In some embodiments, some embodiments, A is . In someembodiments, In some embodiments, A is selected from the group consisting of: , , wherein * indicates the location of a bond to the carbamate group and indicates the location of a bond to the pyrimidine group. In some embodiments, B is an arylene or 5-10 membered heteroarylene, wherein the arylene or 5-10 membered heteroarylene is optionally substituted, wherein the 5-10 membered heteroarylene is not indazolylene. In some embodiments, the compound has one of the following structures of Formula (IA)-(IE): , wherein: R4is a hydrogen, C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, or - C(=O)CH3, wherein the remaining variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IA): wherein: R4is a hydrogen, C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, or - C(=O)CH3, wherein the remaining variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IB): wherein: R4is a hydrogen, C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, or - C(=O)CH3, wherein the remaining variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IC): wherein: R4is a hydrogen, C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, or - C(=O)CH3, wherein the remaining variables are as defined herein. In some embodiments, the compound has the following structure of Formula (ID): wherein: R4is a hydrogen, C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, or - C(=O)CH3, wherein the remaining variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IE): wherein: R4is a hydrogen, C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, or - C(=O)CH3, wherein the remaining variables are as defined herein. In some embodiments, R4is -H, -CH3, -F, -Cl, -CN, -NH2, -CH2OCH3, -OCH3, -CF2H, -CF3, -OH, -C1-C3alkylalcohol, C1-C3alkoxyl, or -C(=O)CH3. In some embodiments, -C1-C3alkylalcohol of R4is C1alkylalcohol. In some embodiments, R4is -H. In some embodiments, R4is -CH3. In some embodiments, R4is -F. In some embodiments, R4is -Cl. In some embodiments, R4is -CN. In some embodiments, R4is -NH2. In some embodiments, R4is - CH2OCH3. In some embodiments, R4is -OCH3. In some embodiments, R4is -CF2H. In some embodiments, R4is -CF3. In some embodiments, R4is -OH. In some embodiments, R4is -C1-C3alkylalcohol. In some embodiments, R4is C1-C3alkoxyl. In some embodiments, R4is -C(=O)CH3. In some embodiments, -C1-C3alkylalcohol of R4is C2alkylalcohol. In some embodiments, -C1-C3alkylalcohol of R4is C3alkylalcohol. In some embodiments, -C1-C3alkylalcohol of R4is -CH2OH, -(CH2)2OH, -CH(CH3)OH, -(CH2)3OH, or -C(CH3)2OH. In some embodiments, -C1-C3alkoxyl of R4is C1alkoxyl. In some embodiments, - C1-C3alkoxyl of R4is C2alkoxyl. In some embodiments, -C1-C3alkoxyl of R4is C3alkoxyl. In some embodiments, -C1-C3alkoxyl of R4is -OCH3, -CH2OCH3, -OCH2CH3, - O(CH2)2CH3, -CH2OCH2CH3, or -(CH2)2OCH3. In some embodiments, the compound has one of the following structures of Formula (IA-1)-(IE-1): , , , (IC-1) wherein the variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IA-1): . (IA-1) wherein the variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IB-1): . (IB-1) wherein the variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IC-1): . wherein the variables are as defined herein. In some embodiments, the compound has the following structure of Formula (ID-1): . (ID-1) wherein the variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IE-1): . wherein the variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IA-2): . (IA-2) wherein the variables are as defined herein. In some embodiments, the compound has the following structure of Formula (IA-3): , (IA-3) or a stereoisomer of the compound, tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein: R4is -H; B is an arylene or heteroarylene, wherein the arylene or heteroarylene is optionally substituted; R1is a hydrogen or C1-C3 alkyl; R2is a hydrogen, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, -(C1-C3alkylene)-heteroaryl, aryl fused to 4-8 membered heterocyclyl, or amine, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, 4-8 membered heterocyclyl, or amine is optionally substituted; L is C1-C8alkylene, C1-C8alkenylene, C1-C8alkynylene, or C1-C8heteroalkylene. wherein the C1-C8alkylene, C1-C8alkenylene, C1-C8alkynylene, or C1-C8heteroalkylene is optionally substituted; X is -O-, -NR3-, or a direct bond, wherein R3is a hydrogen or C1-C3alkyl; and Y is C1-C5alkylene, C1-C5deuteroalkylene, or a direct bond, wherein the C1-C5alkylene or C1-C5deuteroalkylene is optionally substituted, or a stereoisomer of the compound, salt of the compound or tautomer of the compound thereof. In some embodiments, B is arylene or 5-18 membered heteroarylene. In some embodiments, B is arylene or 5-14 membered heteroarylene. In some embodiments, wherein * indicates the location of a bond to L and indicates the location of a bond to the pyridine group, wherein RBis selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O- C1-C4alkylene, halo, hydroxyl, -C(=O)CH3, NH2, -NH(CH3), N(CH3)2; R6is selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene- CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2wherein RX1, RX2: are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy can be substituted with: C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, - C(O)NRX3RX4wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, or prodrug moiety R5. In some embodiments, B is or , wherein * indicates the location of a bond to L and indicates the location of a bond to the pyridine group. In some embodiments, B is an arylene or heteroarylene. In some embodiments, B is an arylene. In some embodiments, the arylene of B is a phenylene or naphthylene. In some specific embodiments, the arylene of B is a phenylene. In some other specific embodiments, the arylene of B is a naphthylene. In some other embodiments, B is a heteroarylene. In some embodiments, the heteroarylene is a 5-6 membered heteroarylene. In some embodiments, the heteroarylene of B is a pyridinylene or indazolylene. In some specific embodiments, the heteroarylene of B is a pyridinylene In some embodiments, the heteroarylene , wherein * indicates the location of a bond to the carbamate group and indicates the location of a bond to the pyrimidine group. In some embodiments, the arylene or heteroarylene of B is optionally substituted with one or more substituents each independently selected from H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1- C3alkyl, NRX1RX2, alkylene-cyclyl, heterocyclyl, aryl, heteroaryl, and a prodrug functional moiety R5, wherein the alkylene-cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy, wherein the C1-4 alkyl, C1-4 haloalkyl, or C1-4alkylene-C1-4alkoxy is optionally substituted with C1-4 alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, or -C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy. In some embodiments, the arylene or heteroarylene of B is optionally substituted with one or more substituents each independently selected from H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1- C3alkyl, NRX1RX2, C1-C4alkylene-C6-C10aryl, C1-C4alkylene-(5-10 membered heteroaryl), C1-C4alkylene-C3-C10cycloalkyl, C1-C4alkylene-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, and a prodrug functional moiety R5, wherein the C1-C4alkylene-C6-C10aryl, C1-C4alkylene-(5-10 membered heteroaryl), C1-C4 alkylene-C3-C10 cycloalkyl, C1-C4 alkylene-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl is optionally substituted, wherein RX1, RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy and wherein the C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy is optionally substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl , heterocyclyl, or -C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy. In some embodiments, the arylene or heteroarylene of B is optionally substituted with one or more substituents each independently selected from C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, CN and a prodrug functional moiety R5. In some embodiments, the arylene or heteroarylene of B is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, and a prodrug functional moiety R5. In some embodiments, wherein the arylene or heteroarylene of B is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from -CH3, -F, -Cl, -CN, -NH2, -CH2OCH3, -OCH3, -CF2H, -CF3, -OH, -C1-C3alkylalcohol, C1-C3alkoxyl, a prodrug functional moiety R5. In some embodiments, -C1-C3alkylalcohol is C1alkylalcohol. In some embodiments, -C1-C3alkylalcohol is C2alkylalcohol. In some embodiments, -C1-C3alkylalcohol is C3alkylalcohol. In some embodiments, -C1-C3alkylalcohol is -CH2OH, - (CH2)2OH, -CH(CH3)OH, -(CH2)3OH, or -C(CH3)2OH. In some embodiments, -C1-C3 alkoxyl is C1 alkoxyl. In some embodiments, -C1-C3 alkoxyl is C2 alkoxyl. In some embodiments, -C1-C3alkoxyl is C3alkoxyl. In some embodiments, -C1-C3alkoxyl is -OCH3, -CH2OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2OCH2CH3, or -(CH2)2OCH3. In some embodiments, the prodrug functional moiety R5is selected from the group wherein: Z1 and Z4 are each independently(i) -NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, C1-4heteroalkyl, or aryl wherein the alkyl, haloalkyl, alkoxy, heteroalkyl, aryl is optionally substituted with C1-4alkyl, C1-4haloalkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, or -C(O)NRX3RX4, wherein the heteroaryl is optionally substituted with C1-4alkyl, RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy; (ii) optionally substituted monocyclic, fused or bridged bicyclic 4-11 membered N- containing heterocyclyl or 4-11 membered N-containing heteroaryl, wherein the point of attachment is on N; (iii) optionally substituted C1-8alkylene, C2-6alkenylene, C2-6alkynylene, or C1-6heteroalkylene; (iv) optionally substituted 4-8 membered cycloalkyl, 4-10 membered aryl; or (v) -OM, wherein M is a metal; 37 Z2is (i) R′′, (R)—O—(R), (R)—S—(R), (R)—O—(R)-X, (R)—S—(R)-X, wherein the X is optionally substituted cycloalkyl, heterocyclyl, aryl, heteroaryl, (R)—O—C(O)—R′, or (R)— O—C(O)—O—R′, wherein R′′is optionally substituted C1-8alkyl, C2-6alkenyl, C2-6alkynyl, or C1-6heteroalkyl, wherein R is optionally substituted C1-8alkylene, C2-6alkenylene, C2-6alkynylene, or C1-6heteroalkylene; wherein R′is optionally substituted -NRX1RX2, C1-8alkyl, C2-6alkenyl, C2-6alkynyl, C1-8haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein RX1and RX2are each independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy; (iv) optionally substituted 4-10 membered aryl, 4-11 membered heteroaryl, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl; Z3is (i) R′′, which is optionally substituted C1-8alkyl, C2-6alkenyl, C2-6alkynyl, or C1-6heteroalkyl; or (ii) amino acid residue wherein amino acid residue is valine, leucine, isoleucine, phenylalanine, glycine, glutamate, aspartate, proline, lysine, tryptophan or serine; or (iii) optionally substituted 4-10 membered aryl, 4-11 membered heteroaryl, 4-8 membered cycloalkyl or 4-10 membered heterocyclyl; Z5 and Z6 are each independently(i) hydrogen; or (ii) R′′, (R)—O—(R), (R)—S—(R), (R)—O—(R)-X, (R)—S—(R)-X, wherein the X is optionally substituted cycloalkyl, heterocyclyl, aryl, heteroaryl, (R)—O—C(O)—R′, or (R)—O—C(O)—O—R′, wherein R′′is optionally substituted C1-8alkyl, C2-6alkenyl, C2-6alkynyl, or C1-6heteroalkyl, wherein R is optionally substituted C1-8alkylene, C2-6alkenylene, C2-6alkynylene, or C1-6heteroalkylene; wherein R′is optionally substituted - NRX1RX2, C1-8alkyl, C2-6alkenyl, C2-6alkynyl, C1-8haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein RX1and RX2are each independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy; or (iii) optionally substituted 4-10 membered aryl, 4-11 membered heteroaryl, 4-8 membered cycloalkyl or 4-10 membered heterocyclyl. In some embodiments, the prodrug functional moiety R5is , wherein Z1is monocyclic, fused or bridged bicyclic 4-11 membered N-containing heterocyclyl or 4-11 membered N-containing heteroaryl optionally substituted with 0 to 4 substituents, wherein the point of attachment is on N. In some embodiments, the prodrug functional moiety R5is , wherein Z1is monocyclic, fused or bridged bicyclic 4-11 membered N-containing heterocyclyl or 4-11 membered N-containing heteroaryl optionally substituted with 2 to 3 substituents, wherein the point of attachment is on N. 5 5 5 5 5 5 5 5 5 5 5 5 C1-3 alkyl, (C1-3 alkylene)—O—(C1-3 alkyl), (C1-3 alkylene)—O—C(O)—X, wherein the alkyl and X are optionally substituted. In some embodiments, the prodrug functional moiety R5is ,wherein Z3is optionally substituted 4-10 membered aryl, 4-11 membered heteroaryl, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl. In some embodiments, the prodrug functional moiety 5 In some embodiments, the prodrug functional moiety R5is , wherein Z4is monocyclic, fused or bridged bicyclic 4-11 membered N-containing heterocyclyl or 4-11 membered N-containing heteroaryl optionally substituted with 0 to 4 substituents, wherein the point of attachment is on N. In some embodiments, the prodrug functional moiety R5is ,wherein Z4is monocyclic, fused or bridged bicyclic 4-11 membered N-containing heterocyclyl or 4-11 membered N-containing heteroaryl optionally substituted with 2 to 3 substituents, wherein the point of attachment is on N. In some embodiments, the prodrug functional moiety , In some embodiments, the prodrug functional moiety , In some embodiments, the prodrug functional moiety R5is , In some embodiments, the prodrug functional moiety R5is selected from the group In some embodiments, the prodrug functional moiety In some embodiments, the prodrug functional moiety R5has one of the following structures: 59 In some embodiments, the prodrug functional moiety R5 is . In someembodiments, the prodrug functional moiety R5 is . In some embodiments, theprodrug functional moiety R5 is . In some embodiments, the prodrug functional. In some embodiments, the prodrug functional moiety R5 is. In some embodiments, the prodrug functional moiety R5is the prodrug functional moiety R5 is . Insome embodiments, the prodrug functional moiety R5is 5 . In some embodiments, the prodrug functional moiety R .5 In some embodiments, the prodrug functional moiety R . In someembodiments, the prodrug functional moiety R5 is . In some embodiments, the prodrug functional moiety R5is . In some embodiments, the prodrugfunctional moiety R5 is In some embodiments, the prodrug functional .In some embodiments, the prodrug functional moiety R5 is . In someembodiments, the prodrug functional moiety some embodiments, the prodrug functional moiety R5 is . In some embodiments, the prodrug functional moiety R5 is . In someembodiments, the prodrug functional moiety R5 . In some embodiments, the prodrug functional moiety R5 is . In some embodiments, the prodrugfunctional moiety R5 is . In some embodiments, the prodrug functionalmoiety R5 is . In some embodiments, the prodrug functional moiety R5 is. In some embodiments, the prodrug functional moiety R5 is .In someembodiments, the prodrug functional moiety R5 is . In some embodiments, the prodrug functional moiety R5 is . In some embodiments, the prodrug functionalmoiety R5 is . In some embodiments, the prodrug functional moiety R5 is. In some embodiments, the prodrug functional moiety R5is some embodiments, the prodrug functional moiety R5is some embodiments, the prodrug functional moiety R5 is .In some embodiments, the prodrug functional moiety R5 is embodiments, the prodrug functional moiety R5 embodiments, the prodrug functional moiety embodiments, the prodrug functional moiety R5 . In someembodiments, the prodrug functional moiety R5 . In some embodiments, theprodrug functional moiety R5 is . In some embodiments, the prodrugfunctional moiety R5 is . In some embodiments, the prodrug functional moiety . In some embodiments, the prodrug functional moiety R5 is. In some embodiments, the prodrug functional moiety R5 is .In some embodiments, the prodrug functional moiety R5 is . In someembodiments, the prodrug functional moiety R5 is . In some embodiments, the5 prodrug functional moiety R . In some embodiments, the prodrugfunctional moiety R5 In some embodiments, the prodrug functional moietysome embodiments, the prodrug functional moiety R5 issome embodiments, the prodrug functional moiety R5is embodiments, the prodrug functional moiety In some embodiments, the prodrug functional moiety someembodiments, the prodrug functional moiety some embodiments, the prodrug functional moiety R5 is . In someembodiments, the prodrug functional moiety R5 is .In some embodiments, B has one of the following structures: wherein * indicates the location of a bond to L and indicates the location of a bond to the pyridine group. In some embodiments, B has one of the following structures: indicates the location of a bond to the pyridine group. In some embodiments, B is some embodiments, B is . In some embodiments, B is . In some embodiments, B is . In some embodiments, B isIn some embodiments, some embodiments, B is . In some embodiments, B is . In some embodiments, B . In some embodiments, B is . In some embodiments, B is . In some embodiments, some embodiments, B is , wherein B is further optionally substituted, wherein * indicates the location of a bond to L and indicates the location of a bond to the pyridine group. In some embodiments, , wherein * indicates the location of a bond to L and indicates the location of a bond to the pyridine group. In one embodiment, L is C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1- C8heteroalkylene. In some embodiments, L is C1-C8alkylene. In some embodiment, L is C2-C8alkenylene. In some embodiments, L is C2-C8alkynylene. In some embodiment, L is C1-C8heteroalkylene. In some other embodiments, L is C1-C6alkylene, C2-C6alkenylene, C2-C6alkynylene, or C1-C6heteroalkylene. In some other embodiments, L is C1-C4alkylene, C2-C4alkenylene, C2-C4alkynylene, or C1-C4heteroalkylene. In some other embodiments, L is C2-C4alkylene, C2-C4alkenylene, C2-C4alkynylene, or C2-C4heteroalkylene. In some other embodiments, L is C2-C6alkylene, C2-C6alkenylene, C2-C6alkynylene, or C2-C6 heteroalkylene. In some embodiments, the C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1- C8heteroalkylene of L is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from halo, -D, C1-C4alkyl, and C3-C5cycloalkyl. In some embodiments, the C1-C8alkylene of L is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from halo, -D, C1-C4alkyl, C3- C5cycloalkyl. In some other embodiments, the C2-C8alkenylene of L is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from halo, -D, C1-C4alkyl, and C3-C5cycloalkyl. In some other embodiments, the C2-C8alkynylene of L is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from halo, -D, C1-C4alkyl, and C3-C5cycloalkyl. In some other embodiments, the C1-C8 heteroalkyl of L is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from halo, -D, C1-C4 alkyl, or C3-C5 cycloalkyl. In some specific embodiments, the C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1-C8heteroalkylene of L is substituted with -F, -D, -CH3, -CH2CH3, -CF3, - CF2H, or one or more carbon atoms of the C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1-C8heteroalkylene are substituted with a substituent each independently selected from . In some specific embodiments, the C1-C8alkylene of L is substituted with -F, -D, -CH3, -CH2CH3, -CF3, -CF2H, or one or more carbon atoms of the C1- C8alkylene are substituted with a substituent each independently selected from and . In some other specific embodiments, the C2-C8 alkenyl of L is substituted with -F, - D, -CH3, -CH2CH3, -CF3, -CF2H, or one or more carbon atoms of the C2-C8alkenylene are substituted with a substituent each independently selected from . In some other specific embodiments, the C2-C8alkynylene of L is substituted with -F, -D, -CH3, - CH2CH3, -CF3, or -CF2H, or one or more carbon atoms of the C2-C8alkynylene are substituted with a substituent each independently selected from and . In some other specific embodiments, the C1-C8heteroalkyl of L is substituted with -F, -D, -CH3, - CH2CH3, -CF3, or -CF2H, or one or more carbon aroms of the C1-C8heteroalkylene is substituted with a substituent each independently selected from and . In some embodiments, L is selected from the group consisting of: C1-C8 alkylene, C2- C8 alkenylene, and C2-C8 alkynylene, wherein the C1-C8 alkylene, C2-C8 alkenylene, and C2- C8alkynylene are optionally substituted with one or more substituents each independently selected from halo and -D. In some embodiments, L is selected from the group consisting of: C1-C6alkylene, C2- C6alkenylene, and C2-C6alkynylene, wherein the C1-C6alkylene, C2-C6alkenylene, and C2- C6alkynylene are optionally substituted with one or more substituents each independently selected from halo and -D. In some embodiments, L is selected from the group consisting of: C2-C4alkylene, C2- C4alkenylene, and C2-C4alkynylene, wherein the C2-C4alkylene, C2-C4alkenylene, and C2- C4alkynylene are optionally substituted with one or more substituents each independently selected from halo and -D. In some embodiments, L is selected from the group consisting of: –(CH2)4-, –(CH2)3-, –(CH2)2-, *–CH2CH=CH–**, *–(CH2)2CH=CH–**, *–(CH2)2C≡C–**, *–CH2C≡C–**, – CH2CHFCH2–, –CH2CF2CH2–, *–CH(CH3)CH2CH2–**, *–(CH2)CH(CH2)- **, *– (CH2)2CH(CH2)- **, *–(CH2)C(CH)2-**, and *–(CH2)2C(CH2)-**, wherein * indicates the location of the bond to the carbamate group and ** indicates the location of the bond to B group. In some embodiments, L is –(CH2)4-. In some embodiments, L is –(CH2)3-. In some embodiments, L is –(CH2)2-. In some embodiments, L is *–CH2CH=CH–**. In some embodiments, L is*–(CH2)2CH=CH–**. In some embodiments, L is *–(CH2)2C≡C–**. In some embodiments, L is *–CH2C≡C–**. In some embodiments, L is –CH2CHFCH2–. In some embodiments, L is –CH2CF2CH2–. In some embodiments, L is *–CH(CH3)CH2CH2– **. In some embodiments, L is *–(CH2)CH(CH2)- **. In some embodiments, L is *– (CH2)2CH(CH2)- **. In some embodiments, L is *–(CH2)C(CH)2-**. In some embodiments, L is *–(CH2)2C(CH2)-**. In some specific embodiments, L is –(CH2)3-, –(CH2)2-, *–(CH2)CH(CH2)- **, *– (CH2)2CH(CH2)-**, *–(CH2)C(CH)2-**, or *–(CH2)2C(CH2)- **, wherein * indicates the location of the bond to the carbamate group and ** indicates the location of the bond to B group. In some other specific embodiments, L is –(CH2)3- or –(CH2)2-. In some embodiments, L is –(CH2)3-. In some embodiments, L is –(CH2)2-. In some embodiments, L is *–(CH2)CH(CH2)- **. In some embodiments, L is *–(CH2)2CH(CH2)- **. In some embodiments, L is *–(CH2)C(CH)2-**. In some embodiments, L is *–(CH2)2C(CH2)- **. In some embodiments, L is –(CH2)3-. In one embodiment, R2is a hydrogen, 4-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, heteroaryl, or amine. In some embodiments, R2is a hydrogen. In some embodiments, R2is 4-8 membered cycloalkyl. In some embodiments, the 4-8 membered cycloalkyl of R2is a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In some embodiments, the 4-8 membered cycloalkyl of R2is a cyclopropyl. In some embodiments, the 4-8 membered cycloalkyl of R2is cyclobutyl. In some embodiments, the 4-8 membered cycloalkyl of R2is cyclopentyl. In some embodiments, the 4-8 membered cycloalkyl of R2is cyclohexyl. In some embodiments, the 4-8 membered cycloalkyl of R2is cycloheptyl. In some embodiments, the 4-8 membered cycloalkyl of R2is cyclooctyl. In some other embodiments, R2is 4-10 membered heterocyclyl. In some embodiments, the 4-10 membered heterocyclyl of R2is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxanyl, piperazinyl, morpholinyl, dioxanyl, azepanyl, oxepanyl, homopiperazinyl, or oxazepanyl. In some embodiments, the 4-10 membered heterocyclyl of R2is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl. In some embodiments, the 4-10 membered heterocyclyl of R2is azetidinyl. In some embodiments, the 4-10 membered heterocyclyl of R2is pyrrolidinyl. In some embodiments, the 4-10 membered heterocyclyl of R2is tetrahydrofuranyl. In some embodiments, the 4-10 membered heterocyclyl of R2is piperidinyl. In some embodiments, the 4-10 membered heterocyclyl of R2is oxanyl. In some embodiments, the 4-10 membered heterocyclyl of R2is piperazinyl. In some embodiments, the 4-10 membered heterocyclyl of R2is morpholinyl. In some embodiments, the 4-10 membered heterocyclyl of R2is dioxanyl. In some embodiments, the 4-10 membered heterocyclyl of R2is azepanyl. In some embodiments, the 4-10 membered heterocyclyl of R2is oxepanyl. In some embodiments, the 4-10 membered heterocyclyl of R2is homopiperazinyl. In some embodiments, the 4-10 membered heterocyclyl of R2is oxazepanyl. In some other embodiments, R2is heteroaryl (e.g., 5-6 membered heteroaryl). In some embodiments, the heteroaryl of R2is imidazolyl, pyrazolyl, or pyridinyl. In some embodiments, the heteroaryl of R2is imidazolyl. In some embodiments, the heteroaryl of R2is pyrazolyl. In some embodiments, the heteroaryl of R2is pyridinyl. In some other embodiments, R2is a bicyclic heterocyclyl. In some embodiments, the bicyclic of R2is a fused bicyclic heterocyclyl, a spiro bicyclic heterocyclyl, or a bridged bicyclic heterocyclyl. In some embodiments, the bicyclic heterocyclyl of R2is a fused bicyclic heterocyclyl. In some embodiments, the fused bicyclic of R2is hexahydro-1H- pyrrolizinyl, octahydro-6λ2-pyrrolo[3,4-b]pyridinyl, octahydro-1H-cyclopenta[b]pyridinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, 2-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.1.0]hexanyl, or 1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, the fused bicyclic heterocyclyl of R2is hexahydro-1H-pyrrolizinyl. In some embodiments, the fused bicyclic heterocyclyl of R2is octahydro-6λ2-pyrrolo[3,4-b]pyridinyl. In some embodiments, the fused bicyclic heterocyclyl of R2is octahydro-1H-cyclopenta[b]pyridinyl. In some embodiments, the fused bicyclic heterocyclyl of R2is hexahydro-1H-pyrrolo[2,1- c][1,4]oxazinyl. In some embodiments, the fused bicyclic heterocyclyl of R2is 2- azabicyclo[3.1.0]hexane, 3-azabicyclo[3.1.0]hexanyl. In some embodiments, the fused bicyclic heterocyclyl of R2is 1,2,3,4-tetrahydroisoquinolinyl. In some embodiments, the bicyclic heterocyclyl of R2is a spiro bicyclic heterocyclyl. In some embodiments, the spiro bicyclic heterocyclyl of R2is tetrahydro-1'H,3'H- spiro[cyclopropane-1,2'-pyrrolizinyl] or 5-azaspiro[2.4]heptanyl. In some embodiments, the spiro bicyclic heterocyclyl of R2is tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizinyl]. In some embodiments, the spiro bicyclic heterocyclyl of R2is 5-azaspiro[2.4]heptanyl. In some embodiments, the bicyclic heterocyclyl of R2is a bridged bicyclic heterocyclyl. In some embodiments, the bridged bicyclic heterocyclyl of R2is 2-oxa-5- azabicyclo[2.2.1]heptanyl. In some embodiments, the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, or amine of R2is substituted with one or more substituents each independently selected from H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4 alkyl, halo, hydroxyl, -C(=O)-C1-C3 alkyl, NRX1RX2, C1-C4 alkylene-C6- C10aryl, C1-C4alkylene-(5-10 membered heteroaryl), C1-C4alkylene-C3-C10cycloalkyl, C1- C4alkylene-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, C1-C4alkylene- NRX1RX2, =CH2, =CF2or =CFH, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy. In some embodiments, the 4-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, heteroaryl, or amine of R2is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from halo, deuterium, C1-C4alkyl, C1-C4heteroalkyl, hydroxyl, =CH2, =CF2, =CFH,heteroaryl, -and (CH2)p-4-6 membered heterocycloalkyl, wherein p is an integer between 1 and 3. In some specific embodiments, the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, or amine of R2is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from -CH3, -F, -CN, -NH2, -CH2OCH3, -OCH3, -CF2H, -CF3, -OH, =CH2, =CF2, =CFH,heteroaryl, -C1-C3alkylalcohol, C1-C3alkoxyl, and deuterium. In some embodiments, R2is aryl (e.g., phenyl) fused to 4-8 membered heterocyclyl, wherein the 4-8 membered heterocyclyl is optionally substituted. In some embodiments, the aryl (e.g., phenyl) fused to 4-8 membered hetererocyclyl is In some embodiments, the 4-8 membered cycloalkyl, 4-10 membered heterocycloalkyl, heteroaryl, or amine of R2is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from halo, deuterium, C1-C4alkyl, C1-C4 alkylene-NRX, C1-C4 alkylene-(4-10 membered heterocyclyl), C1-C4 heteroalkyl, hydroxyl, =CH2, =CF2, =CFHand heteroaryl, each RXis independently hydrogen or C1-C4 alkyl. In some specific embodiments, the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, or amine of R2is substituted with one or more substituents (e.g., 1, 2, 3, 4, or 5 substituents) each independently selected from -CH3, -F, -CN, -NH2, -CH2OCH3, -OCH3, -CF2H, -CF3, -OH, =CH2, =CF2, =CFH,heteroaryl, -C1-C3alkylalcohol, C1-C3alkoxyl, deuterium, -CH2N(CH3)2, and -CH2-(6-membered heterocyclyl). In some embodiments , the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, or amine of R2is substituted with one or more substituents each independentlyselected from the group consisting of -CH3, -F, =CF2, =CFH, =CH2, and -OH.In some other embodiments, R2is an amine. In some embodiments, the amine of R2is -NH2, -NH(CH3), or -N(CH3)2. In some embodiments, the amine of R2is -NH2. In some embodiments, the amine of R2is -NH(CH3). In some embodiments, the amine of R2is - N(CH3)2. In some embodiments, R2is selected from the group consisting of 4-10 membered heterocyclyl, 5-6 membered heteroaryl, and amine, wherein the 4-10 membered heterocyclyl, 5-6 membered heteroaryl, and amine are optionally substituted with one or more substituentseach independently selected from the group consisting of -CH3, -F, =CF2, =CFH, =CH2, and -OH. In some embodiments, R2has one of the following structures: 5 In some embodiments, some embodiments, someembodiments, some embodiments, someembodiments, some embodiments, someembodiments, R2 is . In some embodiments, R2 is . In someembodiments, some embodiments, some embodiments,some embodiments, some embodiments, R2 is. In some embodiments, some embodiments, R2 is some embodiments, R2 is . In some embodiments, R2 is . In some embodiments, R2 is In some embodiments, R2 is . In some embodiments, R2 is . In someembodiments, R2 is . In some embodiments, R2 is . In someembodiments, some embodiments, R2 is . In some embodiments, R2 is . In some embodiments, R2 is . In someembodiments, R2 is . In some embodiments, R2 is . In someembodiments, R2 is . In some embodiments, someembodiments, some embodiments, R2 is .In some embodiments, R2has one of the following structures: In some embodiment, R2is selected from the group consisting of: In some embodiments, R2is . In some other embodiments, R2is . In one embodiment, R1is a hydrogen or C1-C3alkyl. In some embodiments, R1is a hydrogen. In some embodiments, R1is C1-C3alkyl. In some embodiments, R1is a hydrogen, -CH2CH3, or -CH3. In some other specific embodiments, R1is -CH2CH3. In some other specific embodiments, R1is -CH3. In one embodiment, X is -O-, -NR3-, or a direct bond. In one embodiment, X is -O- or a direct bond. In some embodiments, X is -O-. In some other embodiments, X is -NR3-. In some embodiments, when X is -NR3-, R3is a hydrogen or C1-C3alkyl. In some embodiments, when X is -NR3-, R3is a hydrogen or -CH3. In some other embodiments, X is a direct bond. In one embodiment, Y is C1-C5alkylene, C1-C5deuteroalkylene, or a direct bond. In some embodiments, Y is -CH2-, -CD2-, -CH(CH3)-, -CD(CH3)-, -CD(CD3)-, or a direct bond. In some specific embodiments, Y is -CH2-. In some specific embodiments, Y is -CD2-. In some specific embodiments, Y is -CH(CH3)-. In some specific embodiments, Y is -CD(CH3)-. In some specific embodiments, Y is -CD(CD3)-. In some specific embodiments, Y is a direct bond. In some embodiments, Y is -CH2-, -CD2-, -CH2-CH2-, or a direct bond. In some specific embodiments, Y is -CH2-. In some specific embodiments, Y is -CD2-. In some specific embodiments, Y is -CH2-CH2-. In some specific embodiments, Y is a direct bond. In some embodiments, the C1-C5alkylene or C1-C5deuteroalkylene of Y is substituted with methyl, dimethyl, or cyclopropyl. In some embodiments, one or more carbons of the C1-C5 alkylene or C1-C5 deuteroalkylene are substituted with cyclopropyl. In some embodiments, the C1-C5alkylene of Y is substituted with methyl, dimethyl, or cyclopropyl. For example, Y is C1-C5alkylene substituted with a cyclopropyl. In some specific embodiments, Y is , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In another example, Y is , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In some embodiments, the C1-C5 deuteroalkylene of Y is further substituted with methyl, dimethyl, or cyclopropyl. For example, Y is the C1-C5 deuteroalkyl substituted with a cyclopropyl. In some specific embodiments, Y , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In another example, Y is , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In another example, Y is , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In another example, Y is , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In another 1- example, Y isD 3 1-2D D D, wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In another example, Y is wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In another example, Y is , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In another example, Y is , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In another example, Y is , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In some embodiments, Y is , or , wherein * indicates the location of a bond to R2, and indicates the location of a bond to X. In some embodiments, when X and Y are both direct bonds, the compound has the following structure of Formula (II): In some specific a hydrogen. In some embodiments, the compound has the following structure of Formula (III): or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein L is selected from the group consisting of linear C3-C5alkylene and linear C3-C5deuteroalkylene, wherein the linear C3-C5alkylene or linear C3-C5deuteroalkylene is optionally substituted with C1-C2alkyl, C1-C2haloalkyl, CN, halo, OH, NH2, -NH(CH3) or N(CH3)2; RAis selected from the group consisting of alkylenecyclyl, heterocyclyl, aryl, or heteroaryl, H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy, wherein the alkylene-cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted, wherein the C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy is optionally substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl , heterocyclyl, -C(O)NRX3RX4wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, or prodrug moiety R5; RBis selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene- CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the alkyl, haloalkyl, alkoxy can be substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl , heterocyclyl, or -C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy; RCis selected from the group consisting of H, D, C1-C2alkyl, C1-C2alkoxy, halo, CN, NH2, -NH(CH3), and N(CH3)2; RDis selected from the group consisting of H, D, C1-C3 alkyl, C1-C2 deuteroalkyl, C1- C3 haloalkyl, C1-C3 alkylalcohol, (C1-C3 alkylene)-O-(C1-C3 alkyl), and CN; REand RFare each independently selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, and NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the alkyl, haloalkyl, alkoxy can be substituted with: C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, - C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy; R1is selected from the group consisting of H, D, C1-C2alkyl, C1-C2alkoxy, halo, CN, NH2, -NH(CH3), and N(CH3)2; Y is selected from the group consisting of C1-C5 alkylene, C1-C5 deuteroalkylene, or a direct bond, wherein the C1-C5alkylene or C1-C5deuteroalkylene is optionally substituted;R2is selected from the group consisting of hydrogen, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, -(C1-C3alkylene)-heteroaryl, aryl fused to 4-8 membered heterocyclyl, and amine, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, 4-8 membered heterocyclyl, or amine is optionally substituted. In some embodiments, the compound has one of the following structures of Formula (IIIA), (IIIB) or (IIIC): wherein the variables are as defined herein. In some embodiments, the compound has the following structure of Formula (III-1): (III-1) wherein L is selected from the group consisting of linear C3-C5alkylene and linear C3-C5deuteroalkylene, wherein the linear C3-C5alkylene or linear C3-C5deuteroalkylene is optionally substituted with C1-C2alkyl, C1-C2haloalkyl, CN, halo, OH, NH2, -NH(CH3) or N(CH3)2; RAis selected from the group consisting of alkylenecyclyl, heterocyclyl, aryl, or heteroaryl, H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy, wherein the alkylene-cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted, wherein the C1-C4alkyl, C1-C4haloalkyl, C1-4alkylene-C1-4alkoxy is optionally substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl , heterocyclyl, -C(O)NRX3RX4wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, or prodrug moiety R5; RBis selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene- CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the alkyl, haloalkyl, alkoxy can be substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, or -C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4 alkyl, C1-4 haloalkyl, C1-4alkylene-C1-4alkoxy; RDis selected from the group consisting of H, D, C1-C3 alkyl, C1-C2 deuteroalkyl, C1- C3haloalkyl, C1-C3alkylalcohol, (C1-C3alkylene)-O-(C1-C3alkyl), and CN; REand RFare each independently selected from the group consisting of H, C1-C4 alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, and NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the alkyl, haloalkyl, alkoxy can be substituted with: C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, - C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy; R1is selected from the group consisting of H, D, C1-C2alkyl, C1-C2alkoxy, halo, CN, NH2, -NH(CH3), and N(CH3)2; Y is selected from the group consisting of C1-C5alkylene, C1-C5deuteroalkylene, or a direct bond, wherein the C1-C5alkylene or C1-C5deuteroalkylene is optionally substituted;R2is selected from the group consisting of hydrogen, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, -(C1-C3 alkylene)-heteroaryl, aryl fused to 4-8 membered heterocyclyl, and amine, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, 4-8 membered heterocyclyl, or amine is optionally substituted. In some embodiments, the compound has one of the following structures of Formula (IIIA), (IIIB) or (IIIC): (III-1B) (III-1C) wherein the variables are as defined herein. In some embodiments, L is selected from the group consisting of unsubstituted linear C3-alkylene, unsubstituted linear C4-alkylene, linear C3-alkylene substituted with -CH3,CN, F, or Cl, or linear C4-alkylene substituted with -CH3,CN, F, or Cl. In some embodiments, RA is selected from the group consisting of H, OH, C1-C 4alkylalcohol, F, Cl, C1-C2alkyl, C1-C2NHC(O)NHCH3, -CHF2, R5prodrug moiety, In some embodiments, RBis selected from the group consisting of H, C1-C4alkyl, C1- C4haloalkyl, C1-C4heteroalkyl, halo, NH2, -NH(CH3), N(CH3)2, and OH. In some embodiments, RBis selected from the group of H, CH3, F, and Cl. In some embodiments, has the structure of the following: , wherein * indicates the location of a bond to L and indicates the location of a bond to the pyrimidine group. In some embodiments, RC is selected from the group consisting of H, -CH3, and -OCH3. In some embodiments, RDis selected from the group consisting of -CH3,C1-haloalkyl, -CF3, -CH2CH2OH, -CH2OH, -CH2CHF2, and -CH2-O-CH3. In some embodiments, REand RFare each independently selected from the group consisting of H, D, F, Cl, CH3, C1haloalkyl, and -OCH3. wherein * indicates the location of a bond to the carbamate group and indicates the location of a bond to the pyrimidine group. In some embodiments, R1 is selected from the group consisting of H, CH3, and C1haloalkyl. In some embodiments, Y is C1-C3alkylene optionally substituted with C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, cyclopropyl, and NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, or C1-4haloalkyl. In some embodiments, wherein Y is substituted C3alkylene, wherein the substituted C3 alkylene is , wherein represents the point of attachment to X and represents the point of attachment to R2. In some embodiments, R2is selected from the group consisting of , morpholinyl, or pyrrolidinyl, wherein , morpholinyl, or pyrrolidinyl is optionally substituted with C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, cyclopropyl, or NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, or C1-4haloalkyl. In some embodiments, R2is selected from the group consisting of: In some embodiments, the compound has the following structure of Formula (IV): or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein L is selected from the group consisting of : C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, C1-C8heteroalkylene, wherein the C1-C8alkylene, C1-C8alkenylene, C1-C8alkynylene, or C1-C8heteroalkylene is optionally substituted, —O-( C1-C8alkylene)—, —O- (C2-C8alkenylene)—, —O-( C2-C8alkynylene)—, —O-(C1-C8heteroalkylene)—, —S-( C1- C8 alkylene)—, —S-(C2-C8 alkenylene)—, —S-( C2-C8 alkynylene)—, —S-(C1-C8 heteroalkylene)—, —NR-( C1-C8alkylene)—, —NR-(C2-C8alkenylene)—, —NR-( C2-C8alkynylene)—, and —NR-(C1-C8heteroalkylene)—; RBis selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O- C1-C4alkylene, halo, hydroxyl, -C(=O)CH3, NH2, -NH(CH3), N(CH3)2; R6is selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene- CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2wherein RX1, RX2: are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy can be substituted with: C1-4 alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, - C(O)NRX3RX4wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, or prodrug moiety R5; X, Y, and R2are as defined in claim 17; REand RFare each independently H, C1-C4alkyl, C1-C4haloalkyl, C1-C4heteroalkyl, halo, NRX1RX2, hydroxyl, or CN, wherein RX1and RX2are each independently H or C1-4alkyl. In some embodiments, the compound has the following structure of Formula (IVA): wherein the variables are as defined herein. In some embodiments, L is linear C2-C5 alkylene optionally substituted with C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, or CN. In some embodiments, RBis H, F, Cl, -CH3, -CD3, -CF3, -CH2CH3, OH, CN, or NH2. In some embodiments, R6is H, F, Cl, -CH3, -CD3, -CF3, -CH2CH3, OH, CN, or NH2. In some embodiments, RBis CN or Cl. location of a bond to the pyridine group. In some embodiments, REand RFare each independently H, F, Cl, -CH3, -CD3, -CF3, - CH2CH3, OH, CN, or NH2. In some embodiments of Formula (I), (IA-3), (II), (III), or (IV) or a subformula thereof (e.g., Formula (IA), Formula (IA-2), Formula (IIIA), Formula (IIIB), Formula (IIIC), Formula (III-1), Formula (III-1A), Formula (III-1B), Formula (III-1C), Formula (IVA)), each of the optional substituent mentioned herein may be selected from the group consisting of C1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6deuteroalkyl, -D, C1-C6heteroalkyl, CN, C1-C6alkylene-CN, C1-C6alkylalcohol, C1-C6alkylene-O-C1-C6alkyl, halo, hydroxyl, -C(=O)-C1-C6alkyl, NRX1RX2, C1-C6alkylene-phenyl, C1-C6alkylene-(5-10 membered heteroaryl), C1-C6alkylene-(C3-10cycloalkyl), C1-C6alkylene-(5-10 membered heterocyclyl), 5-10 membered heterocyclyl, C3-10cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, and a prodrug functional moiety R5(as defined herein), wherein the 5- 10 membered heterocyclyl, C3-10cycloalkyl, phenyl, naphthyl, or 5-10 membered heteroaryl is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuteroalkyl, -D, C1-C6 heteroalkyl, CN, C1-C6 alkylene-CN, C1-C6 alkylalcohol, C1- C6alkylene-O-C1-C6alkyl, halo, hydroxyl, -C(=O)-C1-C6alkyl, or NRX1RX2, wherein RX1and RX2are each independently H, C1-6alkyl, C1-6haloalkyl, or C1-C6alkylene-(C1-6alkoxy), and wherein the C1-6alkyl, C1-6haloalkyl, or C1-C6alkylene-C1-6alkoxy is optionally substituted with C1-6alkyl, halo, OH, or CN. In some embodiments of Formula (I), (IA-3), (II), (III), or (IV) or a subformula thereof (e.g., Formula (IA), Formula (IA-2), Formula (IIIA), Formula (IIIB), Formula (IIIC), Formula (III-1), Formula (III-1A), Formula (III-1B), Formula (III-1C), Formula (IVA)), each of the optional substituent mentioned herein may be selected from the group consisting of C1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6deuteroalkyl, -D, C1-C6heteroalkyl, CN, C1-C6alkylene-CN, C1-C6alkylalcohol, C1-C6alkylene-O-C1-C6alkyl, halo, hydroxyl, -C(=O)-C1-C6 alkyl, NRX1RX2, 5-10 membered heterocyclyl, C3-10 cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, and a prodrug functional moiety R5(as defined herein), wherein RX1and RX2are each independently H, C1-6alkyl, or C1-6haloalkyl. In some embodiments of Formula (I), (IA-3), (II), (III), or (IV) or a subformula thereof (e.g., Formula (IA), Formula (IA-2), Formula (IIIA), Formula (IIIB), Formula (IIIC), Formula (III-1), Formula (III-1A), Formula (III-1B), Formula (III-1C), Formula (IVA)), each of the optional substituent mentioned herein may be selected from the group consisting of C1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6deuteroalkyl, -D, C1-C6heteroalkyl, CN, C1-C6alkylene-CN, C1-C6alkylalcohol, C1-C6alkylene-O-C1-C6alkyl, halo, hydroxyl, -C(=O)-C1-C6alkyl, NRX1RX2, 5-10 membered heterocyclyl, C3-10cycloalkyl, phenyl, naphthyl, and 5-10 membered heteroaryl, wherein RX1and RX2are each independently H, C1-6alkyl, or C1-6haloalkyl. In some embodiments of Formula (I), (IA-3), (II), (III), or (IV) or a subformula thereof (e.g., Formula (IA), Formula (IA-2), Formula (IIIA), Formula (IIIB), Formula (IIIC), Formula (III-1), Formula (III-1A), Formula (III-1B), Formula (III-1C), Formula (IVA)), each of the optional substituent mentioned herein may be selected from the group consisting of C1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6deuteroalkyl, -D, C1-C6heteroalkyl, CN, C1-C6alkylene-CN, C1-C6alkylalcohol, C1-C6alkylene-O-C1-C6alkyl, halo, hydroxyl, -C(=O)-C1-C6alkyl, NRX1RX2, cyclopropyl, and a prodrug functional moiety R5(as defined herein), wherein RX1and RX2are each independently H, C1-6alkyl, or C1-6haloalkyl. In some embodiments of Formula (I), (IA-3), (II), (III), or (IV) or a subformula thereof (e.g., Formula (IA), Formula (IA-2), Formula (IIIA), Formula (IIIB), Formula (IIIC), Formula (III-1), Formula (III-1A), Formula (III-1B), Formula (III-1C), Formula (IVA)), each of the optional substituent mentioned herein may be selected from the group consisting of C1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6deuteroalkyl, -D, C1-C6heteroalkyl, CN, C1-C6alkylene-CN, C1-C6alkylalcohol, C1-C6alkylene-O-C1-C6alkyl, halo, hydroxyl, -C(=O)-C1-C6alkyl, NRX1RX2, and cyclopropyl, wherein RX1and RX2are each independently H, C1-6alkyl, or C1-6haloalkyl. In one embodiment, the compound of formula of (I), (II), (IA)-(IE), or (IA-1)-(IE-1) has one of the following structures shown in Table 1 below. Table 1: List of Compounds of (I), (II), (IA)-(IE), or (IA-1)-(IE-1)

[0002]

[0003]

[0004]

[0005]

[0006]

[0007]

[0008]

[0009]

[0010]

[0011]

[0012]

[0013]

[0014]

[0015]

[0016] 177

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028] As can be appreciated, the compounds described herein provide new therapies for disease without the need for exotic chemistry or specialized reagents or manufacturing techniques. III Pharmaceutical compositions Other embodiments are directed to pharmaceutical compositions. In an embodiment, the pharmaceutical composition comprises any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent). Non-limiting examples of such additional therapeutic agents are described herein below. Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, optical, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically. In treatment methods according to embodiments of the disclosure, an effective amount of at least one compound of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. Effective amounts or doses may be ascertained by methods such as modeling, dose escalation studies or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. The compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.001 to 0.1 mg, 0.01 to 0.1 mg, 0.5 to 5 mg, 0.5 to 10 mg, 0.01-10 mg, 0.1 to 10 mg, 10 to 5000 mg, 100 to 5000 mg, 1000 mg to 4000 mg per day, or 1000 to 3000 mg per day are examples of dosages that are used in some embodiments. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. In some embodiments, compounds of the disclosure are administered in a single dose. In an embodiment, the single dose is administered orally. In another embodiment, the single dose is administered by injection. However, other routes are used as appropriate. In some embodiments, compounds of the disclosure are administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment compounds of the disclosure and another agent (e.g., an additional anti-cancer agent) are administered together about once per day to about 6 times per day. In another embodiment the administration of compounds of the disclosure and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary. Administration of compounds of the disclosure may continue as long as necessary. In some embodiments, compounds of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, compounds of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, compounds of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. In some embodiments, the compounds of the disclosure are administered in individual dosage forms. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the disclosed compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999). Provided herein are pharmaceutical compositions comprising one or more compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III- 1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA),and a pharmaceutically acceptable carrier. Also provided herein are pharmaceutical compositions comprising one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more compounds of Formula (I), (II), (IA)- (IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)- (IIIC), (IV) or (IVA). A pharmaceutical composition, as used herein, refers to a mixture of one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, therapeutically effective amounts of one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures. In one embodiment, one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III- 1C)), (IIIA)-(IIIC), (IV) or (IVA) are formulated in aqueous solutions. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer. In other embodiments, one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients. In another embodiment, compounds described herein are formulated for oral administration. Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like. In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a pharmaceutically acceptable salt thereof such as sodium alginate. In one embodiment, the oral dosage forms, such as a pill, capsule or tablet, comprises one or more suitable layers or coatings. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses. In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. In additional embodiments, suspensions of one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient, and one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, pharmaceutically acceptable salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances. Methods for the preparation of compositions comprising the compounds described herein include formulating the compound(s) with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid composition. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, ointments, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth. In some embodiments, pharmaceutical compositions comprising one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a suspension, a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran. Pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers. Furthermore, pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range. Compositions also, optionally, include one or more pharmaceutically acceptable salts in an amount required to bring osmolality of the composition into an acceptable range. Such pharmaceutically acceptable salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable pharmaceutically acceptable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride. Compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. Compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite. In certain embodiments, aqueous suspension compositions are packaged in single- dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials are useful herein. In some embodiments, sustained release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed. In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and / or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof. In some embodiments, the concentration of one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) provided in the pharmaceutical compositions is greater than 90%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v. In another embodiment, the amount of a compound selected from compounds of (I), (II), (IA)-(IE), or (IA-1)-(IE-1) in the pharmaceutical compositions is an amount between about any two of the values recited in the preceding sentence, for example, between about 2-70 w / w%, 3.5-80 w / w%, 1-30 w / w%, etc. In some embodiments, the concentration of one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) provided in the pharmaceutical compositions of the present disclosure is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v. In some embodiments, the amount the one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) provided in the pharmaceutical compositions of the present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g. In some embodiments, the amount of the one or more compounds selected from compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) provided in the pharmaceutical compositions of the present disclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g. Packaging materials for use in packaging pharmaceutical compositions described herein include those found in, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein. For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device is accompanied by instructions for administration, or the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. As mentioned above, the compounds and compositions of the disclosure will find utility in a broad range of diseases and conditions mediated by protein kinases, including diseases and conditions mediated by kinase. Such diseases may include by way of example and not limitation, cancers such as lung cancer, NSCLC (non small cell lung cancer), oat-cell cancer, bone cancer, pancreatic cancer, skin cancer, dermatofibrosarcoma protuberans, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colon-rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's Disease, hepatocellular cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer (particularly hormone-refractory), chronic or acute leukemia, solid tumors of childhood, hypereosinophilia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), pediatric malignancy, neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumors, medulloblastoma, brain stem gliomas or pituitary adenomas), Barrett's esophagus (pre-malignant syndrome), neoplastic cutaneous disease, psoriasis, mycoses fungoides, and benign prostatic hypertrophy, diabetes related diseases such as diabetic retinopathy, retinal ischemia, and retinal neovascularization, hepatic cirrhosis, angiogenesis, cardiovascular disease such as atherosclerosis, immunological disease such as autoimmune disease and renal disease. In some embodiments, a pharmaceutical composition has a compound described above and a pharmaceutically acceptable carrier including, for example, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. In one embodiment, a pharmaceutical composition comprising the compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) and a therapeutic agent is disclosed. In some embodiments, the compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) or the pharmaceutical composition comprising the compounds of Formula (I), (II), (IA)-(IE), (IA- 1)-(IE-1), (IA-2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) for use in treating a disease associated with mutations in KRAS is also disclosed. A method of treating a disease associated with G12D, G12V, G12C, G12S, G12A, G12R, Q61H, and / or G13D mutation in KRAS, and / or wild-type KRAS mutations, comprising: administering the compounds of Formula (I), (II), (IA)-(IE), (IA-1)-(IE-1), (IA- 2): (IA-3), (II), (III), (III-1), (III-1A), (III-1B), (III-1C)), (IIIA)-(IIIC), (IV) or (IVA) or the pharmaceutical composition to a subject in need thereof. The subject is an animal. In some embodiments, the subject is a human. In some embodiments, the disease associated with mutations in KRAS is a cancer. In some embodiments, the cancer is pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, endometrial endometrioid adenocarcinoma, rectal adenocarcinoma, gastric cancer, or lung cancer. In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the cancer is a pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the cancer is a colorectal cancer. In some embodiments, the cancer is an endometrial endometrioid adenocarcinoma. In some embodiments, the cancer is a rectal adenocarcinoma. In some embodiments, the cancer is a gastric cancer. In some embodiments, the cancer is a lung cancer. IV. Methods of Preparation Preparation methods for the above compounds and compositions are described herein below and / or known in the art. It will be appreciated by those skilled in the art that in the process described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t- butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include —C(O)— R″ (where R″ is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin. It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All prodrugs of compounds of this invention are included within the scope of the invention. In some embodiments, for example, a phosphate bearing compound of (I), (II), (IA)-(IE), or (IA-1)-(IE-1) is a prodrug and the structure of such example is described in the disclosure. Furthermore, all compounds of the invention which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the invention can be converted to their free base or acid form by standard techniques. EXAMPLES The following section describes abbreviations used in the examples and includes examples for making intermediate compounds I1-I22 (Examples 1-21) and examples for making compounds 1-78 (Examples 22-52). Abbreviations: Sat.: Saturated Aq.: Aqueous DIPEA: N,N-Diisopropylethylamine MeCN: Acetonitrile TFA: 2,2,2-Trifluoroacetic acid DCM: Dichloromethane Pd / C: Palladium on activated carbon DMF: N,N-Dimethylformamide MeOH: Methanol Quant.: Quantitative K2CO3: Potassium Carbonate Cs2CO3: Cesium Carbonate Na2SO4: Sodium Sulfate MgSO4: Magnesium Sulfate LCMS: Liquid chromatography mass spectrometry EtOAc: Ethyl acetate THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide HPLC: High-performance liquid chromatography n-BuLi: n-butyl lithium MTBE: Methyl tert-butyl ether Bop-Cl: Bis(2-oxo-3-oxazolidinyl)phosphonic chloride LiHMDS: Lithium bis(trimethylsilyl)amide DMAP: 4-Dimethylaminopyridine TBS: tert-Butyldimethylsilyl Syntheses of intermediate compounds Example 1 Intermediate I1 tert-butyldimethyl(3-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)propoxy)silane Step A. 1-bromo-8-iodonaphthalene. To a 500 mL three-necked round-bottom flask equipped with a magnetic stir bar was added 1,8- dibromonaphthalene 1 (20.0 g, 69.9 mmol) followed by the addition of THF (160 mL). The flask was evacuated and backfilled with nitrogen three times. The solution was cooled to -70 °C. n-BuLi (2.5 M, 28.0 mL) was added dropwise. After 15 min, a solution of molecular iodine (17.8 g, 69.9 mmol) in THF (160 mL) was added dropwise. The mixture was warmed to 25 °C under an atmosphere of nitrogen for 1.5 h in the dark. The mixture was quenched by slow addition of saturated aqueous ammonium chloride (300 mL), transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (100 mL x 3). The organic layers were combined and washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To the crude product was added MTBE (50 mL) and this slurry was stirred at 25 °C for 10 min. The suspension was filtered and the filter cake was washed with MTBE (10 mL). The solid was concentrated under vacuum to give 1-bromo-8-iodonaphthalene (14.0 g, 60% yield) as a light yellow solid. 1H NMR: (400 MHz, CDCl3) δ = 8.40 (dd, J = 0.8, 7.6 Hz, 1H), 7.99 - 7.89 (m, 1H), 7.85 - 7.73 (m, 2H), 7.26 - 7.21 (m, 1H), 7.05 (t, J = 8.0 Hz, 1H). Step B.3-(8-bromonaphthalen-1-yl)propanal. To a 500 mL three-necked round-bottom equipped with a magnetic stir bar was added 1-bromo-8-iodo-naphthalene (14.0 g, 42.0 mmol), Pd(OAc)2 (0.50 g, 2.20 mmol), NaHCO3 (8.83 g, 105 mmol), and tetrabutylammonium chloride (11.7 g, 42.1 mmol) followed by the addition of DMF (200 mL). The flask was purged with nitrogen three times and allyl alcohol (14.3 mL, 210 mmol) was added to the mixture at 25 °C. The mixture was stirred at 40 °C under an atmosphere of nitrogen for 20 h. The mixture was quenched by slow addition of H2O (150 mL), transferred to a separatory funnel and the aqueous layer extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (400 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-4% EtOAc in petroleum ether) to give 3-(8-bromonaphthalen-1- yl)propanal (3.70 g, 33% yield) as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ = 9.90 (s, 1H), 7.86 (ddd, J = 1.2, 8.0, 15.6 Hz, 2H), 7.78 (dd, J = 1.6, 7.6 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.31 - 7.25 (m, 1H), 3.92 - 3.87 (m, 2H), 2.98 - 2.93 (m, 2H). Step C. 3-(8-bromonaphthalen-1-yl)propan-1-ol. To a 250 mL three-necked round- bottom flask equipped with a magnetic stir bar was added 3-(8-bromonaphthalen-1-yl)propanal (3.60 g, 13.7 mmol) followed by the addition of EtOH (30 mL). The solution was cooled to 0°C. The flask was purged with nitrogen three times and NaBH4(1.12 g, 29.6 mmol) was added in batches to the solution. The mixture was stirred for 0.5 h at 0 °C and quenched by slow addition of saturated aqueous ammonium chloride (30 mL). The mixture was transferred to a separatory funnel and the aqueous layer extracted with ethyl acetate (30 mL x 3). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (15% EtOAc in petroleum ether) to give 3-(8-bromonaphthalen-1-yl)propan-1-ol (2.80 g, 77% yield) as a yellow oil. 1H NMR: (400 MHz, MeOD-d4) δ = 7.89 - 7.82 (m, 2H), 7.78 (dd, J = 1.6, 8.0 Hz, 1H), 7.45 - 7.35 (m, 2H), 7.25 (t, J = 8.0 Hz, 1H), 3.65 (q, J = 6.4 Hz, 2H), 3.61 - 3.52 (m, 1H), 3.15 (dd, J = 7.2, 8.8 Hz, 1H), 1.98 - 1.91 (m, 2H). Step D. (3-(8-bromonaphthalen-1-yl)propoxy)(tert-butyl)dimethylsilane. To a 250 mL three-necked round-bottom flask equipped with a magnetic stir bar was added 3-(8- bromonaphthalen-1-yl)propan-1-ol (2.80 g, 10.6 mmol) and imidazole (1.44 g, 21.1 mmol) followed by the addition of THF (30 mL). The solution was cooled to 0 °C and tert- butyldimethylsilyl chloride (1.91 g, 12.7 mmol) in THF (30 mL) was added dropwise. The mixture was warmed to 20 °C and stirred for 1 h. The mixture was quenched by slow addition of H2O (30 mL). The mixture was transferred to a separatory funnel and the aqueous layer extracted with ethyl acetate (40 mL x 3). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100% petroleum ether) to give (3-(8- bromonaphthalen-1-yl)propoxy)(tert-butyl)dimethylsilane (3.20 g, 80% yield) as a colorless oil. 1H NMR: (400 MHz, CDCl3) δ = 7.87 - 7.79 (m, 2H), 7.74 - 7.71 (m, 1H), 7.43 - 7.38 (m, 2H), 7.23 (t, J = 8.0 Hz, 1H), 3.74 - 3.72 (m, 2H), 3.62 - 3.53 (m, 2H), 2.00 - 1.96 (m, 2H), 0.94 (s, 9H), 0.09 (s, 6H). Step E. tert-butyldimethyl(3-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)propoxy)silane. To a 40 mL vial equipped with a magnetic stir bar was added (3-(8- bromonaphthalen-1-yl)propoxy)(tert-butyl)dimethylsilane (3.20 g, 8.44 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (3.22 g, 12.7 mmol) followed by the addition of dioxane (30 mL). [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.62 g, 0.84 mmol) and potassium acetate (1.66 g, 16.9 mmol) were added into the mixture. The mixture was sparged with nitrogen for 2 min. The mixture was heated to 90 °C and stirred for 18 h. The mixture was quenched by addition of H2O (30 mL), the mixture transferred to a separatory funnel and the aqueous layer extracted with ethyl acetate (30 mL x 3). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (2% EtOAc in petroleum ether) to give tert- butyldimethyl(3-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)propoxy)silane (1.10 g, 30% yield) as a colorless oil. LCMS (MM-ES+APCI, Pos): m / z 427.2 (M+H). Example 2 Intermediate I2 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine Step A. 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (3.00 g, 11.9 mmol) and 1,4-dioxane (30 mL) in a 250 mL round-bottomed flask was added benzyl alcohol (1.85 mL, 17.8 mmol) and N,N- diisopropylethylamine (6.20 mL, 35.7 mmol). The mixture was stirred at 85 °C for 1 h. The reaction mixture was concentrated to dryness. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give 4-(benzyloxy)-2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidine (1.80 g, 47 %) as a white crystalline solid. LCMS (MM- ES+APCI, Pos): m / z 324.0 (M+H). Step B. 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidine (1.80 g, 5.55 mmol) in THF (18.5 mL) in a 100 mL round-bottomed flask was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methanol (1.06 g, 6.66 mmol) and N,N-diisopropylethylamine (1.93 mL, 11.1 mmol). The mixture was stirred at 50 °C for 21 h. The reaction mixture was concentrated to dryness and partitioned between H2O (20 mL) and DCM (20 mL). The layers were separated and the aqueous phase was extracted with DCM (2 X 10 mL). The combined organic extracts were concentrated to dryness and purified via silica gel chromatography (0 – 20 % MeOH in CH2Cl2) to give 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (1.87 g, 75%) as an orange solid. LCMS (MM- ES+APCI, Pos): m / z 447.2 (M+H). Example 3 Intermediate I3 (8-chloronaphthalen-1-yl)trimethylstannane Step A. (8-chloronaphthalen-1-yl)trimethylstannane. To a solution of 1-bromo-8- chloronaphthalene (15 g, 62 mmol) in toluene (200 mL) was added Pd(PPh3)4(7.2 g, 6.2 mmol) and hexamethylditin (25 mL, 122 mmol). The flask was evacuated and backfilled with nitrogen three times. The mixture was heated to 110 °C for 16 h and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (100% petroleum ether) to give (8-chloronaphthalen-1-yl)trimethylstannane (19 g, 94% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.88 - 7.83 (m, 2H), 7.81 - 7.77 (m, 1H), 7.62 (dd, J = 1.2, 7.2 Hz, 1H), 7.48 (dd, J = 6.8, 8.0 Hz, 1H), 7.41 - 7.36 (m, 1H), 0.43 (s, 9H). Example 4 Intermediate I4 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine Step A. 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. A flask containing 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (12 g, 48 mmol) in DCM (120 mL) was evacuated and backfilled with nitrogen three times. The mixture was cooled to 0 °C and a solution of 2,2,2-trifluoroethanol (3.2 mL, 44 mmol) and DIPEA (12 mL, 71 mmol) in DCM (40 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h and diluted with H2O (150 mL). The aqueous layer was extracted with DCM (150 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10 – 15% EtOAc in petroleum ether) to give 2,7-dichloro-8-fluoro-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (14.2 g, 86% yield) as a yellow solid. LCMS (MM- ES+APCI, Pos): m / z 315.9 (M+H). Step B. 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 2,7-dichloro- 8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (13 g, 41 mmol) in THF (160 mL) was added (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (7.50 g, 47.1 mmol) and DIPEA (15 mL, 83 mmol). The mixture was stirred at rt for 16 h and diluted with H2O (200 mL). The mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by silica gel chromatography (10 – 100% EtOAc in petroleum ether) to give 7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (16.2 g, 78% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 439.0 (M+H). Step C. 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (9.0 g, 19 mmol) and (8- chloronaphthalen-1-yl)trimethylstannane, Intermediate I3 (12 g, 38 mmol), in toluene (140 mL) was added Pd(dppf)Cl2(1.4 g, 1.9 mmol), CuI (1.4 g, 7.1 mmol) and BINAP (2.7 g, 4.4 mmol). The flask was evacuated and backfilled with nitrogen three times and heated to 90 °C for 16 h. The suspension was filtered through a pad of Celite and the pad washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (50 – 75% EtOAc in petroleum ether). The residue was purified by preparative HPLC (20 - 50% MeCN in 0.1% aqueous formic acid). Fractions containing the product were lyophilized to obtain 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (4.5 g, 40% yield) was obtained as a white solid. LCMS (MM-ES+APCI, Pos): m / z 565.2 (M+H).

[0029] Example 5 Intermediate I5 2-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)ethyl (4-nitrophenyl) carbonate Step A. 4-(benzyloxy)-7-(8-(2-((tert-butyldimethylsilyl)oxy)ethyl)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine. To a solution of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.00 g, 4.16 mmol) and tert-butyldimethyl(2-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen- 1-yl)ethoxy)silane (2.2 g, 5.2 mmol) in 1,4-dioxane (20 mL) and H2O (2 mL) was added Cs2CO3(3.4 g, 10 mmol) and mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′- biphenyl)]palladium(II) (0.38 g, 0.52 mmol). The solution was sparged with nitrogen for 5 min. The reaction was heated to 90 °C for 1 h and diluted with H2O (80 mL). The mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (17-33% EtOAc in petroleum ether) to give 4-(benzyloxy)-7-(8-(2-((tert- butyldimethylsilyl)oxy)ethyl)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.0 g, 51% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 697.3 (M+H). Step B. 2-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)ethan-1-ol. To a solution of 4-(benzyloxy)-7-(8-(2-((tert-butyldimethylsilyl)oxy)ethyl)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.0 g, 2.7 mmol) in DCM (20 mL) was added TFA (1.0 mL, 14 mmol). The solution was cooled to 0 °C and stirred at this temperature for 1 h. The reaction was quenched by the addition of saturated NaHCO3 (5 mL). The mixture was diluted with H2O (10 mL) and extracted with DCM (6 mL × 3). The organic phase was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-10% MeOH in DCM) to obtain 2-(8-(4- (benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)ethan-1-ol (1.3 g, 80% yield) was as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 583.2 (M+H). Step C. 2-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)ethyl (4-nitrophenyl) carbonate. To a solution of 2-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)ethan-1-ol (0.400 g, 0.654 mmol) in THF (5 mL) at 0 °C was added triethylamine (0.28 mL 1.98 mmol) followed by a solution of 4-nitrophenyl chloroformate (0.26 g, 1.3 mmol) in THF (2 mL). The mixture was warmed to rt and stirred at this temperature for 16 h. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2- (8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)ethyl (4-nitrophenyl) carbonate (0.30 g, 59% yield) as a light yellow solid. LCMS (MM-ES+APCI, Pos): m / z 748.1 (M+H). Example 6 Intermediate I6 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)propyl (4-nitrophenyl) carbonate Intermediate I6 was synthesized with intermediate I1, following the general procedure of intermediate I5. LCMS (MM-ES+APCI, Pos): m / z 762.3 (M+H).

[0030] Example 7 Intermediate I7 tert-butyl ((R)-1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3- yl)carbamate Step A. tert-butyl ((R)-1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)carbamate. A solution of tert-butyl (R)-(3-methylpiperidin-3- yl)carbamate (0.045 g, 0.21 mmol), 7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine, Intermediate I4 (0.10 g, 0.18 mmol), and DIPEA (0.15 mL, 0.88 mmol) in MeCN (1.0 mL) was stirred at 80 °C for 16 h. The solution was concentrated under reduced pressure to obtain tert-butyl ((R)-1-(7-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3- methylpiperidin-3-yl)carbamate (0.12 g), which was taken onto the next step without further purification. LCMS (MM-ES+APCI, Pos): m / z 679.3 (M+H). Example 8 Intermediate I8 tert-butyl 3-amino-3-(cyanomethyl)piperidine-1-carboxylate Step A. tert-butyl 3-(cyanomethylene)piperidine-1-carboxylate. To a solution of tert- butyl 3-oxopiperidine-1-carboxylate (5.0 g, 25 mmol) and diethyl (cyanomethyl)phosphonate (4.1 mL, 25.09 mmol) in THF (50 mL) was added K2CO3(4.2 g, 30 mmol). The reaction was stirred at 70˚C for 12 h and then it was diluted with H2O (100 mL). The mixture was extracted with EtOAc (3 X 100 mL). The combined organic layers were washed with brine (5 X 100mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether) to give tert-butyl 3- (cyanomethylene)piperidine-1-carboxylate (6.0 g) which was taken onto the next step without further purification.1H NMR: (400 MHz, CDCl3) δ = 5.24 (br s, 1H), 3.97 (s, 2H), 3.50 (br d, J = 5.6 Hz, 2H), 2.70 - 2.55 (m, 2H), 1.74 (br d, J = 5.6 Hz, 2H), 1.45 (s, 9H). Step B. tert-butyl 3-amino-3-(cyanomethyl)piperidine-1-carboxylate. To a solution of tert-butyl 3-(cyanomethylene)piperidine-1-carboxylate (6.0 g, 27 mmol) in MeOH (12 mL) was added NH3∙H2O (30%; 33 mL, 260 mmol). The reaction was heated to 90 °C for 4 h and and concentrated under reduced pressure. The residue was diluted with H2O (100 mL) and extracted with ethyl acetate (120 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% MeOH in DCM) to give tert-butyl 3- amino-3-(cyanomethyl)piperidine-1-carboxylate (1.3 g, 20% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ = 3.59 - 3.35 (m, 2H), 3.34 - 3.10 (m, 2H), 2.46 (br s, 2H), 1.81 - 1.66 (m, 2H), 1.57 (br s, 2H), 1.47 (s, 9H). Example 9 Intermediate I9 tert-butyl 3-amino-3-(hydroxymethyl)piperidine-1-carboxylate Step A. tert-butyl 3-amino-3-(hydroxymethyl)piperidine-1-carboxylate. To a solution of 3-amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (4.5 g, 18.42 mmol) in THF (45 mL) at -10 °C was added BH3∙THF (1.0 M; 55 mL, 55 mmol). The solution was warmed to rt and stirred at this temperature for 12 h. The suspension was cooled to 0 °C and slowly quenched with MeOH (100 mL). The mixture was stirred at 0 °C for 2 h, warmed to rt and stirred at rt for 22 h. The mixture was treated with diethylamine (340 mL) and heated at 50 °C for 3 h. The suspension was concentrated under reduced pressure and the residue was solubilized with MeOH (5 mL). The solution was slowly added into 3:1 mixture of brine / 1 N NaOH (1000 mL) and extracted with 15% IPA in DCM (500 mL). The organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-20% MeOH in DCM) to give tert-butyl 3-amino-3- (hydroxymethyl)piperidine-1-carboxylate (3.3 g, 78% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ = 3.97 - 2.72 (m, 6H), 1.62 (br d, J = 10.2 Hz, 4H), 1.49 (s, 9H). Example 10 Intermediate I10 tert-butyl 3-amino-5-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine-1-carboxylate Step A. 1-(tert-butyl) 3-methyl 5-((tert-butyldimethylsilyl)oxy)piperidine-1,3- dicarboxylate. To a solution of 1-(tert-butyl) 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate (1.5 g, 5.78 mmol) in DCM (30 mL) was added tert-butyldimethylsilyl chloride (1.3 g, 8.7 mmol), DMAP (0.14 g, 1.2 mmol) and 1H-imidazole (0.98 g, 14 mmol). The mixture was stirred at rt for 16 h and diluted with saturated aqueous NH4Cl (30 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-15% EtOAc in petroleum ether) to give 1-(tert- butyl) 3-methyl 5-((tert-butyldimethylsilyl)oxy)piperidine-1,3-dicarboxylate (3.2 g, 67% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 318.1 (M+H, -tBu). Step B. 1-(tert-butyl) 3-methyl 5-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine- 1,3-dicarboxylate. To a solution of 1-(tert-butyl) 3-methyl 5-((tert- butyldimethylsilyl)oxy)piperidine-1,3-dicarboxylate (0.50 g, 1.34 mmol) in THF (10 mL) at - 65 °C was added LiHMDS (1.0 M in THF; 6.7 mL, 0.67 mmol) dropwise over the course of 10 min, followed by addition of iodomethane (0.42 mL, 6.69 mmol) in THF (2 mL). The reaction was warmed to rt and stirred at this temperature for 15 min. The mixture was quenched by slow addition of saturated aqueous NH4Cl (20 mL). The mixture extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 20% EtOAc in petroleum ether) to give 1-(tert-butyl) 3- methyl 5-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine-1,3-dicarboxylate (0.51 g, 49% yield) as yellow oil. LCMS (MM-ES+APCI, Pos): m / z 410.2 (M+Na). Step C. 1-(tert-butoxycarbonyl)-5-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine- 3-carboxylic acid. To a solution of 1-(tert-butyl) 3-methyl 5-((tert-butyldimethylsilyl)oxy)-3- methylpiperidine-1,3-dicarboxylate (1.1 g, 2.8 mmol) in THF (2 mL), H2O (2 mL) and MeOH (2 mL) was added LiOH (0.20 g, 8.4 mmol). The mixture was stirred at rt for 2 h and concentrated under redued pressure to obtain 1-(tert-butoxycarbonyl)-5-((tert- butyldimethylsilyl)oxy)-3-methylpiperidine-3-carboxylic acid (0.52 g, 49% yield), which was taken onto the next step without further purification. Step D. tert-butyl 3-amino-5-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine-1- carboxylate. To a solution of 1-(tert-butoxycarbonyl)-5-((tert-butyldimethylsilyl)oxy)-3- methylpiperidine-3-carboxylic acid (0.50 g, 1.3 mmol) in THF (20 mL) was added DPPA (1.2 mL, 5.4 mmol) and DIPEA (3.26 mL, 19 mmol). The mixture was stirred at 80 °C for 2 h, and KOH (1.5 g, 27 mmol) in H2O (8 mL) was added. The mixture was stirred at rt for 2 h and followed by dilution with H2O (2 mL). The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (55% – 85% acetonitrile in 0.05% aqueous NH4HCO3). The fractions containing the product were lyophilized to obtain tert-butyl 3-amino-5-((tert- butyldimethylsilyl)oxy)-3-methylpiperidine-1-carboxylate (0.14 g, 30% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 345.2 (M+H). Example 11 Intermediates I11 and I12 1-benzyl 3-methyl (rel-3R,5R)-5-fluoro-3-methylpiperidine-1,3-dicarboxylate 1-benzyl 3-methyl (rel-3R,5S)-5-fluoro-3-methylpiperidine-1,3-dicarboxylate Step A.1-(tert-butyl) 3-methyl 5-fluoropiperidine-1,3-dicarboxylate. To a solution of 1-(tert-butyl) 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate (100 g, 390 mmol) in DCM (1000 mL) at -78 °C was added DAST (61 mL, 460 mmol) dropwise. The reaction was stirred at -78 °C for 2 h and warmed to rt and stirred for an additional 3 h. The mixture was quenched by slow addition of aqueous NaHCO3(500 mL) at 0 °C. The mixture was extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether) to give 1-(tert-butyl) 3-methyl 5-fluoropiperidine-1,3-dicarboxylate (47 g, 47% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 4.81 - 4.37 (m, 1H), 4.33 - 4.18 (m, 1H), 3.72 (br d, J = 3.2 Hz, 3H), 3.14 - 2.69 (m, 2H), 2.64 - 2.23 (m, 2H), 1.89 - 1.73 (m, 1H), 1.67 - 1.58 (m, 1H), 1.47 (d, J = 3.2 Hz, 9H). Step B. methyl 5-fluoropiperidine-3-carboxylate. A solution of 1-(tert-butyl) 3-methyl 5-fluoropiperidine-1,3-dicarboxylate (47 g, 180 mmol) in HCl in dioxane (4.0 M; 470 mL, 120 mmol) was stirred at rt for 1 h. The solution was concentrated under reduced pressure to give methyl 5-fluoropiperidine-3-carboxylate (35 g, 98% yield) as a yellow oil, which was taken onto the next step without further purification. Step C. 1-benzyl 3-methyl 5-fluoropiperidine-1,3-dicarboxylate. To a solution of methyl 5-fluoropiperidine-3-carboxylate (35 g, 180 mmol) and NaHCO3 (150 g, 1800 mmol) in THF (300 mL) and H2O (300 mL) at 0 °C was added benzyl chloroformate (28 mL, 190 mmol). The reaction was stirred at rt for 1 h and diluted with H2O (1000 mL). The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether) to give 1-benzyl 3-methyl 5-fluoropiperidine-1,3-dicarboxylate (46 g, 88% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.39 - 7.35 (m, 5H), 5.15 (br d, J = 4.4 Hz, 2H), 4.63 - 4.23 (m, 2H), 3.74 - 3.66 (m, 3H), 3.18 - 2.88 (m, 2H), 2.69 - 2.22 (m, 2H), 2.05 (s, 1H), 1.94 - 1.73 (m, 1H). Step D. 1-benzyl 3-methyl (rel-3R,5R)-5-fluoro-3-methylpiperidine-1,3-dicarboxylate and 1-benzyl 3-methyl (rel-3R,5S)-5-fluoro-3-methylpiperidine-1,3-dicarboxylate. To a solution of 1-benzyl 3-methyl 5-fluoropiperidine-1,3-dicarboxylate (46 g, 155 mmol) in THF (500 mL) at -78 °C under an atmosphere of nitrogen was added LiHMDS (1.0 M in THF; 230 mL, 230 mmol) dropwise. The mixture was stirred at -78 °C for 1 h and then MeI (29 mL, 470 mmol) was added dropwise. The reaction was warmed to rt and stirred for an additional 2 h at rt. The mixture was quenched by slow addition of saturated aqueous NH4Cl (1000 mL) at 0 °C. The aqueous phase was extracted with ethyl acetate (800 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether1) to give 1-benzyl 3-methyl (rel-3R,5R)-5-fluoro-3-methylpiperidine-1,3- dicarboxylate (27 g, 56% yield) as a yellow oil and 1-benzyl 3-methyl (rel-3R,5S)-5-fluoro-3- methylpiperidine-1,3-dicarboxylate (15 g, 31% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.41 - 7.34 (m, 5H), 5.19 - 5.12 (m, 2H), 4.71 (s, 1H), 4.10 - 3.89 (m, 2H), 3.70 - 3.53 (m, 3H), 3.47 - 3.03 (m, 2H), 2.52 - 2.30 (m, 1H), 1.73 - 1.64 (m, 1H), 1.28 (br d, J = 7.2 Hz, 3H).1H NMR: (400 MHz, CDCl3) δ 7.43 - 7.30 (m, 5H), 5.27 - 5.01 (m, 2H), 4.86 - 4.58 (m, 1H), 4.09 - 3.95 (m, 1H), 3.83 - 3.41 (m, 5H), 3.22 (br d, J = 13.2 Hz, 1H), 2.47 - 2.27 (m, 1H), 1.91 - 1.73 (m, 1H), 1.25 - 1.11 (m, 3H). Example 12 Intermediate I13 benzyl (rel-3R,5R)-3-amino-5-fluoro-3-methylpiperidine-1-carboxylate Step A. (rel-3R,5R)-1-((benzyloxy)carbonyl)-5-fluoro-3-methylpiperidine-3- carboxylic acid. To a solution of 1-benzyl 3-methyl (rel-3R,5R)-5-fluoro-3-methylpiperidine- 1,3-dicarboxylate (27 g, 87 mmol) in MeOH (100 mL), THF (100 mL) and H2O (100 mL) was added LiOH (6.3 g, 260 mmol). The reaction was stirred at 25 °C for 1 h after which the pH of mixture was adjusted to 3 with HCl (1.0 M). The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (rel-3R,5R)-1- ((benzyloxy)carbonyl)-5-fluoro-3-methylpiperidine-3-carboxylic acid (27g, 87% yield) as a yellow oil. The product was used into the next step without further purification. LCMS (MM- ES+APCI, Neg): m / z 294.2 (M-H). Step B. benzyl (rel-3R,5R)-3-carbamoyl-5-fluoro-3-methylpiperidine-1-carboxylate. To a solution of (rel-3R,5R)-1-((benzyloxy)carbonyl)-5-fluoro-3-methylpiperidine-3- carboxylic acid (27 g, 76 mmol), NH4Cl (40 g, 760 mmol), HATU (57 g, 150 mmol) in DMF (300 mL) was added DIPEA (160 mL, 910 mmol). The mixture was heated to 50 °C for 12 h. The solution was diluted with H2O (200 mL) and then extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc in petroleum ether) to give benzyl (rel-3R,5R)-3- carbamoyl-5-fluoro-3-methylpiperidine-1-carboxylate (16 g, 55% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 295.1 (M+H). Step C. benzyl (rel-3R,5R)-3-amino-5-fluoro-3-methylpiperidine-1-carboxylate. To a solution of benzyl (rel-3R,5R)-3-carbamoyl-5-fluoro-3-methylpiperidine-1-carboxylate (16 g, 42 mmol) in MeCN (50 mL) and H2O (200 mL) at 0 °C was added NaOH (5.0 M; 42 mL, 210 mmol) and NBS (11 g, 63 mmol). The reaction was heated to 80 °C and stirred for 30 min. The mixture was diluted with H2O (50 mL), and then extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% EtOAc in petroleum ether) to give benzyl (rel-3R,5R)-3-amino-5- fluoro-3-methylpiperidine-1-carboxylate (9.0 g, 78% yield) as a yellow oil. LCMS (MM- ES+APCI, Pos): m / z 267.1 (M+H). Example 13 Intermediate I14 benzyl (rel-3R,5S)-3-amino-5-fluoro-3-methylpiperidine-1-carboxylate Intermediate I14 was synthesized using intermediate I12, according to the procedure of intermediate I13. LCMS (MM-ES+APCI, Pos): m / z 267.3 (M+H). Example 14 Intermediate 15 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)prop-2-yn-1- Step A. 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (8.4 g, 17 mmol) and triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)ethynyl)silane (10 g, 20 mmol) in 1,4-dioxane (150 mL) and H2O (30 mL) was added K2CO3(5.8 g, 42 mmol) and mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′- amino-1,1′-biphenyl)]palladium (II) (1.1 g, 1.5 mmol). The flask was evacuated and backfilled with nitrogen three times. The mixture was heated at 90 °C and stirred under an atmosphere of nitrogen for 1 h. The suspension was filtered through a pad of Celite and the filter cake washed with ethyl acetate (400 mL). The combined organics were concentrated under reduced pressure and purified by silica gel chromatography (11-17% EtOAc in petroleum ether) to give 4- (benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidine (13 g, 89% yield) as a yellow gum. LCMS (MM-ES+APCI, Pos): m / z 779.4 (M+H). Step B.4-(benzyloxy)-7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1- yl)pyrido[4,3-d]pyrimidine (13 g, 15 mmol) in DMF (130 mL) was added CsF (4.6 g, 30 mmol). The reaction was stirred at rt for 1.5 h. The mixture was diluted with H2O (500 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (11-100% EtOAc in petroleum ether) to give 4-(benzyloxy)-7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine (6.5 g, 64% yield) as a brown solid. LCMS (MM-ES+APCI, Pos): m / z 623.4 (M+H). Step C.3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)prop- 2-yn-1-ol. A solution of 4-(benzyloxy)-7-(8-ethynyl-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine (4.2 g, 6.3 mmol) and paraformaldehyde (2.1 g) in THF (252 mL) was purged with nitrogen three times. The solution was cooled to -70 °C, and LiHMDS (1.0 M, 1.4 mL) was added to the mixture and stirred for 2 h. The mixture was warmed to rt and was stirred for an additional 1.5 h. The mixture was quenched by slow addition of H2O (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (50-75% EtOAc in petroleum ether) to give 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)prop- 2-yn-1-ol (0.77 g, 17% yield) as a yellow gum. LCMS (MM-ES+APCI, Pos): m / z 653.2 (M+H). Example 15 Intermediate I16 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-(3- hydroxypropyl)-3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol Step A.8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(8-(3-hydroxypropyl)-3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol. To a solution of 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)prop- 2-yn-1-ol (1.1 g, 1.6 mmol) in THF (12 mL) and MeOH (4.0 mL) was added Pd(OH)2(20 wt% Pd; 0.28 g, 0.40 mmol). The mixture was sparged with H2for 10 min and stirred at rt for 19 h under 1 atm of hydrogen. The mixture was filtered through a Celite plug and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography (5 - 20 % MeOH in DCM) to give 8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-(3- hydroxypropyl)-3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-ol (0.67 g, 74%) as an orange solid. LCMS (MM-ES+APCI, Pos): m / z 567.3 (M+H). Example 16 Intermediate I17 tert-butyl(3-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)propoxy)dimethylsilane Step A. (E)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime. To a solution of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (100 g, 620 mmol) in EtOH (1000 mL) was added O-methylhydroxylamine hydrochloride (103 g, 1200 mmol) and pyridine (200 mL, 2.5 mol). The mixture was stirred at 80 °C for 2 h after which it was diluted with H2O (500 mL). The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (E)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime (115 g) as a black oil, which was taken onto the next step without further purification. Step B. (E)-5-(methoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl acetate. To a solution of (E)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one O-methyl oxime (115 g, 601 mmol) in DCM (1200 mL) at 0 °C was added pyridine (97 mL, 1200 mol) and acetyl chloride (51 mL, 720 mmol). The mixture was warmed to rt and stirred for 1 h. The reaction was slowly diluted with water (1000 mL) and the mixture extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAc in petroleum ether) to give (E)-5-(methoxyimino)-5,6,7,8- tetrahydronaphthalen-2-yl acetate (131 g, 93% yield) as white solid.1H NMR: (400 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 1H), 6.95 - 6.84 (m, 2H), 3.98 (s, 3H), 2.78 - 2.68 (m, 4H), 2.30 (s, 3H), 1.90 - 1.77 (m, 2H). Step C. (E)-4-bromo-5-(methoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl acetate. To a solution of (E)-5-(methoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl acetate (105 g, 450 mmol) in AcOH (1000 mL) was added NBS (96 g, 540 mmol) and Pd(OAc)2(5.05 g, 23 mmol) in portions. The reaction was heated to 90 °C and stirred at this temperature for 1 h. The mixture was cooled to rt and diluted with H2O (1500 mL). The mixture was extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAC in petroleum ether) to give (E)-4-bromo- 5-(methoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl acetate (82 g, 88% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.24 - 7.18 (m, 1H), 6.81 (d, J = 2.4 Hz, 1H), 4.01 - 3.91 (m, 3H), 2.67 (t, J = 6.8 Hz, 2H), 2.58 - 2.50 (m, 2H), 2.21 - 2.20 (m, 3H), 1.79 - 1.60 (m, 2H). Step D. 8-bromo-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one. To a solution (E)-4- bromo-5-(methoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl acetate (61 g, 195 mmol) in 1,4- dioxane (630 mL) was added HCl in dioxane (2.0 M; 908 mL, 1800 mmol). The reaction was heated to 110 °C and stirred for 1 h. After cooling to rt, the solution was diluted with H2O (1000 mL) and extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% EtOAC in petroleum ether) to give 8-bromo-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (35 g, 74% yield) as a yellow solid.1H NMR: (400 MHz, MeOH-d4) δ 7.01 (d, J = 2.4 Hz, 1H), 6.71 - 6.67 (m, 1H), 2.93 (t, J = 6.0 Hz, 2H), 2.61 (t, J = 6.8 Hz, 2H), 2.09 - 2.01 (m, 2H). Step E. 8-bromo-6-(methoxymethoxy)-3,4-dihydronaphthalen-1(2H)-one. To a solution of 8-bromo-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (75 g, 310 mmol) in DCM (1300 mL) at 0 °C was added DIPEA (16 mL, 930 mol) and 1-bromomethyl methyl ether (51 mL, 620 mmol). The mixture was allowed to warm to rt and stirred for 1 h. The reaction was slowly diluted with H2O (800 mL) and then extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-12% EtOAc in petroleum ether) to give 8-bromo-6-(methoxymethoxy)-3,4- dihydronaphthalen-1(2H)-one (71 g, 80% yield) as yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.24 (d, J = 2.4 Hz, 1H), 6.87 - 6.83 (m, 1H), 5.20 (s, 2H), 3.48 (s, 3H), 2.94 (t, J = 6.0 Hz, 2H), 2.66 (t, J = 6.8 Hz, 2H), 2.11 - 2.04 (m, 2H). Step F. 1-allyl-8-bromo-6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthalen-1-ol. Two solutions were prepared and pumped through a flow reactor. Solution one, containing 8-bromo- 6-(methoxymethoxy)-3,4-dihydronaphthalen-1(2H)-one (70 g, 250 mmol) in THF (700 mL), was pumped at 61.3 mL / min at -10 °C. A second line pumped allylmagnesium bromide (1.0 M in diethyl ether; 500 mL) at 61.3 mL / min at -10 °C. The two pumps were started at the same time and were combined in three tandem flow reactors (FLR3, GL, CSTRs, 500 mL, -10 °C) with residence time of 5 min each. The mixture was collected at the end in a bottle containing NH4Cl solution (1.0 M; 1000 mL). The reaction was run for 15 min after which it was diluted with saturated NH4Cl solution (3000 mL). The solution was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc in petroleum ether) to give 1-allyl-8-bromo-6- (methoxymethoxy)-1,2,3,4-tetrahydronaphthalen-1-ol (75 g, 93% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.15 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 5.96 - 5.75 (m, 1H), 5.23 – 4.98 (m, 4H), 3.59 - 3.43 (m, 3H), 3.41 (s, 1H), 3.15 - 2.54 (m, 4H), 2.38 - 2.09 (m, 2H), 1.85 - 1.68 (m, 2H). Step G. 8-bromo-1-(3-hydroxypropyl)-6-(methoxymethoxy)-1,2,3,4- tetrahydronaphthalen-1-ol. Three solutions were prepared and pumped through a flow reactor. Solution one, containing 1-allyl-8-bromo-6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthalen- 1-ol (71 g, 217 mmol) in THF (710 mL) was pumped at 26.4 mL / min. A second line pumped BH3∙THF (1.0 M; 220 mL, 430 mmol) was pumped at 16.3 mL / min. A third line pumped a solution of NaOH (26 g, 650 mmol) and H2O2(30 mL, 1300 mmol) was pumped at 14.6 mL / min. The first two pumps started at the same time and the third pump started 3 min later. Solution one and two were combined in PFA coil reactor (213 mL, rt). The resonance time for this step was 5 min. The combined solution was pumped into a second flow reactor (FLR2, GL, CSTRs, 284 mL, 0 °C) along with solution three. The residence time for flow reactor 2 was 5 min. The mixture was collected at the end and was stirred with a saturated solution of sodium sulfite (3000 mL) for 30 min at 0 °C. The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-45% EtOAc in petroleum ether) to give 8-bromo-1-(3-hydroxypropyl)- 6-(methoxymethoxy)-1,2,3,4-tetrahydronaphthalen-1-ol (62 g, 83% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.14 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 5.13 (s, 2H), 3.69 (t, J = 6.4 Hz, 2H), 3.49 - 3.44 (m, 3H), 2.96 - 2.70 (m, 2H), 2.36 - 2.24 (m, 1H), 2.17 - 1.90 (m, 2H), 1.88 - 1.65 (m, 5H). Step H. 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(methoxymethoxy)- 1,2,3,4-tetrahydronaphthalen-1-ol. To a solution of 8-bromo-1-(3-hydroxypropyl)-6- (methoxymethoxy)-1,2,3,4-tetrahydronaphthalen-1-ol (61 g, 177 mmol) and imidazole (24 g, 353 mmol) in DCM (610 mL) at 0 °C was added TBSCl (35 mL, 230 mol). The mixture was warmed to rt and stirred for 1 h. The reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-2% EtOAc in petroleum ether) to give 8- bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(methoxymethoxy)-1,2,3,4- tetrahydronaphthalen-1-ol (68 g, 82% yield) as yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.14 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.12 (s, 2H), 3.67 - 3.62 (m, 2H), 3.54 (br s, 1H), 3.49 - 3.45 (m, 3H), 2.89 - 2.70 (m, 2H), 2.45 - 2.18 (m, 1H), 2.13 - 1.99 (m, 2H), 1.89 - 1.61 (m, 5H), 0.96 - 0.84 (m, 9H), 0.05 (m, 6H). Step I. (3-(8-bromo-6-(methoxymethoxy)-3,4-dihydronaphthalen-1-yl)propoxy)(tert- butyl)dimethylsilane. To a solution of 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-6- (methoxymethoxy)-1,2,3,4-tetrahydronaphthalen-1-ol (68 g, 148 mmol) in toluene (730 mL) was added burgess reagent (53 g, 222 mmol). The reaction was heated to 90 °C for 12 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% EtOAc in petroleum ether) to give (3-(8-bromo-6-(methoxymethoxy)- 3,4-dihydronaphthalen-1-yl)propoxy)(tert-butyl)dimethylsilane (55 g, 84% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.17 (m, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.09 - 5.98 (m, 1H), 5.14 (d, J = 3.2 Hz, 2H), 3.72 (t, J = 7.2 Hz, 1H), 3.58 (t, J = 6.8 Hz, 1H), 3.48 (d, J = 2.8 Hz, 3H), 2.89 (t, J = 7.6 Hz, 1H), 2.63 - 2.43 (m, 4H), 2.12 - 1.97 (m, 1H), 1.75 (m, 1H), 1.66 - 1.59 (m, 1H), 0.93 - 0.82 (m, 9H), 0.11 - 0.05 (m, 6H). Step J. (3-(8-bromo-6-(methoxymethoxy)naphthalen-1-yl)propoxy)(tert- butyl)dimethylsilane. To a solution of (3-(8-bromo-6-(methoxymethoxy)-3,4- dihydronaphthalen-1-yl)propoxy)(tert-butyl)dimethylsilane (54 g, 122 mmol) in DCM (540 mL) at 0 °C was added DDQ (33 g, 147 mmol). The mixture was warmed to rt and stirred for 1 h after which it was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% EtOAc in petroleum ether) to give (3-(8-bromo-6- (methoxymethoxy)naphthalen-1-yl)propoxy)(tert-butyl)dimethylsilane (26 g, 49% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.65 - 7.60 (m, 2H), 7.39 - 7.31 (m, 2H), 7.28 (d, J = 7.2 Hz, 1H), 5.27 (s, 2H), 3.71 (t, J = 6.4 Hz, 2H), 3.60 - 3.45 (m, 5H), 2.12 - 1.89 (m, 2H), 1.13 - 0.84 (m, 9H), 0.12 - 0.07 (m, 6H). Step K. tert-butyl(3-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)naphthalen-1-yl)propoxy)dimethylsilane. Three solutions were prepared and pumped through a flow reactor. Solution one, containing (3-(8-bromo-6-(methoxymethoxy)naphthalen- 1-yl)propoxy)(tert-butyl)dimethylsilane (20 g, 45.5 mmol) in THF (200 mL) was pumped at 98.3 mL / min. A second line pumped n-BuLi (2.5 M in hexanes; 85 mL, 213 mmol) was pumped at 19.9 mL / min. A third line pumped 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (21.2 g, 137 mmol) in THF (200 mL) was pumped at 104 mL / min. The first two pumps started at the same time and the third pump started 0.09 min later. Solutions one and two were combined in PFA coil reactor (10 mL, -40 °C). The resonance time for this step was 0.09 min. The combined solution was pumped into a second PFA coil reactor (10 mL, -40 °C) along with solution three. The resonance time for this step was 0.05 min. The mixture was collected at the end in a bottle containing NH4Cl solution (1.0 M; 1000 mL). The reaction was run for 15 min after which it was diluted with saturated NH4Cl solution (200 mL). The solution was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-8% EtOAc in petroleum ether). The material was repurified by preparative MPLC (0% – 1% EtOH in hexanes) to give tert-butyl(3-(6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-1-yl)propoxy)dimethylsilane (7.3 g, 32 % yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.60 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.29 - 7.24 (m, 1H), 5.30 (s, 2H), 3.65 (t, J = 6.4 Hz, 2H), 3.52 (s, 3H), 3.23 (t, J = 7.2 Hz, 2H), 1.99 (m, 2H), 1.44 (s, 12H), 0.97 - 0.74 (m, 9H), 0.06 - 0.02 (m, 6H). Example 17 Intermediate I18 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)propan-1-ol Step A. 4-(benzyloxy)-7-(8-(3-((tert-butyldimethylsilyl)oxy)propyl)-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of Intermediate I2 (4.7 g, 10 mmol) and Intermediate I17 (5.0 g, 10 mmol) in 1,4-dioxane (50 mL) and H2O (5 mL) was added K2CO3(2.8 g, 21 mmol) and mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′- biphenyl)]palladium(II) (0.75 g, 1.0 mmol). The reaction was sparged with nitrogen for 5 min after which it was heated to 90 °C for 4 h. The solution was diluted with H2O (30 mL) and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% EtOAc in petroleum ether) to give 4-(benzyloxy)-7-(8-(3-((tert-butyldimethylsilyl)oxy)propyl)-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (6.3 g, 68% yield) as a yellow gum. LCMS (MM- ES+APCI, Pos): m / z 771.5 (M+H). Step B. 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1- yl)propan-1-ol. To a solution of 4-(benzyloxy)-7-(8-(3-((tert-butyldimethylsilyl)oxy)propyl)- 3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (6.3 g, 7.0 mmol) in THF (70 mL) was added triethylamine-trihydrofluoride (3.4 mL, 21 mmol). The reaction was stirred at rt for 2 h after which it was diluted with H2O (30 mL). The pH of mixture was adjusted to 8 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced. The residue was purified by silica gel chromatography (0-80% EtOAc in petroleum ether) to give 3-(8-(4-(benzyloxy)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-6-(methoxymethoxy)naphthalen-1-yl)propan-1-ol (1.04 g, 92% yield) as an off-white solid. LCMS (MM-ES+APCI, Pos): m / z 657.3 (M+H). Example 18 Intermediate I19 1-(benzyloxy)-3-(8-bromonaphthalen-1-yl)propan-2-ol Step A.2-((benzyloxy)methyl)oxirane. To a solution of oxiran-2-ylmethanol (9.0 mL, 135 mmol) in THF (100 mL) at 0 °C was added NaH (60% in mineral oil; 6.5 g, 162 mmol) portion wise. The mixture was warmed to rt and was stirred for 1 h, then benzyl bromide (24 mL, 203 mmol) was added and the reaction was stirred for an additional 2 h. The mixture was quenched by slow addition of saturated aqueous NH4Cl (20 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc in petroleum ether) to give 2-((benzyloxy)methyl)oxirane (7.0 g, 31% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.40 - 7.24 (m, 5H), 4.57 (q, J = 12.0 Hz, 2H), 3.75 (dd, J = 3.2, 11.2 Hz, 1H), 3.42 (dd, J = 5.6, 11.2 Hz, 1H), 3.25 - 3.13 (m, 1H), 2.86 - 2.73 (m, 1H), 2.60 (dd, J = 2.8, 5.2 Hz, 1H). Step B. 1-(benzyloxy)-3-(8-bromonaphthalen-1-yl)propan-2-ol. A solution of 1,8- dibromonaphthalene (9.2 g, 32 mmol) in THF (100 mL) was evacuated and backfilled with nitrogen three times. The solution was cooled to -78 °C and then n-BuLi (2.5 M in hexanes; 12.9 mL, 32 mmol) was added dropwise. The mixture was cooled to -78 °C and stirred for 30 min, after which 2-((benzyloxy)methyl)oxirane (6.04 mL, 39 mmol) was added dropwise. The mixture was warmed to 0 °C and stirred for 1.5 h at this temperature. The reaction was quenched by slow addition of saturated aqueous NH4Cl (20 mL). The mixture was stirred for 30 min and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% EtOAc in petroleum ether) to give 1-(benzyloxy)-3-(8-bromonaphthalen-1-yl)propan-2-ol (3.7 g, 29% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): m / z 392.9 / 394.9 (M+Na). Example 19 Intermediate I20 8-fluoro-7-(7-fluoro-8-(3-hydroxypropyl)-3-(methoxymethoxy)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol Step A. 4-(benzyloxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. A solution of ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (7.46 g, 14.5 mmol), 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (5.00 g, 11.2 mmol), mesylate[(di(1- adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.1 g, 1.5 mmol), and potassium phosphate (7.1 g, 34 mmol) in THF (40 mL) and H2O (10 mL) was sparged with argon for 10 min. The solution was heated to 80 °C for 2 h. The reaction solution was diluted with H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (20 - 100% EtOAc in hexanes) to give 4-(benzyloxy)-8-fluoro- 7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (7.191 g, 81%). LCMS (MM-ES+APCI, Pos): m / z 797.3 (M+H). Step B. 4-(benzyloxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine. To a solution of 4-(benzyloxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (6.51 g, 8.16 mmol) in THF (40 mL) at 0 °C was added TBAF (1.0 M in THF; 9.4 mL, 9.4 mmol). The reaction was stirred at this temperature for 40 min and diluted with H2O (100 mL). The slurry was filtered by vacuum filtration and the pad was washed with H2O (100 mL). The precipitate was dried under reduced pressure to obtain 4-(benzyloxy)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (5.0 g, 86 %). LCMS (MM-ES+APCI, Pos): m / z 641.2 (M+H). Step C. 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen- 1-yl)prop-2-yn-1-ol. To a solution of 4-(benzyloxy)-7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (4.99 g, 7.783 mmol) in THF (70.0 mL) at -78 °C was added LiHMDS (1.0 M in THF; 8.95 mL, 8.95 mmol). This mixture was stirred at -78 °C for 50 minutes and paraformaldehyde (2.3 g, 78 mmol) was added in one portion. The mixture was warmed to rt and stirred for 1 h. The solution was diluted with saturated NaHCO3solution (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 10% MeOH in DCM) to afford 3-(8-(4-(benzyloxy)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)prop-2-yn-1-ol (2.97 g, 57%). LCMS (MM- ES+APCI, Pos): m / z 671.3 (M+H). Step D. 8-fluoro-7-(7-fluoro-8-(3-hydroxypropyl)-3-(methoxymethoxy)naphthalen-1- yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-ol. To a solution of 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6- (methoxymethoxy)naphthalen-1-yl)prop-2-yn-1-ol (2.97 g, 4.43 mmol) in THF (33 mL) and MeOH (11 mL) was added Pd(OH)2(20% wt; 933 mg, 1.33 mmol). The mixture was sparged with H2for 10 min and was stirred at rt for 2.5 days under 1 atm of H2. The mixture was filtered through Celite and the pad was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 - 15 % MeOH in DCM) to give 8-fluoro-7-(7-fluoro-8-(3-hydroxypropyl)-3- (methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (1.49 g, 57%). LCMS (MM-ES+APCI, Pos): m / z 585.3 (M+H). Example 20 Intermediate I21 Step A. 4-(benzyloxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen- 1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- pyrimidine. A solution of ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- naphthalen-1-yl)ethynyl)triisopropylsilane (6.7 g, 15 mmol), 4-(benzyloxy)-7-chloro-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine (6.0 g, 13 mmol), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino- 1,1'-biphenyl)]palladium(II) (0.98 g, 1.3 mmol), K2CO3(5.6 g, 40 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) was stirred at 80 °C for 16 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (30 - 50% EtOAc in petroleum ether) to give 4-(benzyloxy)-8- fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (8.5 g, 86% yield). LCMS (MM-ES+APCI, Pos): m / z 737.6 (M+H). Step B. 4- 7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- - pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (8.5 g, 12 mmol) in DMF (50 mL) was added CsF (8.8 g, 58 mmol). The reaction was stirred at rt for 16 h. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (80 - 100% EtOAc in petroleum ether) to give 4-(benzyloxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (4.5 g, 67% yield). LCMS (MM-ES+APCI, Pos): m / z 581.4 (M+H). Step C. 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a -yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoronaphthalen-1-yl)prop-2-yn-1-ol. To a of 4-(benzyloxy)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (4.0 g, 6.9 mmol) in THF (200 mL) at -60 °C was added LiHMDS (1.0 M in THF; 10 mL, 10 mmol). The reaction was stirred for 5 min and then paraformaldehyde (2.0 g) was added. The reaction was stirred at -65 °C for 2 h, warmed to rt and stirred for an additional 2 h. The mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (50 - 70% EtOAc in petroleum ether) to give 3-(8-(4-(benzyloxy)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-2-fluoronaphthalen-1-yl)prop-2-yn-1-ol (1.2 g, 29% yield). LCMS (MM- ES+APCI, Pos): m / z 611.4 (M+H). Step D. 8-fluoro-7-(7-fluoro-8-(3-hydroxypropyl)naphthalen-1-yl)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. A solution of 3-(8-(4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoronaphthalen-1-yl)prop-2-yn-1-ol (0.500 g, 0.491 mmol) and Pd / C (10% wt; 3.5 g, 3.3 mmol) in MeOH (100 mL) and THF (10 mL) was stirred at 35 °C for 2 h under an atmosphere of H2. The reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure to give 8-fluoro-7-(7-fluoro-8-(3- hydroxypropyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.33 g, 77% yield), which was used directly in the next step without further purification. LCMS (MM-ES+APCI, Pos): m / z 525.3 (M+H). Example 21 Intermediate I22 benzyl 3-amino-5,5-difluoro-3-methylpiperidine-1-carboxylate Step A. 1-benzyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate. To a solution of 1-((benzyloxy)carbonyl)-5,5-difluoropiperidine-3-carboxylic acid (1.8 g, 6.0 mmol) and K2CO3(1.7 g, 12 mmol) in DMF (20 mL) was added MeI (1.1 mL, 18 mmol). The reaction was heated to 50 °C and stirred for 12 h. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-17% EtOAc in petroleum ether) to give 1-benzyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate (1.8 g, 96% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ = 7.42 - 7.32 (m, 5H), 5.16 (br s, 2H), 4.64 - 4.26 (m, 2H), 3.73 (s, 3H), 3.20 - 2.78 (m, 3H), 2.60 - 2.40 (m, 1H). Step B. 1-benzyl 3-methyl 5,5-difluoro-3-methylpiperidine-1,3-dicarboxylate. To a solution of 1-benzyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate (1.8 g, 5.8 mmol) followed by in THF (20 mL) at -78 °C was added LiHMDS (1.0 M in THF; 8.62 mL) drop wise. The reaction was stirred at -78 °C under an atmosphere of nitrogen for 1 h after which MeI (1.1 mL, 17 mmol) was added dropwise. The reaction warmed to rt and stirred for 2 h. The mixture was quenched by slow addition of saturated aqueous NH4Cl (20 mL) and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-17% EtOAc in petroleum ether) to give 1-benzyl 3-methyl 5,5-difluoro-3-methylpiperidine-1,3-dicarboxylate (1.45 g, 77% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ = 7.47 - 7.29 (m, 5H), 5.19 (s, 2H), 3.69 (br s, 7H), 2.49 (br s, 1H), 2.12 - 1.95 (m, 1H), 1.28 (br d, J = 7.2 Hz, 3H). Step C. 1-((benzyloxy)carbonyl)-5,5-difluoro-3-methylpiperidine-3-carboxylic acid. To a solution of 1-benzyl 3-methyl 5,5-difluoro-3-methylpiperidine-1,3-dicarboxylate (0.75 g, 2.3 mmol) in MeOH (5 mL), THF (5 mL), and H2O (5 mL) was added LiOH (0.16 g, 6.8 mmol). The reaction was stirred at rt for 1 h. The pH of solution was adjusted to 3 with HCl (1 M) and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-33% EtOAc in petroleum ether) to give 1-((benzyloxy)carbonyl)-5,5-difluoro-3-methylpiperidine- 3-carboxylic acid (0.70 g, 98% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ = 7.41 - 7.31 (m, 5H), 3.91 - 3.40 (m, 4H), 2.61 - 2.41 (m, 1H), 2.05 - 1.95 (m, 1H), 1.33 (br s, 3H). Step D. benzyl 3-carbamoyl-5,5-difluoro-3-methylpiperidine-1-carboxylate. To a solution of 1-((benzyloxy)carbonyl)-5,5-difluoro-3-methylpiperidine-3-carboxylic acid (0.50 g, 1.6 mmol) in DMF (8 mL) was added NH4Cl (0.85 g, 16 mmol), DIPEA (3.3 mL, 19 mmol) and HATU (1.2 g, 3.2 mmol). The reaction was heated to 50 °C for 12 h. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-33% EtOAc in petroleum ether) to give benzyl 3-carbamoyl-5,5-difluoro- 3-methylpiperidine-1-carboxylate (0.42 g, 50% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 313.1 (M+H). Step E. benzyl 3-amino-5,5-difluoro-3-methylpiperidine-1-carboxylate. To solution of benzyl 3-carbamoyl-5,5-difluoro-3-methylpiperidine-1-carboxylate (0.42 g, 0.79 mmol) in MeCN (5 mL) at 0 °C was added NaOH (5.0 M; 1.7 mL) and NBS (0.21 g, 1.2 mmol). The reaction was stirred at rt for 12 h. The mixture was slowly poured into water (10 mL), and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (100% EtOAc) to give benzyl 3- amino-5,5-difluoro-3-methylpiperidine-1-carboxylate (0.17 g, 65% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 285.1 (M+H). Intermediate I23 benzyl 3-amino-3-ethylpiperidine-1-carboxylate Step A. benzyl 3-amino-3-ethylpiperidine-1-carboxylate. To solution of 1- ((benzyloxy)carbonyl)-3-ethylpiperidine-3-carboxylic acid (0.50 g, 1.7 mmol) and DIPEA (3.0 mL, 17.16 mmol) in 1,4-dioxane (8.0 mL) was added DPPA (1.5 mL, 6.9 mmol). The mixture was heated to 100 °C and stirred for 2 h. After cooling to rt, HCl (6.0 M; 8.0 mL) was added to the reaction and it was stirred for an additional 14 h. The mixture was diluted with H2O (10 mL) and washed with EtOAc (10 mL x 3). The aqueous phase was neutralized to pH 9 with aqueous Na2CO3and then it was extracted with DCM (10 mL x 3). The organic layer was dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain benzyl 3-amino-3-ethylpiperidine-1-carboxylate (180 mg, 38% yield, which was taken onto the next step without further purification. LCMS (MM-ES+APCI, Pos): m / z 263.1 (M+H). (13R)-28-fluoro-13-methyl-22-(methylsulfonyl)-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina- 1(1,3)-piperidina-3(1,8)-naphthalenacyclononaphan-8-one Step A.4-(benzyloxy)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine. To solution of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (38 g, 120 mmol) in DCM (380 mL) was added sodium methanethiolate (9.1 g, 130 mmol). The mixture was stirred at rt for 3 h. The mixture was quenched by slow addition of H2O (500 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (400 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The suspension was filtered, and the filter cake was washed with 10% MeOH in DCM (500 mL). The solid was concentrated under vacuum to give 4-benzyloxy-7-chloro-8-fluoro-2- methylsulfanyl-pyrido [4, 3-d] pyrimidine (29 g, 64% yield). LCMS (MM-ES+APCI, Pos): m / z 336.0 (M+1). Step B.4-(benzyloxy)-7-(8-(3-((tert-butyldimethylsilyl)oxy)propyl)naphthalen-1-yl)-8- fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine. To a solution of 4-benzyloxy-7-chloro-8- fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidine (10 g, 30 mmol) and Intermediate 1 (25 g, 60 mmol) in dioxane (200 mL) and H2O (20 mL) was added K3PO4(19 g, 89 mmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (1.9 g, 3.0 mmol). The mixture was purged with nitrogen for 2 min, then heated to 90 °C for 1 h. The mixture was quenched by slow addition of H2O (300 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 – 20% EtOAc in petroleum ether) to give 4- (benzyloxy)-7-(8-(3-((tert-butyldimethylsilyl)oxy)propyl)naphthalen-1-yl)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidine (5.9 g, 24% yield). LCMS (MM-ES+APCI, Pos): m / z 600.4 (M+1). Step C.3-(8-(4-(benzyloxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 1-yl)propan-1-ol. To a solution of 4-(benzyloxy)-7-(8-(3-((tert- butyldimethylsilyl)oxy)propyl)naphthalen-1-yl)-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidine (5.9 g, 9.8 mmol) in MeOH (60 mL) was added TEA-HF (3.6 g, 98 mmol). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure, then diluted with ethyl acetate (300 mL) and extracted with H2O (300 mL × 3). The combined organic layers were washed with brine (100 mL), and concentrated under reduced pressure to give 3-(8-(4-(benzyloxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-1-yl)propan-1-ol (2.4 g, 47% yield). LCMS (MM-ES+APCI, Pos): m / z 486.3 (M+1). Step D.3-(8-(4-(benzyloxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-7-yl)naphthalen- 1-yl)propyl (4-nitrophenyl) carbonate. To a solution of 3-(8-(4-(benzyloxy)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)propan-1-ol (2.4 g, 4.9 mmol) in DCM (20 mL) and pyridine (1.4 mL, 17 mmol) was added a solution of 4-nitrophenyl carbonochloridate (2.8 g, 14 mmol) in DCM (20 mL). The mixture was stirred at rt for 12 h then quenched by slow addition of H2O (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20 – 30% EtOAc in petroleum ether) to give 3-(8-(4- (benzyloxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)propyl (4- nitrophenyl) carbonate (2.1 g, 63% yield). LCMS (MM-ES+APCI, Pos): m / z 651.2 (M+1). Step E. tert-butyl (R)-3-(((3-(8-(4-(benzyloxy)-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-1-yl)propoxy)carbonyl)amino)-3-methylpiperidine-1- carboxylate. To a solution of 3-(8-(4-(benzyloxy)-8-fluoro-2-(methylthio)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-1-yl)propyl (4-nitrophenyl) carbonate (2.0 g, 3.0 mmol) and tert-butyl (3R)-3-amino-3-methyl-piperidine-1-carboxylate (0.95 g, 4.5 mmol) in DMF (20 mL) was added DIPEA (1.6 mL, 8.9 mmol). The mixture was stirred at rt for 12 h, then quenched by slow addition of H2O (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure affording the residue. The residue was purified by silica gel column chromatography (20 – 30% EtOAc in petroleum ether) to give tert-butyl (R)-3-(((3-(8-(4-(benzyloxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-1-yl)propoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (2.5 g, 82% yield). LCMS (MM-ES+APCI, Pos): m / z 726.4 (M+1). Step F.3-(8-(8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1- (R)-(3-methylpiperidin-3-yl)carbamate. To a solution of tert-butyl (R)-3-(((3-(8-(4- -8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1- yl)propoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (2.5 g, 2.4 mmol) in DCM (21 mL) was added TFA (7.0 mL, 94 mmol). The mixture was stirred at rt for 1 h then quenched by slow addition of H2O (50 mL) followed by aqueous NaHCO3 until pH 7 was reached. The resulting mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (18 – 48% MeCN in 0.1% aqueous NH4HCO3). The fractions containing the product were lyophilized to obtain 3-(8-(8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-1-yl)propyl (R)-(3-methylpiperidin-3-yl)carbamate (800 mg, 56% yield). LCMS (MM-ES+APCI, Pos): m / z 536.2 (M+1). Step G. (13R)-28-fluoro-13-methyl-22-(methylthio)-7-oxa-9-aza-2(4,7)-pyrido[4,3- d]pyrimidina-1(1,3)-piperidina-3(1,8)-naphthalenacyclononaphan-8-one. To a solution of 3- (8-(8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-1-yl)propyl (R)-(3-methylpiperidin-3-yl)carbamate (650 mg, 1.1 mmol) in DCM (650 mL) was added DIPEA (0.95 mL, 5.5 mmol) and BOP-Cl (0.84 g, 3.3 mmol). The mixture was stirred at rt for 16 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 – 100% EtOAc in petroleum ether) to give (13R)-28-fluoro-13- methyl-22-(methylthio)-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)- naphthalenacyclononaphan-8-one (0.24 g, 42% yield) as a white solid. LCMS (MM- ES+APCI, Pos): m / z 518.3 (M+1). Step H. (13R)-28-fluoro-13-methyl-22-(methylsulfonyl)-7-oxa-9-aza-2(4,7)-pyrido[4,3- d]pyrimidina-1(1,3)-piperidina-3(1,8)-naphthalenacyclononaphan-8-one. To a solution of (13R)-28-fluoro-13-methyl-22-(methylthio)-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina- 1(1,3)-piperidina-3(1,8)-naphthalenacyclononaphan-8-one (0.30 g, 0.57 mmol) in DCM (5 mL) at 0 °C was added m-CPBA (0.35 g, 1.7 mmol) portionwise. The mixture was stirred at rt for 1 h. The mixture was quenched by slow addition of aqueous Na2SO3(50 mL) at 0 °C. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 – 50% EtOAc in petroleum ether) and the pure fractions lyophilized to give (13R)-28-fluoro-13- methyl-22-(methylsulfonyl)-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina- 3(1,8)-naphthalenacyclononaphan-8-one (0.067 g, 19% yield) as a white solid. LCMS (MM- ES+APCI, Pos): m / z 550.2 (M+1). tert-butyl 3-amino-3-(methoxymethyl)piperidine-1-carboxylate amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (4.5 g, 18 mmol) in THF (300 mL) at 0 °C was added BH3∙THF (1.0 M; 37 mL). The reaction was heated to 80 °C for 4 h. After cooling to 0 °C, the reaction was quenched with MeOH (10 mL) and then it was stirred for an additional 16 h at rt. The mixture was concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-15% MeOH in DCM) to give tert-butyl 3-amino-3-(hydroxymethyl)piperidine-1-carboxylate (2.6 g, 61% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): m / z 231.1 (M+H). Step B. tert-butyl 3-(((benzyloxy)carbonyl)amino)-3-(hydroxymethyl)piperidine-1- carboxylate. To a solution of tert-butyl 3-amino-3-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 4.3 mmol) and DIPEA (2.3 mL, 13 mmol) in DCM (20 mL) at 0 °C was added CbzCl (0.68 mL, 4.8 mmol). The mixture was warmed to rt and stirred for 16 h after which it was concentrated under recued pressure. The residue was purified by silica gel chromatography (0- 60% EtOAc in petroleum ether) to give tert-butyl 3-(((benzyloxy)carbonyl)amino)-3- (hydroxymethyl)piperidine-1-carboxylate (1.1 g, 61% yield) as a white solid. LCMS (MM- ES+APCI, Pos): m / z 265.1 (M+H - Boc). Step C. tert-butyl 3-(((benzyloxy)carbonyl)amino)-3-(methoxymethyl)piperidine-1- carboxylate. To a solution of tert-butyl 3-(((benzyloxy)carbonyl)amino)-3- (hydroxymethyl)piperidine-1-carboxylate (1.0 g, 2.5 mmol) in MeCN (10 mL) was added Ag2O (2.2 g, 9.5 mmol) and MeI (4.7 mL, 75 mmol). The mixture was heated to 40 °C for 48 h. The suspension was filtered and the filter cake was washed with MeCN (30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% EtOAc in petroleum ether) to give tert-butyl 3- (((benzyloxy)carbonyl)amino)-3-(methoxymethyl)piperidine-1-carboxylate (0.15 g, 14% yield) as a colorless oil. LCMS (MM-ES+APCI, Pos): m / z 279.1 (M+H - Boc). Step D. tert-butyl 3-amino-3-(methoxymethyl)piperidine-1-carboxylate. To a solution of tert- butyl 3-(((benzyloxy)carbonyl)amino)-3-(methoxymethyl)piperidine-1-carboxylate (0.20 g, 0.45 mmol) in THF (5.0 mL) was added 10 % Pd / C (0.048 g, 0.045 mmol). The mixture was stirred under an atmosphere of H2 for 16 h. The suspension was filtered and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 3-amino-3-(methoxymethyl)piperidine-1-carboxylate (110 mg) as a colorless oil, which was taken onto the next step without further purification. Intermediate I26 Step A.1-benzyl 3-methyl 5-((tert-butyldimethylsilyl)oxy)piperidine-1,3-dicarboxylate. To a solution of 1-benzyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate (5.0 g, 17 mmol) and TBSCl (3.9 g, 26 mmol) in DCM (50 mL) was added imidazole (2.3 g, 34 mmol) and DMAP (1.0 g, 8.5 mmol). The mixture was stirred at rt for 2 h and then the solution was diluted with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-90% EtOAc in petroleum ether) to give 1-benzyl 3-methyl 5-((tert- butyldimethylsilyl)oxy)piperidine-1,3-dicarboxylate (12 g, 79% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 408.1 (M+H). Step B.1-benzyl 3-methyl 5-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine-1,3- dicarboxylate. To a solution of 1-benzyl 3-methyl 5-((tert-butyldimethylsilyl)oxy)piperidine- 1,3-dicarboxylate (3.5 g, 8.6 mmol) in THF (70 mL) at -65 °C was added LiHMDS (1.0 M; 26 mL) dropwise. A solution of MeI (1.5 mL, 25 mmol) in THF (10 mL) was added to the reaction. The reaction was warmed to rt and stirred for 30 min after which it was diluted with saturated aqueous NH4Cl (20 mL) and then extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-90% EtOAc in petroleum ether) to give 1-benzyl 3-methyl 5-((tert- butyldimethylsilyl)oxy)-3-methylpiperidine-1,3-dicarboxylate (8.0 g, 86% yield) as colorless oil. LCMS (MM-ES+APCI, Pos): m / z 422.2 (M+H). Step C.1-benzyl 3-methyl 5-hydroxy-3-methylpiperidine-1,3-dicarboxylate. To solution of 1- benzyl 3-methyl 5-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine-1,3-dicarboxylate (8.0 g, 19 mmol) in THF (80 mL) was added NEt3∙HF (16 mL, 95 mmol). The mixture was stirred at rt for 2 h after which it was diluted with H2O (100 mL) and then extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-17% EtOAc in petroleum ether) to give 1- benzyl 3-methyl 5-hydroxy-3-methylpiperidine-1,3-dicarboxylate (5.8 g, 99% yield) as colorless oil. Step D.1-benzyl 3-methyl 3-methyl-5-oxopiperidine-1,3-dicarboxylate. To a solution of 1- benzyl 3-methyl 5-hydroxy-3-methylpiperidine-1,3-dicarboxylate (3.8 g, 12 mmol) in DCM (60 mL) at 0 °C was added DMP (7.9 g, 19 mmol) was added. The mixture was allowed to warm to rt and stirred for 1 h. The mixture was diluted with NaOH (1.0 M; 15 mL) and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (9-50% EtOAc in petroleum ether) to give 1-benzyl 3-methyl 3-methyl-5-oxopiperidine-1,3-dicarboxylate (2.9 g, 77% yield) as colorless oil. Step E.1-benzyl 3-methyl (rel-3R,5R)-5-cyano-3-methylpiperidine-1,3-dicarboxylate. To a solution of 1-benzyl 3-methyl 3-methyl-5-oxopiperidine-1,3-dicarboxylate (2.9 g, 9.5 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (3.0 g, 15 mmol) in DME (290 mL) and MeOH (3.5 mL) was added aqueous t-BuOK (1.0 M; 19 mL). The mixture was stirred at rt for 12 h after which it was diluted with H2O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in petroleum ether) to give 1-benzyl 3-methyl (rel- 3R,5R)-5-cyano-3-methylpiperidine-1,3-dicarboxylate (1.1 g, 35% yield) as yellow oil.1H NMR: (400 MHz, MeOH-d4) δ 7.43 - 7.25 (m, 5H), 5.20 - 5.08 (m, 2H), 4.53 - 4.20 (m, 2H), 3.56 (br d, J = 16.0 Hz, 3H), 3.19 - 2.94 (m, 2H), 2.93 - 2.78 (m, 1H), 2.56 - 2.43 (m, 1H), 1.68 (br t, J = 12.8 Hz, 1H), 1.31 - 1.12 (m, 3H). Step F. (rel-3R,5R)-1-((benzyloxy)carbonyl)-5-cyano-3-methylpiperidine-3-carboxylic acid. To a solution of 1-benzyl 3-methyl (rel-3R,5R)-5-cyano-3-methylpiperidine-1,3- dicarboxylate (1.0 g, 3.2 mmol) in H2O (10 mL) and THF (10 mL) was added LiOH (0.38 g, 16 mmol). The mixture was heated to 70 °C for 1 h after which it was diluted with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The aqueous phase was adjusted to pH 3 with aqueous HCl (1 M) and was then extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (rel-3R,5R)-1-((benzyloxy)carbonyl)-5-cyano-3- methylpiperidine-3-carboxylic acid (0.90 g) as yellow oil, which was used in the next step without further purification. Step G. benzyl (rel-3R,5R)-3-carbamoyl-5-cyano-3-methylpiperidine-1-carboxylate. To a solution of (rel-3R,5R)-1-((benzyloxy)carbonyl)-5-cyano-3-methylpiperidine-3-carboxylic acid (0.90 g, 3.0 mmol) in DMF (20 mL) was added NH4Cl (1.6 g, 30 mmol), DIPEA (6.2 mL, 36 mmol) and HATU (2.3 g, 6.0 mmol). The mixture was heated to 50 °C for 12 after which it was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% EtOAc in petroleum ether) to give benzyl (rel-3R,5R)-3- carbamoyl-5-cyano-3-methylpiperidine-1-carboxylate (0.60 g, 67% yield) as a light yellow oil. Step H. benzyl (rel-3R,5R)-3-amino-5-cyano-3-methylpiperidine-1-carboxylate. To a solution of benzyl (rel-3R,5R)-3-carbamoyl-5-cyano-3-methylpiperidine-1-carboxylate (0.50 g, 1.7 mmol) in MeCN (5.0 mL) at 0 °C was added NBS (0.44 g, 2.5 mmol) followed by a solution of NaOH (0.3 g, 8.3 mmol) in H2O (20 mL). The mixture was heated to 60 °C for 8 h after which it was diluted with H2O (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-100% EtOAc in petroleum ether) to give benzyl (rel-3R,5R)-3- amino-5-cyano-3-methylpiperidine-1-carboxylate (0.30 g, 55% yield) as colorless oil. Intermediate I27 benzyl 3-amino-3-(2-hydroxyethyl)piperidine-1-carboxylate Step A. benzyl 3-amino-3-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate. To a solution of benzyl 3-oxopiperidine-1-carboxylate (2.0 g, 8.6 mmol) in EtOH (20 mL) was added NH4OAc (2.0 g, 26 mmol) and 3-ethoxy-3-oxopropanoic acid (1.7 g, 13 mmol). The mixture was heated to 80 °C for 16 h after which it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc in petroleum ether) to give benzyl 3-amino-3-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (1.8 g, 32% yield) as yellow oil. LCMS (MM-ES+APCI, Pos): m / z 321.0 (M+H). Step B. benzyl 3-amino-3-(2-hydroxyethyl)piperidine-1-carboxylate. To a solution of benzyl 3-amino-3-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (1.8 g, 2.7 mmol) in THF (10 mL) at 0 °C was added LiAlH4(2.5 M solution in THF; 2.7 mL). The mixture was stirred at 0 °C for 2 h after which it was quenched by slow addition of Na2SO4·10H2O (3.2 mL, 13.7 mmol). The mixture was warmed to rt and stirred for 16 h. The suspension was filtered and the filter cake was washed with THF (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (10% – 40% MeCN in 0.05% aqueous NH4OH). The fractions containing the product were lyophilized to obtain benzyl 3-amino-3- (2-hydroxyethyl)piperidine-1-carboxylate (0.40 g, 53% yield) as yellow oil. LCMS (MM- ES+APCI, Pos): m / z 279.2 (M+H). benzyl 3-amino-3-(2,2-difluoroethyl)piperidine-1-carboxylate Step A.1-benzyl 3-methyl 3-(2,2-difluoroethyl)piperidine-1,3-dicarboxylate. To a solution of 1-benzyl 3-methyl piperidine-1,3-dicarboxylate (3.0 g, 11 mmol) in THF (30 mL) at -78 °C was added LiHMDS (1.0 M in THF; 16mL). The reaction was stirred for 1 h at -78 °C, after which 1,1-difluoro-2-iodoethane (3.1 g, 16 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h and then at rt for 12 h. The mixture was diluted with saturated aqueous NH4Cl (50 mL) at 0 °C and was then extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17-25% EtOAc in petroleum ether) to give 1-benzyl 3-methyl 3- (2,2-difluoroethyl)piperidine-1,3-dicarboxylate (2.0 g, 54% yield) as yellow liquid. LCMS (MM-ES+APCI, Pos): m / z 342.2 (M+H). Step B.1-((benzyloxy)carbonyl)-3-(2,2-difluoroethyl)piperidine-3-carboxylic acid. To a solution of 1-benzyl 3-methyl 3-(2,2-difluoroethyl)piperidine-1,3-dicarboxylate (1.9 g, 5.6 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH.H2O (1.2 g, 28 mmol). The mixture was stirred at rt for 12 h, after which it was diluted with H2O (10 mL) and extracted with EtOAc (20 mL). The pH of aqueous phase was adjusted to 3 with HCl (4.0 M). The aqueous phase was concentrated under reduced pressure. To the slurry was added DCM (40 mL) and the mixture was stirred for 1 h. The slurry was filtered and then the organic phase of the filtrate was concentrated under reduced pressure to give 1-((benzyloxy)carbonyl)-3-(2,2- difluoroethyl)piperidine-3-carboxylic acid (1.6 g, 88% yield) as yellow gum. LCMS (MM- ES+APCI, Pos): m / z 326.2 (M+H). Step C. benzyl 3-carbamoyl-3-(2,2-difluoroethyl)piperidine-1-carboxylate. To a solution of 1-((benzyloxy)carbonyl)-3-(2,2-difluoroethyl)piperidine-3-carboxylic acid (1.5 g, 4.6 mmol), DIPEA (2.4 mL, 14 mmol), and HATU (2.6 g, 6.9 mmol) in DMF (10 mL) was added NH4Cl (0.49 g, 9.2 mmol). The mixture was stirred at rt for 1 h after which it was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17-25% EtOAc in petroleum ether) to give benzyl 3-carbamoyl-3-(2,2-difluoroethyl)piperidine-1-carboxylate (1.1 g, 74% yield) as colorless gum. LCMS (MM-ES+APCI, Pos): m / z 327.1 (M+H). Step D. benzyl 3-amino-3-(2,2-difluoroethyl)piperidine-1-carboxylate. To a solution of benzyl 3-carbamoyl-3-(2,2-difluoroethyl)piperidine-1-carboxylate (1.0 g, 3.1 mmol) in MeCN (5 mL) at 0 °C was added NBS (0.82 g, 4.6 mmol). The mixture was stirred at rt for 30 min and then a solution of NaOH (0.61 g, 15 mmol) in H2O (20 mL) was added. The mixture was heated to 60 °C for 30 min and then it was diluted with H2O (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-100% EtOAc in petroleum ether) to give benzyl 3-amino-3-(2,2-difluoroethyl)piperidine-1-carboxylate (0.35 g, 38% yield) as yellow gum. LCMS (MM-ES+APCI, Pos): m / z 299.1 (M+H). Intermediate I29 tert-butyl (6-chloro-5-iodo-4-methylpyridin-2-yl)carbamate Step A.6-chloro-5-iodo-4-methylpyridin-2-amine. To a solution of 6-chloro-4- methylpyridin-2-amine (3.0 g, 21 mmol) in DMF (100 mL) was added NIS (5.7 g, 25 mmol). The mixture was stirred at 80 °C for 2 h and then it was diluted with H2O (50 mL) and extracted with EtOAc (100 mL x 3). The organics were washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in petroleum ether) to give 6- chloro-5-iodo-4-methylpyridin-2-amine (4.0 g, 62% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 6.32 (s, 1H), 4.53 (br s, 2H), 2.39 - 2.33 (m, 3H). Step B. tert-butyl (6-chloro-5-iodo-4-methylpyridin-2-yl)carbamate. To a solution of 6- chloro-5-iodo-4-methylpyridin-2-amine (6.0 g, 20 mmol) and NEt3(8.2 mL, 59 mmol) in DCM (60 mL) was added DMAP (0.24 g, 2.0 mmol) and di-tert-butyl dicarbonate (5.2 g, 24 mmol). The mixture was stirred at rt for 16 h and then it was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The organic phases were washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-16% EtOAc in petroleum ether) to give tert-butyl (6-chloro-5-iodo-4-methylpyridin-2-yl)carbamate (2.0 g, 27% yield) as a yellow solid.1H NMR: (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.19 (s, 1H), 2.49 (s, 3H), 1.52 (s, 9H). Intermediate I30 tert-butyl (6-chloro-4-methyl-5-(4-((triisopropylsilyl)oxy)but-1-yn-1-yl)pyridin-2- Step A. tert-butyl (6-chloro-4-methyl-5-(4-((triisopropylsilyl)oxy)but-1-yn-1-yl)pyridin-2- yl)carbamate. To a solution of tert-butyl (6-chloro-5-iodo-4-methylpyridin-2-yl)carbamate (2.0 g, 5.4 mmol) and (but-3-yn-1-yloxy)triisopropylsilane (1.8 g, 8.1 mmol) in DMF (20 mL) was added Pd(PPh3)2Cl2 (0.38 g, 0.54 mmol), CuI (0.10 g, 0.54 mmol) and NEt3 (2.2 mL, 16 mmol). The flask was then evacuated and backfilled with nitrogen three times and then it was heated to 65 °C for 16 h. After cooling to rt, the reaction was diluted with H2O (50 mL) and extracted with EtOAc (100 mL x 3). The organic phases were washed with brine (50 mL x 2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% EtOAc in petroleum ether) to give tert-butyl (6-chloro-4-methyl-5-(4-((triisopropylsilyl)oxy)but-1-yn-1-yl)pyridin-2- yl)carbamate (1.6 g, 62% yield) as yellow oil. Intermediate I31 tert-butyl (6-chloro-4-methyl-5-(3-((triisopropylsilyl)oxy)propyl)pyridin-2-yl)carbamate Step A. tert-butyl (6-chloro-4-methyl-5-(3-((triisopropylsilyl)oxy)prop-1-yn-1-yl)pyridin-2- yl)carbamate. To a solution tert-butyl (6-chloro-5-iodo-4-methylpyridin-2-yl)carbamate (4.0 g, 10 mmol) and triisopropyl(prop-2-yn-1-yloxy)silane (6.7 g, 31 mmol) in DMF (40 mL) was added Pd(PPh3)2Cl2 (0.74 g, 1.1 mmol), CuI (0.20 g, 1.1 mmol) and NEt3 (4.4 mL, 32 mmol). The flask was evacuated and backfilled with nitrogen three times and then it was heated to 65 °C for 16 h. After cooling to rt, the reaction was diluted with H2O (100 mL) and extracted with EtOAc (150 mL x 3). The organic phases were washed with brine (50 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-3% EtOAc in petroleum ether) to give tert- butyl (6-chloro-4-methyl-5-(3-((triisopropylsilyl)oxy)prop-1-yn-1-yl)pyridin-2-yl)carbamate (3.8 g, 63% yield). LCMS (MM-ES+APCI, Pos): m / z 397.2 (M+H). Step B. tert-butyl (6-chloro-4-methyl-5-(3-((triisopropylsilyl)oxy)propyl)pyridin-2- yl)carbamate. A solution of tert-butyl (6-chloro-4-methyl-5-(3-((triisopropylsilyl)oxy)prop-1- yn-1-yl)pyridin-2-yl)carbamate (2.0 g, 4.3 mmol) in MeOH (50 mL) and THF (50 mL) was passed through a fixed bed (5 mL, FLR1; 10% Ru / SiO2) at 0.3 mL / min at 45 °C. The reactor was pressurized with hydrogen 1 MPa at a flow rate of 20 mL / min. The solution was collected from the reactor and then concentrated under reduced pressure to afford tert-butyl (6-chloro-4-methyl-5-(3-((triisopropylsilyl)oxy)propyl)pyridin-2-yl)carbamate (2.0 g, 88% yield) as brown oil. LCMS (MM-ES+APCI, Pos): m / z 457.3 (M+H). Intermediate I33 (13R,15R)-15,28,37-trifluoro-33-(methoxymethoxy)-13-methyl-22-(2,2,2-trifluoroethoxy)-7- oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)- naphthalenacyclononaphan-8-one Step A.4-(benzyloxy)-7-chloro-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (0.50 g, 1.4 mmol) and 2,2,2-trifluoroethan-1-ol (0.20 mL, 2.8 mmol) in MeCN (6 mL) was added DIPEA (0.49 mL, 2.8 mmol). The reaction was heated to 40 °C for 12 h and then it was diluted with H2O (40 mL). The suspension was stirred for 10 min and then it was filtered. The filter cake was washed with H2O (10 mL) and petroleum ether (10 mL). The precipitate was further dried under vacuum to obtain 4-(benzyloxy)-7-chloro-8-fluoro-2-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.50 g, 89% yield). LCMS (MM-ES+APCI, Pos): m / z 388.0 (M+H). Step B.4-(benzyloxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(3- ((triisopropylsilyl)oxy)propyl)naphthalen-1-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine. To a solution of 4-(benzyloxy)-7-chloro-8-fluoro-2-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.50 g, 1.3 mmol) and (3-(2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1- yl)propoxy)triisopropylsilane (0.77 g, 1.3 mmol) in dioxane (6 mL) and H2O (0.6 mL) was added mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′- biphenyl)]palladium(II) (0.094 g, 0.13 mmol) and Cs2CO3 (0.82 g, 1.5 mmol). The mixture was sparged with N2for 2 m in and then it was heated to 90 °C for 1 h. The solution was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% EtOAc in petroleum ether) to give 4-(benzyloxy)-8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-(3-((triisopropylsilyl)oxy)propyl)naphthalen-1-yl)-2-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (0.83 g, 77% yield) as a yellow oil. LCMS (MM- ES+APCI, Pos): m / z 772.3 (M+H). Step C.3-(8-(4-(benzyloxy)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)- 2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)propan-1-ol. To a solution of 4-(benzyloxy)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(3-((triisopropylsilyl)oxy)propyl)naphthalen-1-yl)- 2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin (0.83 g, 0.97 mmol) in THF (10 mL) was added NEt3-3HF (0.47 mL, 2.9 mmol). The mixture was stirred at 50 °C for 48 h and then it was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% EtOAc in petroleum ether) to give 3-(8-(4-(benzyloxy)-8-fluoro-2- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6- (methoxymethoxy)naphthalen-1-yl)propan-1-ol (0.45 g, 72% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 616.2 (M+H). Step D.3-(8-(4-(benzyloxy)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)- 2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)propyl (2,5-dioxopyrrolidin-1-yl) carbonate. To a solution of 3-(8-(4-(benzyloxy)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1-yl)propan-1-ol (0.20 g, 0.31 mmol) and pyridine (0.073 mL, 0.92 mmol) in DCM (3 mL) was added N,N′-disuccinimidyl carbonate (0.23 g, 0.92 mmol). The mixture was stirred at rt for 1 h and then it was diluted with H2O (10 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-(8-(4-(benzyloxy)-8-fluoro-2-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1- yl)propyl (2,5-dioxopyrrolidin-1-yl) carbonate (0.23 g, 99% yield). Step E. benzyl (3R,5R)-3-(((3-(8-(4-(benzyloxy)-8-fluoro-2-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1- yl)propoxy)carbonyl)amino)-5-fluoro-3-methylpiperidine-1-carboxylate. To a solution of 3- (8-(4-(benzyloxy)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6- (methoxymethoxy)naphthalen-1-yl)propyl (2,5-dioxopyrrolidin-1-yl) carbonate (0.23 g, 0.30 mmol) and DIPEA (0.11 mL, 0.61 mmol) in DCM (3 mL) was added benzyl (R)-3-amino-3- methylpiperidine-1-carboxylate (0.10 g, 0.36 mmol). The mixture was stirred 35 °C for 2 h and then it was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc in petroleum ether) to give benzyl (3R,5R)-3- (((3-(8-(4-(benzyloxy)-8-fluoro-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-2- fluoro-6-(methoxymethoxy)naphthalen-1-yl)propoxy)carbonyl)amino)-5-fluoro-3- methylpiperidine-1-carboxylate (0.22 g, 73% yield) as white solid. LCMS (MM-ES+APCI, Pos): m / z 908.5 (M+H). Step F.3-(2-fluoro-8-(8-fluoro-4-hydroxy-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7- yl)-6-(methoxymethoxy)naphthalen-1-yl)propyl ((3R,5R)-5-fluoro-3-methylpiperidin-3- yl)carbamate. To a solution of benzyl (3R,5R)-3-(((3-(8-(4-(benzyloxy)-8-fluoro-2-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-1- yl)propoxy)carbonyl)amino)-5-fluoro-3-methylpiperidine-1-carboxylate (0.22 g, 0.24 mmol) in THF (4 mL) was added 10% Pd / C (0.25 g, 0.24 mmol). The flask was evacuated and backfilled with H2three times. The mixture was stirred at rt under an atmosphere of H2for 2 h. The suspension was filtered through Celite, and the filter cake was washed with THF (30 mL x 3). The filtrate was concentrated under reduced pressure to give 3-(2-fluoro-8-(8- fluoro-4-hydroxy-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- (methoxymethoxy)naphthalen-1-yl)propyl ((3R,5R)-5-fluoro-3-methylpiperidin-3- yl)carbamate (0.16 g, 99% yield) as a white solid. Step G. (13R,15R)-15,28,37-trifluoro-33-(methoxymethoxy)-13-methyl-22-(2,2,2- trifluoroethoxy)-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)- naphthalenacyclononaphan-8-one. To a solution of 3-(2-fluoro-8-(8-fluoro-4-hydroxy-2- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1- yl)propyl ((3R,5R)-5-fluoro-3-methylpiperidin-3-yl)carbamate (0.16 g, 0.23 mmol) and DIPEA (0.20 mL, 1.2 mmol) in MeCN (80 mL) was added BrOP (0.27 g, 0.70 mmol). The mixture was stirred at rt for 12 h and then it was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced. The residue was purified by silica gel chromatography (0-50% EtOAc in petroleum ether) to give (13R,15R)- 15,28,37-trifluoro-33-(methoxymethoxy)-13-methyl-22-(2,2,2-trifluoroethoxy)-7-oxa-9-aza- 2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)-naphthalenacyclononaphan-8-one. To a solution of 3-(2-fluoro-8-(8-fluoro-4-hydroxy-2-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidin-7-yl)-6-(methoxymethoxy)naphthalen-1-yl)propyl ((3R,5R)-5-fluoro-3- methylpiperidin-3-yl)carbamate (0.50 g, 30% yield) as a white solid. LCMS (MM-ES+APCI, Pos): m / z 666.3 (M+H). (13R)-15,15,28,37-tetrafluoro-33-(methoxymethoxy)-13-methyl-22-(2,2,2-trifluoroethoxy)-7- oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)- naphthalenacyclononaphan-8-one Steps A-G were performed following the procedure of Intermediate I33. Intermediate I35 benzyl (rel-3R,5S)-3-amino-5-cyano-3-methylpiperidine-1-carboxylate Step A.1-benzyl 3-methyl (rel-3R,5S)-5-cyano-3-methylpiperidine-1,3-dicarboxylate. To a solution of 1-benzyl 3-methyl 3-methyl-5-oxopiperidine-1,3-dicarboxylate (5.0 g, 16 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (5.1 g, 26 mmol) in DME (500 mL) and MeOH (6 mL) was added t-BuOK (3.7 g, 33 mmol). The reaction was stirred for 12 h and then it was diluted with H2O (50 mL) and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in petroleum ether) to give 1-benzyl 3-methyl (rel-3R,5S)-5-cyano-3-methylpiperidine-1,3-dicarboxylate (1.0 g, 19% yield) as a yellow oil.1H NMR: (400 MHz, MeOH-d4) δ 7.47 - 7.32 (m, 5H), 5.26 - 5.11 (m, 2H), 3.95 (br d, J = 13.2 Hz, 1H), 3.83 - 3.62 (m, 5H), 3.42 - 3.34 (m, 1H), 3.15 - 3.06 (m, 1H), 2.36 (dd, J = 7.2, 14.0 Hz, 1H), 1.96 (dd, J = 4.4, 13.9 Hz, 1H), 1.18 (br s, 3H). Step B. (rel-3R,5S)-1-((benzyloxy)carbonyl)-5-cyano-3-methylpiperidine-3-carboxylic acid. To a solution of 1-benzyl 3-methyl (rel-3R,5S)-5-cyano-3-methylpiperidine-1,3- dicarboxylate (1.0 g, 3.2 mmol) in THF (10 mL) and H2O (2.5 mL) was added LiOH (0.30 g, 13 mmol). The mixture was stirred for 12 h and then it was diluted with H2O (5 mL). The pH of mixture was adjusted to 7 with 1 M HCl. The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (rel- 3R,5S)-1-((benzyloxy)carbonyl)-5-cyano-3-methylpiperidine-3-carboxylic acid (0.90 g, 94% yield) as a yellow oil, which was used into the next step without further purification. Step C. benzyl (rel-3R,5S)-3-amino-5-cyano-3-methylpiperidine-1-carboxylate. To a solution of (rel-3R,5S)-1-((benzyloxy)carbonyl)-5-cyano-3-methylpiperidine-3-carboxylic acid (0.90 g, 3.0 mmol) in THF (80 mL) was added DPPA (2.6 mL, 12 mmol) and DIPEA (7.3 mL, 42 mmol). The mixture was heated to 75 °C and stirred for 4 h. The solution was cooled to rt then a solution of KOH (3.3 g, 60 mmol) in H2O (25 mL) was added dropwise. The mixture was stirred for 12 h and then it was diluted with H2O (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25-75% EtOAc in petroleum ether) to give benzyl (rel-3R,5S)-3-amino-5-cyano-3-methylpiperidine-1-carboxylate (0.50 g, 61% yield) as a colorless oil.1H NMR: (400 MHz, MeOH-d4) δ 7.47 - 7.25 (m, 5H), 5.23 - 5.05 (m, 2H), 4.19 - 4.06 (m, 1H), 3.75 - 3.56 (m, 1H), 3.28 - 3.11 (m, 1H), 2.99 (ddd, J = 4.0, 9.6, 14.0 Hz, 2H), 2.00 - 1.89 (m, 1H), 1.81 - 1.68 (m, 1H), 1.05 (br s, 3H). Intermediate I36 ((1R,3r,5S)-6-methyl-6-azabicyclo[3.1.1]heptan-3-yl)methanol Step A. ((1R,3r,5S)-6-methyl-6-azabicyclo[3.1.1]heptan-3-yl)methanol. To a solution of (1R,3r,5S)-6-(tert-butoxycarbonyl)-6-azabicyclo[3.1.1]heptane-3-carboxylic acid (0.10 g, 410 mmol) in THF (7.5 mL) at 0˚C was added LiAlH4(2.5 M in THF; 1.0 mL). The reaction was heated to 70˚C for 1 h. After cooling to 0˚C the reaction was quenched with H2O (10 mL). The mixture was extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ((1R,3r,5S)-6-methyl-6-azabicyclo[3.1.1]heptan-3- yl)methanol (0.020 g, 34% yield), which was used in the next step without further purification. Intermediate I37 benzyl (R)-3-methyl-3-(((4-nitrophenoxy)carbonyl)oxy)piperidine-1-carboxylate Step A. benzyl (R)-3-methyl-3-(((4-nitrophenoxy)carbonyl)oxy)piperidine-1-carboxylate. To a solution of benzyl (R)-3-hydroxy-3-methylpiperidine-1-carboxylate (0.60 g, 2.4 mmol) and pyridine (0.39 mL, 4.8 mmol) in DCM (6 mL) at 0˚C was added 4-nitrophenyl carbonochloridate (1.5 g, 7.2 mmol). The reaction was stirred at rt for 12 h and then it was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (44-74% MeCN in 0.1% aqueous NH4HCO3) to give benzyl (R)-3-methyl-3-(((4- nitrophenoxy)carbonyl)oxy)piperidine-1-carboxylate (0.47 g, 47% yield). LCMS (MM- ES+APCI, Pos): m / z 415.2 (M+H). Intermediate I38 benzyl (R)-3-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1- carboxylate Step A. benzyl (R)-3-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)amino)-3-methylpiperidine- 1-carboxylate. To a solution of benzyl (R)-3-amino-3-methylpiperidine-1-carboxylate (0.10 g, 0.40 mmol) and pyridine (0.16 mL, 2.0 mmol) in DCM (1 mL) was added N,N'- disuccinimidyl carbonate (0.21 g, 0.81 mmol). The reaction was stirred at 30 ˚C for 2 h and then it was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give benzyl (R)-3-((((2,5- dioxopyrrolidin-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (0.15 g, 96% yield). LCMS (MM-ES+APCI, Pos): m / z 390.0 (M+H). (13R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-13- methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)- naphthalenacyclononaphane-33-yl (4-nitrophenyl) carbonate Step A. (13R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 13-methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)- naphthalenacyclononaphane-33-yl (4-nitrophenyl) carbonate. To a solution of (13R)-28- fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-33-hydroxy-13- methyl-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)- naphthalenacyclononaphan-8-one (0.051 g, 0.078 mmol) and DIPEA (0.027 mL, 0.16 mmol) in DCM (0.5 mL) was added 4-nitrophenyl carbonochloridate (0.019 g, 0.093 mmol). The reaction was stirred at rt for 1 h. The mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (13R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-13- methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)- naphthalenacyclononaphane-33-yl (4-nitrophenyl) carbonate (0.060 g, 96% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): 810.7 (M+H). Intermediate I40 2,5-dioxopyrrolidin-1-yl ((13R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-13-methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- piperidina-3(1,8)-naphthalenacyclononaphane-33-yl) carbonate Intermediate I40 was synthesized using N,N -disuccinimidyl carbonate according to Intermediate I39 procedures. (13R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-13- methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina-3(1,8)- naphthalenacyclononaphane-33-yl (4-nitrophenyl) carbonate Intermediate I41 was synthesized according to Intermediate I39 procedures. 4-nitrophenyl ((13R)-15,15,28-trifluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-13-methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- piperidina-3(1,8)-naphthalenacyclononaphane-33-yl) carbonate Intermediate I42 was synthesized according to Intermediate I39 procedures. Intermediate I43 (13R,15R)-15,28-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-13-methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)-piperidina- 3(1,8)-naphthalenacyclononaphane-33-yl (4-nitrophenyl) carbonate Intermediate I43 was synthesized according to Intermediate I39 procedures. Intermediate I44

[0031] 4-nitrophenyl ((13R)-15,15,28,37-tetrafluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-13-methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- piperidina-3(1,8)-naphthalenacyclononaphane-33-yl) carbonate Intermediate I44 was synthesized according to Intermediate I39 procedures. Intermediate I45 2,5-dioxopyrrolidin-1-yl ((13R)-15,15,28,37-tetrafluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-13-methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina- 1(1,3)-piperidina-3(1,8)-naphthalenacyclononaphane-33-yl) carbonate Intermediate I45 was synthesized using N,N -disuccinimidyl carbonate according to Intermediate I39 procedures. 4-nitrophenyl ((13R,15R)-15,28,37-trifluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-13-methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,3)- piperidina-3(1,8)-naphthalenacyclononaphane-33-yl) carbonate Intermediate I43 was synthesized according to Intermediate I39 procedures. Intermediate I47 2,5-dioxopyrrolidin-1-yl ((13R,15R)-15,28,37-trifluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-13-methyl-8-oxo-7-oxa-9-aza-2(4,7)-pyrido[4,3-d]pyrimidina- 1(1,3)-piperidina-3(1,8)-naphthalenacyclononaphane-33-yl) carbonate Intermediate I47 was synthesized using N,N -disuccinimidyl carbonate according to Intermediate I39 procedures. Intermediate I48 Step A. tert-butyl 3,3-difluoro-[1,4'-bipiperidine]-1'-carboxylate. To a solution of tert-butyl 4- oxopiperidine-1-carboxylate (0.25 g, 1.3 mmol) and 3,3-difluoropiperidine (0.20 g, 1.3 mmol) in DMF (3 mL) was added DIPEA (0.22 mL, 1.3 mmol). The mixture was sparged with nitrogen for 5 min and then it was heated to 50 °C for 2 h. Then, to the reaction was added AcOH (0.072 mL, 1.3 mmol) and NaBH(OAc)3(0.66 g, 3.1 mmol). The mixture was sparged with nitrogen for 5 min and then it was heated to 50 °C for 10 h. The mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC (17% EtOAc in petroleum ether) to give tert-butyl 3,3-difluoro-[1,4'-bipiperidine]-1'- carboxylate (0.10 g, 26% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 4.15 (br s, 2H), 2.78 - 2.63 (m, 4H), 2.60 - 2.46 (m, 3H), 1.88 (dt, J = 6.8, 13.6 Hz, 2H), 1.79 - 1.66 (m, 5H), 1.46 (s, 9H), 1.43 - 1.39 (m, 1H). Step B.3,3-difluoro-1,4'-bipiperidine. To a solution of tert-butyl 3,3-difluoro-[1,4'- bipiperidine]-1'-carboxylate (0.050 g, 0.16 mmol) in DCM (1 mL) was added 2 M HCl in dioxane (1.0 mL). The reaction was stirred at rt for 1 h. The mixture was concentrated under reduced pressure to give 3,3-difluoro-1,4'-bipiperidine (0.30 g, 76% yield) as a white solid. Intermediate I49 (rel-1R,5S)-3,3-difluoro-8-azabicyclo[3.2.1]octane Step A. tert-butyl (rel-1R,5S)-3,3-difluoro-8-azabicyclo[3.2.1]octane-8-carboxylate. To a solution of tert-butyl (rel-1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.2 mmol) in DCM (4 mL) was added DAST (6.0 mL, 45 mmol). The reaction was stirred at rt for 16 h and then it was quenched with sat. aq. NaHCO3solution (10 mL) at 0 °C. The mixture was extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (9-25% EtOAc in petroleum ether) to give tert-butyl (rel-1R,5S)-3,3-difluoro-8-azabicyclo[3.2.1]octane-8-carboxylate (0.22 g, 40% yield) as brown oil. LCMS (MM-ES+APCI, Pos): 192.1 (M+H-tBu). Step B. (rel-1R,5S)-3,3-difluoro-8-azabicyclo[3.2.1]octane. To a solution of tert-butyl (rel- 1R,5S)-3,3-difluoro-8-azabicyclo[3.2.1]octane-8-carboxylate (0.22 g, 0.89 mmol) in DCM (10 mL) was added 2 M HCl in 1,4-dioxane (5 mL). The reaction was stirred for 2 h and then it was concentrated under reduced pressure to give (rel-1R,5S)-3,3-difluoro-8- azabicyclo[3.2.1]octane (160 mg), which was taken onto the next step without further purification. Intermediate I50 3,3-difluoro-2-methylpyrrolidine Step A. tert-butyl 3,3-difluoro-2-methylpyrrolidine-1-carboxylate. To a solution of tert-butyl 2-methyl-3-oxopyrrolidine-1-carboxylate (0.50 g, 2.5 mmol) in DCM (6 mL) was added DAST (10 mL, 76 mmol). The reaction was stirred at rt for 12 h and then it was quenched with ice water (100 mL). The resulting mixture extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (9% EtOAc in petroleum ether) to give tert-butyl 3,3-difluoro-2- methylpyrrolidine-1-carboxylate (0.20 g, 36% yield) as a yellow oil.1H NMR : (400 MHz, CDCl3) δ 4.07 - 3.83 (m, 1H), 3.52 (br t, J = 6.4 Hz, 2H), 2.38 - 2.21 (m, 2H), 1.49 (s, 9H), 1.29 - 1.22 (m, 3H). Step B.3,3-difluoro-2-methylpyrrolidine. To a solution of tert-butyl 3,3-difluoro-2- methylpyrrolidine-1-carboxylate (0.20 g, 0.90 mmol) in DCM (1 mL) was added 2 M HCl in 1,4-dioxane (1 mL). The reaction was stirred for 30 min and then it was concentrated under reduced pressure to give 3,3-difluoro-2-methylpyrrolidine (100 mg), which was taken onto the next step without further purification. Intermediate I51 Step A.1-chloroethyl 2-methylbenzoate. To a solution of 2-methylbenzoyl chloride (0.42 mL, 3.2 mmol) and ZnCl2 (0.0088 g, 0.065 mmol) in DCM (5 mL) at -10 °C was added a solution of acetaldehyde (5 M in THF, 0.65 mL) in DCM (1.5 mL). The mixture was allowed to warm to rt and was stirred for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-2% EtOAc in petroleum ether) to give 1-chloroethyl 2-methylbenzoate (0.45 g, 70% yield) as colorless oil.1H NMR: (400 MHz, DMSO-d6) δ 7.87 (d, J = 7.6 Hz, 1H), 7.59 - 7.51 (m, 1H), 7.41 - 7.32 (m, 2H), 6.80 (q, J = 5.6 Hz, 1H), 2.54 (s, 3H), 1.88 (d, J = 5.6 Hz, 3H). Intermediate I52 Intermediate I52 was synthesized according to Intermediate I51 procedures.1H NMR: (400 MHz, CDCl3) δ 7.27 - 7.19 (m, 1H), 7.06 (d, J = 7.6 Hz, 2H), 6.85 - 6.76 (m, 1H), 2.36 (s, 6H), 1.89 (d, J = 6.0 Hz, 3H). Intermediate I53 2-chloro-4,6-bis(trifluoromethyl)benzoyl chloride Step A.2-chloro-4,6-bis(trifluoromethyl)benzoyl chloride. To a solution of 2-chloro-4,6- bis(trifluoromethyl)benzoic acid (0.020 g, 0.068 mmol) in DCM (1 mL) at 0 °C was added oxalyl chloride (0.0066 mL, 0.075 mmol) followed by DMF (0.1 mL). The reaction was allowed to warm to rt and was stirred for 1 h. The mixture was concentrated under reduced pressure to obtain 2-chloro-4,6-bis(trifluoromethyl)benzoyl chloride (0.020 g, 94% yield), which was taken onto the next step without further purification. Intermediate I54 5-chloro-2,4-dimethylnicotinic acid Step A.3-bromo-5-chloro-2,4-dimethylpyridine. To a solution of 5-bromo-4,6- dimethylpyridin-3-amine (1.0 g, 5.0 mmol) in MeCN (10 mL) was added CuCl (0.74 g, 7.5 mmol) and t-BuONO (1.2 mL, 10 mmol). The reaction was stirred at 50 °C for 1 h and then it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-17% EtOAc in petroleum ether) to give 3-bromo-5-chloro-2,4- dimethylpyridine (0.70 g, 64% yield) as a colorless liquid. GCMS (MM-ES+APCI, Pos): 218.8 / 220.8 (M+H). Step B.5-chloro-2,4-dimethylnicotinic acid. To a solution of 3-bromo-5-chloro-2,4- dimethylpyridine (0.30 g, 1.4 mmol) in THF (5 mL) at -78 °C was added n-BuLi (2.5 M in THF, 0.82 mL). The reaction was stirred at -78 °C for 1 h, then CO2 (0.060 g, 1.4 mmol) was added. The reaction mixture was allowed to stir at -78 °C for 1 h and then it was slowly diluted with H2O (5 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The pH of aqueous phase was adjusted to 4 with 1 M HCl, and then it was concentrated under reduced pressure. The residue was purified by preparative HPLC (0 – 20% MeCN in 0.1% aqueous formic acid). The fractions containing the product were lyophilized to obtain 5- chloro-2,4-dimethylnicotinic acid (0.035 g, 14% yield) as a yellow solid. LCMS (MM- ES+APCI, Pos): 186.0 (M+H). Intermediate I55 2-(tert-butyl)-4-cyanobenzoic acid Step A.2-(tert-butyl)-4-cyanophenyl trifluoromethanesulfonate. To a solution of 3-(tert- butyl)-4-hydroxybenzonitrile (0.35 g, 2.0 mmol) and pyridine (0.32 mL, 4.0 mmol) in DCM (0.5 mL) at 0 °C was added Tf2O (0.66 mL, 4.0 mmol). The mixture was stirred at 0 °C for 1 h and then it was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-9% EtOAc in petroleum ether) to give 2-(tert-butyl)-4- cyanophenyl trifluoromethanesulfonate (0.50 g, 82% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.71 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 2.0, 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 1.37 (s, 9H). Step B. methyl 2-(tert-butyl)-4-cyanobenzoate. Two solutions were prepared and pumped through a flow reactor. Solution 1 containing 2-(tert-butyl)-4-cyanophenyl trifluoromethanesulfonate (0.50 g, 1.6 mmol) and Pd(dppf)Cl2(0.13 g, 0.16 mmol) in DMF (5 mL), MeOH (5 mL), and EtOAc (0.50 mL) was pumped at 1 mL / min at 3.5 MPa. Solution 2 containing DMF (5 mL) and MeOH (5 mL) was pumped at 0.1 mL / min. The two pumps were combined in a flow reactor (FLR1, SS, Coils reactor) along with CO(g) which was pumped at 30 mL / min at 4.0 MPa. After 60 min in the reactor, the mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting (0-9% EtOAc in petroleum ether) to give methyl 2-(tert-butyl)-4-cyanobenzoate (0.30 g, 85% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.79 (d, J = 1.2 Hz, 1H), 7.54 (dd, J = 1.6, 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 3.95 (s, 3H), 1.42 (s, 9H). Step C.2-(tert-butyl)-4-cyanobenzoic acid. To a solution of methyl 2-(tert-butyl)-4- cyanobenzoate (0.050 g, 0.23 mmol) in EtOAc (0.5 mL) was added LiI (0.092 g, 0.69 mmol). The mixture was heated to 70 °C and stirred for 12 h. The mixture was quenched with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The aqueous phase pH was adjusted to 1 with 1 M HCl (5mL) and then it was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-(tert-butyl)-4-cyanobenzoic acid (0.040 g, 86% yield,) as yellow oil, which was taken onto the next step without further purification. Intermediate I56 Step A.2-cyano-6-methylbenzoic acid. To a solution of 2-bromo-3-methylbenzonitrile (0.20 g, 1.0 mmol) in THF (2 mL) at -78 °C was added n-BuLi (2.5 M in THF; 0.49 mL). The reaction was stirred at -78 °C for 30 min and then dry ice was added to the reaction. The mixture was allowed to warm to rt and was stirred for 16 h. The mixture was diluted with sat. aq. NH4Cl (2 mL) and then it was extracted with ethyl acetate (4 mL). The pH of aqueous layer was adjusted to 3 with 1 M HCl, which was then lyophilized to give 2-cyano-6- methylbenzoic acid (0.10 mg, 46% yield) as a yellow solid. LCMS (MM-ES+APCI, Pos): 162.2 (M+H). Intermediate I57 4-methoxy-3-(trifluoromethyl)piperidine Step A. tert-butyl 4-methoxy-3-(trifluoromethyl)piperidine-1-carboxylate. To a solution of tert-butyl 4-hydroxy-3-(trifluoromethyl)piperidine-1-carboxylate (0.20 g, 0.74 mmol) in THF (5 mL) at 0 °C was added NaH (60% in mineral oil; 0.059 g, 1.5 mmol). The mixture was stirred for 1 h and then CH3I (0.093 mL, 1.5 mmol). The reaction was stirred for 1 h and then it was diluted with H2O (10 mL) extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17-25% EtOAc in petroleum ether) to obtain tert-butyl 4-methoxy- 3-(trifluoromethyl)piperidine-1-carboxylate (0.20 g, 95% yield) as a colorless liquid.1H NMR: (400 MHz, CDCl3) δ 4.16 - 3.75 (m, 3H), 3.38 (s, 3H), 3.22 (br d, J = 12.4 Hz, 1H), 3.11 - 3.02 (m, 1H), 2.38 - 2.19 (m, 1H), 2.05 - 1.92 (m, 1H), 1.47 (s, 9H). Step B.4-methoxy-3-(trifluoromethyl)piperidine. A solution of tert-butyl 4-methoxy-3- (trifluoromethyl)piperidine-1-carboxylate (0.10 g, 0.35 mmol) in 2 M HCl in dioxane (0.88 mL) was stirred for 1 h. The mixture was concentrated under reduced pressure to give 4- methoxy-3-(trifluoromethyl)piperidine (0.060 g, 93% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 9.80 (br d, J = 1.6 Hz, 1H), 3.87 (br s, 1H), 3.46 (br d, J = 9.2Hz, 1H), 3.38 (s, 3H), 3.34 (br s, 1H), 3.20 (br s, 1H), 3.05 (br s, 1H), 2.68 - 2.28 (m, 1H), 2.23 - 1.95 (m, 2H). Intermediate I58 2,5-bis(trifluoromethyl)pyrrolidine Step A.1-benzyl-2,5-bis(trifluoromethyl)-1H-pyrrole. To a solution of 1-benzyl-1H-pyrrole (2.0 g, 13 mmol) in MeCN (200 mL) was added sodium 2,2,2-trifluoroacetate (10 g, 76 mmol), Fe(OTf)2(0.45 g, 1.3 mmol,), 4,4'-dimethoxy-2,2'-bipyridine (0.28 g, 1.3 mmol) and K2S2O8(10 g, 38 mmol). The mixture was stirred at rt under an atmosphere of nitrogen for 16 h while irradiated with a 395 nm LED. The suspension was filtered and the filter cake was washed with MeCN (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% hexanes) to give 1-benzyl- 2,5-bis(trifluoromethyl)-1H-pyrrole (2.0 g, 54% yield) as colorless oil.1H NMR: (400 MHz, DMSO-d6) δ 7.36 - 7.30 (m, 2H), 7.27 (d, J = 7.2 Hz, 1H), 6.95 (s, 2H), 6.86 (d, J = 7.2 Hz, 2H), 5.43 (s, 2H). Step B.2,5-bis(trifluoromethyl)pyrrolidine. A solution of 1-benzyl-2,5-bis(trifluoromethyl)- 1H-pyrrole (0.40 g, 1.4 mmol) in THF (20 mL) was pumped at a rate of 0.3 mL / min through a fixed bed (FLR1, SS, Fixed bed, 6.350 (1 / 4’’) mm, 1 mL, 100 °C) of Pd(OH)2 / Al2O3(3.5 g). The H2back pressure regulator was adjusted to 3 MPa, and the flow rate was adjusted to 30 mL / min. The solution was collected and concentrated under reduced pressure to afford 2,5-bis(trifluoromethyl)pyrrolidine (0.28 g, 99% yield) as a colorless oil, which was taken onto the next step without further purification. Intermediate I59 (rel-2R,4S)-4-methoxy-2-(trifluoromethyl)piperidine Step A. (rel-2R,4S)-4-methoxy-2-(trifluoromethyl)piperidine. A solution of 4-methoxy-2- (trifluoromethyl)pyridine (0.10 g, 0.57 mmol) in MeOH (30 mL) was pumped at a rate of 0.4 mL / min through a fixed bed (FLR1, SS, Fixed bed, 6.350 (1 / 4") mm, 1 mL, 95 °C) of 10% Ru / SiO2(3.3 g). The H2back pressure regulator was adjusted to 2.5 MPa, and the flow rate of adjusted to 30 mL / min. The solution was collected and concentrated under reduced pressure to afford (rel-2R,4S)-4-methoxy-2-(trifluoromethyl)piperidine (0.030 g, 29% yield) as yellow oil.1H NMR: (400 MHz, DMSO-d6) δ 3.50 - 3.35 (m, 1H), 3.34 - 3.25 (m, 1H), 3.22 (s, 3H), 3.05 (br d, J = 12.0 Hz, 1H), 2.63 - 2.55 (m, 1H), 2.14 (br d, J = 11.6 Hz, 1H), 1.95 (br d, J = 11.2 Hz, 1H), 1.28 - 1.06 (m, 2H). Intermediate I60 3-methoxypiperidine-3-carbonitrile Step A. tert-butyl 3-cyano-3-methoxypiperidine-1-carboxylate. To a solution of tert-butyl 3- cyano-3-hydroxypiperidine-1-carboxylate (0.10 g, 0.44 mmol) in DCM (1 mL) at 0 °C was added trimethyloxonium tetrafluoroborate (0.098 g, 0.66 mmol). The mixture was allowed to warm to rt and was stirred for 10 min. The solution was cooled to 0 °C, then 1,8- bis(dimethylamino)naphthalene (0.14 g, 0.66 mmol, 1.5 eq) was added. The reaction was allowed to warm to rt and was stirred for 12 h. The mixture was diluted with H2O (5 mL) and sat. NH4Cl solution (2 mL) and then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% EtOAc in petroleum ether) to give tert-butyl 3-cyano-3-methoxypiperidine-1-carboxylate (0.070 g, 66% yield) as yellow oil. 1H NMR: (400 MHz,CDCl3) δ 3.92 (br d, J = 13.2 Hz, 1H), 3.70 - 3.16 (m, 6H), 2.27 - 2.10 (m, 1H), 1.94 - 1.75 (m, 2H), 1.68 (dt, J = 3.6, 8.4 Hz, 1H), 1.53 - 1.47 (m, 9H). Step B.3-methoxypiperidine-3-carbonitrile. To a solution of tert-butyl 3-cyano-3- methoxypiperidine-1-carboxylate (0.050 g, 0.21 mmol) in DCM (0.50 mL) was added 2 M HCl in dioxane (0.50 mL). The reaction was stirred for 1 h and then it was concentrated under reduced pressure to give 3-methoxypiperidine-3-carbonitrile (0.035 g, 95%), which was taken onto the next step without further purification. Intermediate I61 (rel-3S,4R)-3-fluoro-4-(trifluoromethyl)pyrrolidine Step A.1-benzyl-4-(trifluoromethyl)pyrrolidin-2-one. To a solution of 4- (trifluoromethyl)pyrrolidin-2-one (1.0 g, 6.5 mmol) in THF (10 mL) at 0 °C was added NaH (60% in mineral oil; 0.52 g, 13 mmol). The mixture was stirred for 1 h at this temperature and then benzyl bromide (2.2 g, 13 mmol) was added. The reaction was warmed to rt and was stirred for 1 h. The mixture was diluted with sat. aq. NH4Cl solution (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (17-25% EtOAc in petroleum ether) to give1-benzyl-4-(trifluoromethyl)pyrrolidin-2-one (1.5 g, 85% yield).1H NMR: (400MHz, CDCl3) δ 7.39 - 7.29 (m, 3H), 7.24 (d, J = 6.8 Hz, 2H), 4.23 - 4.07 (m, 2H), 3.50 - 3.33(m, 2H), 3.16 - 3.00 (m, 1H), 2.82 - 2.53 (m, 2H). Step B. (rel-3S,4R)-1-benzyl-3-fluoro-4-(trifluoromethyl)pyrrolidin-2-one. To a solution of 1-benzyl-4-(trifluoromethyl)pyrrolidin-2-one (0.6 g, 2.2 mmol) in THF (48 mL) at -78 °C was added LDA (2.5 M in THF; 1.3 mL). The mixture was stirred at -78 °C for 30 min, then N-(benzene sulfonyl)-N-fluoro-benzene sulfonamide (1.05 g, 3.33 mmol, 1.5 eq) was added N-fluorobenzenesulfonimide (1.1 g, 3.3 mmol). The reaction was stirred at -78 °C for 30 min and warmed to rt and stirred for 1 h. The solution was diluted with 1 M aq. NH4Cl solution and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (rel-3S,4R)-1-benzyl-3-fluoro-4-(trifluoromethyl)pyrrolidin-2-one (0.34 g, 50% yield). LCMS (MM-ES+APCI, Pos): 261.9 (M+H). Step C. (rel-3S,4R)-1-benzyl-3-fluoro-4-(trifluoromethyl)pyrrolidine. To a solution of (rel- 349 3S,4R)-1-benzyl-3-fluoro-4-(trifluoromethyl)pyrrolidin-2-one (0.34 g, 1.1 mmol) at 0 °C was added BH3∙THF (1.0 M; 5.9 mL). The reaction was stirred at rt for 1 h and then it was quenched with MeOH (10 mL). The mixture was warmed to 70 °C and was stirred for 1 h. The solution was concentrated under reduced pressure to give (rel-3S,4R)-1-benzyl-3-fluoro- 4-(trifluoromethyl)pyrrolidine (0.27 g, 98% yield). LCMS (MM-ES+APCI, Pos): 248.0 (M+H). Step D. (rel-3S,4R)-3-fluoro-4-(trifluoromethyl)pyrrolidine. To a solution of (rel-3S,4R)-1- benzyl-3-fluoro-4-(trifluoromethyl)pyrrolidine (0.27 g, 1.1 mmol) in THF (10 mL) was added 10% Pd / C (2.3 g). The flask was evacuated and backfilled with H2three times and then it was stirred at rt under an atmosphere of H2for 1 h. The suspension was filtered and the filter cake was washed with THF (10 mL). The mixture was concentrated under reduced pressure to give (rel-3S,4R)-3-fluoro-4-(trifluoromethyl)pyrrolidine (0.15 g, 87% yield), which was taken onto the next step without further purification. Intermediate I62 (rel-2R,3S)-3-methoxy-2-(trifluoromethyl)piperidine Step A.3-methoxy-2-(trifluoromethyl)pyridine. To a solution of 2-(trifluoromethyl)pyridin- 3-ol (0.30 g, 1.8 mmol) and K2CO3 (0.51 g, 3.7 mmol) in DMF (3 mL) was added MeI (0.23 mL, 3.7 mmol). The reaction ws stirred for 16 h and then it was diluted with H2O (2 mL) and extracted with EtOAc (2 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% EtOAc in petroleum ether) to give 3-methoxy- 2-(trifluoromethyl)pyridine (0.25 g, 76% yield) as a white solid. LCMS (MM-ES+APCI, Pos): 178.2 (M+H). Step B. (rel-2R,3S)-3-methoxy-2-(trifluoromethyl)piperidine. A solution of give 3-methoxy- 2-(trifluoromethyl)pyridine (0.25 g, 1.3 mmol) in THF (10 mL) and 2,2,2-trifluoroethanol (10 mL) was pumped at a rate of 0.3 mL / min through a fixed bed (FLR1, SS, Fixed bed, 6.350 (1 / 4") mm, 5 mL, 100 °C) of 10% Ru / SiO2(2.7 g). The H2back pressure regulator was adjusted to 2.5 MPa, and the flow rate of adjusted to 30 mL / min. The solution was collected and concentrated under reduced pressure to afford (rel-2R,3S)-3-methoxy-2- (trifluoromethyl)piperidine (0.080 g, 42% yield) as yellow oil.1H NMR: (400 MHz, DMSO- d6) δ 3.87 (dq, J = 6.8, 9.6 Hz, 1H), 3.50 - 3.46 (m, 1H), 3.34 (s, 1H), 3.26 (s, 3H), 2.90 (br d, J = 13.2 Hz, 1H), 2.54 (s, 1H), 2.10 - 1.93 (m, 2H), 1.60 - 1.50 (m, 1H), 1.49 (br s, 1H). Intermediate I63 (rel-2R,5R)-5-methoxy-2-(trifluoromethyl)piperidine Steps A-B were performed with 6-(trifluoromethyl)pyridin-3-ol following the procedures forIntermediate I62.1H NMR: (400 MHz, CDCl3) δ 3.35 (s, 3H), 3.29 - 3.21 (m, 2H), 3.12 (br s,1H), 2.73 (br d, J = 12.4 Hz, 1H), 2.13 (br d, J = 14.0 Hz, 1H), 1.74 - 1.68 (m, 2H), 1.68 - 1.52 (m, 2H). Intermediate I64 (3S,4S)-4-methoxypyrrolidine-3-carbonitrile Steps A-B were performed with tert-butyl (3S,4S)-3-cyano-4-hydroxypyrrolidine-1- carboxylate following the procedures for Intermediate I60. Intermediate I65 (S)-2-(piperidin-2-yl)acetonitrile Step A. tert-butyl (S)-2-formylpiperidine-1-carboxylate. To a solution of tert-butyl (S)-2- (hydroxymethyl)piperidine-1-carboxylate (0.50 g, 2.3 mmol) in DCM (5 mL) at 0 °C was added DMP (1.5 g, 3.5 mmol). The reaction was stirred at rt for 2 h and then it was diluted with H2O (10 mL). The pH of mixture was adjusted to 9 with 3 M NaOH and then it was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in petroleum ether) to give tert-butyl (S)-2-formylpiperidine-1-carboxylate (0.30 g, 61% yield) as colorless oil. Step B. tert-butyl (S)-2-(cyanomethyl)piperidine-1-carboxylate. To a solution of tert-butyl (S)-2-formylpiperidine-1-carboxylate (0.30 g, 1.4 mmol) and tosylmethyl isocyanide (0.44 g, 2.3 mmol) in DME (30 mL) and MeOH (0.5 mL) was added KOtBu (0.32 g, 2.8 mmol). The reaction was stirred for 12 h and then it was diluted with H2O (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in petroleum ether) to give tert-butyl (S)-2-(cyanomethyl)piperidine-1-carboxylate (0.060 g, 19% yield).1H NMR: (400 MHz, CDCl3) δ 4.63 (br d, J = 6.8 Hz, 1H), 4.17 - 3.98 (m, 1H), 2.82 - 2.69 (m, 1H), 2.62 (d, J = 7.6 Hz, 2H), 1.88 - 1.79 (m, 1H), 1.78 - 1.65 (m, 3H), 1.53 - 1.47 (m, 10H). Step C. (S)-2-(piperidin-2-yl)acetonitrile. To a solution of tert-butyl (S)-2- (cyanomethyl)piperidine-1-carboxylate (0.060 g, 0.27 mmol) in DCM (0.50 mL) was added 2 M HCl in dioxane (0.50 mL). The reaction was stirred for 1 h and then it was concentrated under reduced pressure to give (S)-2-(piperidin-2-yl)acetonitrile (0.040 g, 93%), which was taken onto the next step without further purification. Intermediate I66 (R)-2-(morpholin-2-yl)acetonitrile Step A. tert-butyl (R)-2-(cyanomethyl)morpholine-4-carboxylate. To a solution of tert-butyl (S)-2-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate (0.30 g, 1.0 mmol) in DMF (5 mL) was added NaCN (0.060 g, 1.2 mmol). The reaction was heated to 80 °C for 16 h and then it was diluted with H2O (10 mL). The pH of mixture was adjusted to 11 with sat. aq. NaOH solution and then it was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc in hexanes to give tert-butyl (R)-2- (cyanomethyl)morpholine-4-carboxylate (0.060 g, 26% yield).1H NMR: (400 MHz, CDCl3) δ 4.08 - 3.78 (m, 3H), 3.72 - 3.63 (m, 1H), 3.57 (dt, J = 2.8, 11.6 Hz, 1H), 2.97 (br t, J = 11.6 Hz, 1H), 2.85 - 2.66 (m, 1H), 2.64 - 2.48 (m, 2H), 1.48 (s, 9H). Step B. (R)-2-(morpholin-2-yl)acetonitrile. To a solution of tert-butyl (R)-2- (cyanomethyl)morpholine-4-carboxylate (0.060 g, 0.27 mmol) in DCM (2 mL) was added 2 M HCl in dioxane (2.7 mL). The reaction was heated to 40 °C for 1 h and then it was concentrated under reduced pressure to give (R)-2-(morpholin-2-yl)acetonitrile (0.040 g, 93% yield) as a white solid, which was taken onto the next step without further purification. Intermediate I67 (R)-2-(piperidin-3-yl)acetonitrile Step A. benzyl (S)-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate. To a solution of benzyl (S)-3-(hydroxymethyl)piperidine-1-carboxylate (0.30 g, 1.2 mmol) and NEt3 (0.33 mL, 2.4 mmol) in DCM (4 mL) at 0 °C was added methanesulfonic anhydride (0.36 g, 2.1 mmol). The reaction was stirred at rt for 30 min and then it was diluted with H2O (3 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in petroleum ether) to give benzyl (S)-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (0.36 g, 91% yield).1H NMR: (400 MHz, CDCl3) δ 7.44 - 7.29 (m, 5H), 5.14 (s, 2H), 4.19 - 3.99 (m, 3H), 3.92 (br d, J = 12.6 Hz, 1H), 3.11 - 2.80 (m, 5H), 2.05 - 1.92 (m, 1H), 1.90 - 1.79 (m, 1H), 1.77 - 1.65 (m, 1H), 1.56 - 1.45 (m, 1H), 1.41 - 1.30 (m, 1H). Step B. benzyl (R)-3-(cyanomethyl)piperidine-1-carboxylate. To a solution of benzyl (S)-3- (((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (0.36 g, 1.1 mmol) in DMF (5 mL) was added NaCN (0.064 g, 1.3 mmol) and KI (0.091g, 0.55 mmol). The reaction was heated to 45 °C for 2 h and then 70 °C for 12 h. The mixture was diluted with H2O (10 mL). The pH of mixture was adjusted to 11 with sat. aq. NaOH solution and then it was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc in hexanes) to give benzyl (R)-3-(cyanomethyl)piperidine-1-carboxylate (0.23 g, 81% yield).1H NMR: (400 MHz, CDCl3) δ 7.41 - 7.30 (m, 6H), 5.14 (br d, J = 2.4 Hz, 2H), 4.17 - 4.02 (m, 1H), 3.97 (td, J = 4.0, 13.2 Hz, 1H), 3.01 - 2.90 (m, 1H), 2.90 - 2.69 (m, 1H), 2.43 - 2.32 (m, 1H), 2.32 - 2.24 (m, 1H), 2.03 - 1.87 (m, 2H), 1.73 (td, J = 34.0, 13.2 Hz, 1H), 1.53 (br d, J = 11.6 Hz, 1H), 1.40 (ddd, J = 3.2, 10.8, 13.2 Hz, 1H). Step C. (R)-2-(piperidin-3-yl)acetonitrile. To a solution of benzyl (R)-3- (cyanomethyl)piperidine-1-carboxylate (0.080 g, 0.31 mmol) in THF (3 mL) was added 10% Pd / C (0.030 g, 0.028 mmol). The flask was then evacuated and backfilled with H2three times and then it was stirred under an atmosphere of H2for 2 h. The suspension was filtered through Celite, and the filter cake was washed with THF (200 mL x 3). The filtrate was concentrated under reduced pressure to give (R)-2-(piperidin-3-yl)acetonitrile (0.038 g, 99% yield) as colorless oil.1H NMR: (400 MHz, CDCl3) δ 3.12 (br d, J = 12.0 Hz, 1H), 2.99 (td, J = 3.6, 12.0 Hz, 1H), 2.58 (dt, J = 2.8, 11.6 Hz, 1H), 2.49 - 2.40 (m, 1H), 2.39 - 2.31 (m, 1H), 2.29 (dd, J = 2.8, 6.8 Hz, 2H), 1.97 - 1.90 (m, 1H), 1.88 - 1.82 (m, 1H), 1.74 - 1.68 (m, 1H), 1.55 - 1.46 (m, 1H), 1.32 - 1.24 (m, 1H). Intermediate I68 Step A. tert-butyl (E)-5-((benzylideneamino)oxy)-3-oxoazepane-1-carboxylate. To a solution of tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (0.50 g, 2.4 mmol), (E)- benzaldehyde oxime (0.43 g, 3.6 mmol) in MeCN (10 mL) was added DBU (0.014 mL, 0.095 mmol). The reaction was stirred for 16 h and then it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-20% EtOAc in petroleum ether) to give tert-butyl (E)-5-((benzylideneamino)oxy)-3-oxoazepane-1-carboxylate (0.40 g, 48% yield). 1H NMR: (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.57 (dd, J =2.8, 6.8 Hz, 2H), 7.41 - 7.35 (m, 3H), 4.72 - 4.53 (m, 1H), 4.42 - 4.22 (m, 1H), 3.97 - 3.61 (m, 2H), 3.42 - 3.19 (m, 1H), 3.11 - 2.97 (m, 1H), 2.96 - 2.82 (m, 1H), 2.38 - 2.07 (m, 2H), 1.54 - 1.45 (m, 9H). Step B. tert-butyl (E)-5-((benzylideneamino)oxy)-3,3-difluoroazepane-1-carboxylate. To a solution of give tert-butyl (E)-5-((benzylideneamino)oxy)-3-oxoazepane-1-carboxylate (0.400 g, 1.1 mmol) in DCM (10 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (1.3 mL, 5.7 mmol). The reaction was heated to 50 °C for 12 h and then it was quenched with aq. NaHCO3(10 mL). The resulting mixture was extracted with DCM (8 mL x 3). The combined organic layers were washed with brine (6 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-9% EtOAc in petroleum ether) to give tert-butyl (E)-5- ((benzylideneamino)oxy)-3,3-difluoroazepane-1-carboxylate (0.250 g, 62% yield) as colorless oil. LCMS (MM-ES+APCI, Pos): 299.2 (M+H-tBu). Step C. tert-butyl 3,3-difluoro-5-hydroxyazepane-1-carboxylate. To a solution tert-butyl (E)- 5-((benzylideneamino)oxy)-3,3-difluoroazepane-1-carboxylate (0.25 g, 0.71 mmol) in MeOH (10 mL) was added 10% Pd / C (0.25 g,). The flask was then evacuated and backfilled with H2three times and then it was stirred under an atmosphere of H2for 1 h. The suspension was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl 3,3-difluoro-5-hydroxyazepane-1-carboxylate (0.15 g) as colorless oil. 1H NMR: (400 MHz,CDCl3) δ 4.09 (br t, J = 8.4 Hz, 1H), 3.91 - 3.60 (m, 3H), 3.45 - 3.22 (m, 1H), 2.48 - 2.16 (m, 2H), 2.11 - 1.97 (m, 1H), 1.96 - 1.77 (m, 1H), 1.47 (br s, 9H). Step D. tert-butyl 3,3-difluoro-5-methoxyazepane-1-carboxylate. To a solution of tert-butyl 3,3-difluoro-5-hydroxyazepane-1-carboxylate (0.15 g, 0.60 mmol) in THF (3 mL) at 0 °C was added NaH (60% in mineral oil; 0.036 g, 0.90 mmol). The mixture was stirred at rt for 1 h and then CH3I (0.074 mL, 1.2 mmol) was added. The reaction was stirred at rt for 2 h and then it was diluted with H2O (5 mL) and then extracted with ethyl acetate (4 mL x 3). The combined organic layers were washed with brine (4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (9-25% EtOAc in petroleum ether) to tert-butyl 3,3-difluoro-5-methoxyazepane-1-carboxylate (0.10 g, 60% yield) as colorless oil. 1H NMR: (400 MHz,CDCl3) δ 3.95 - 3.61 (m, 2H), 3.60 - 3.23 (m, 6H), 2.47 - 2.14 (m, 2H), 2.12 - 1.98 (m, 1H), 1.94 - 1.67 (m, 1H), 1.47 (s, 9H). Step E.3,3-difluoro-5-methoxyazepane. To a solution of tert-butyl 3,3-difluoro-5- methoxyazepane-1-carboxylate (0.045 g, 0.16 mmol) in MeOH (0.5 mL) was added 2 M HCl in dioxane (1.0 mL). The mixture was stirred at 40 °C for 1 h and then it was concentratedunder reduced pressure to give 3,3-difluoro-5-methoxyazepane (0.030 g). LCMS (MM-ES+APCI, Pos): 166.2 (M+H). Intermediate I69 (R)-3,3-difluoro-6-methoxyazepane Steps A-B were performed with tert-butyl (R)-3,3-difluoro-6-hydroxyazepane-1-carboxylatefollowing the procedures for Intermediate I60.1H NMR: (400 MHz, MeOH-d4) δ 3.84 - 3.66(m, 3H), 3.66 - 3.52 (m, 2H), 3.43 - 3.36 (m, 3H), 2.55 - 2.32 (m, 1H), 2.28 - 2.09 (m, 2H), 1.95 (br s, 1H). Intermediate I70 7-methoxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine Steps A-B were performed with tert-butyl 7-hydroxy-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate following the procedures for Intermediate I60.1H NMR:(400 MHz, D2O) δ 7.44 (d, J = 1.6 Hz, 1H), 6.43 (s, 1H), 4.81 (dd, J = 5.6, 15.6 Hz, 1H), 4.60 (d, J = 15.6 Hz, 1H), 4.50 (d, J = 15.6 Hz, 1H), 4.29 (d, J = 15.6 Hz, 1H), 3.97 (t, J = 4.4Hz, 1H), 3.83 (dd, J = 4.4, 14.0 Hz, 1H), 3.46 (d, J = 14.0 Hz, 1H), 3.30 (s, 3H). Intermediate I71 3-methoxy-3-phenylpyrrolidine Steps A-B were performed with tert-butyl 3-hydroxy-3-phenylpyrrolidine-1- carboxylatefollowing the procedures for Intermediate I60. Intermediate I72 Steps A-B were performed with tert-butyl 3-hydroxy-3-phenylpiperidine-1-carboxylate following the procedures for Intermediate I62. Intermediate I73 (S)-3-fluoro-3-(methoxymethyl)piperidine Steps A-B were performed with tert-butyl (S)-3-fluoro-3-(hydroxymethyl)piperidine-1- carboxylate following the procedures for Intermediate I60. Intermediate I74 3-fluoro-3-(trifluoromethyl)piperidine Step A. tert-butyl 3-fluoro-3-(trifluoromethyl)piperidine-1-carboxylate. To a solution of tert- butyl 3-hydroxy-3-(trifluoromethyl)piperidine-1-carboxylate (0.10 g, 0.37 mmol) in DCM (1 mL) at -78 °C was added DAST (0.20 mL, 1.5 mmol). The reaction was stirred at -78 °C for 2 h and then it was warmed to 0 °C and stirred for 2 h. The mixture was quenched with ice water (5 mL) and then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (17% EtOAc in petroleum ether) to tert-butyl 3-fluoro-3-(trifluoromethyl)piperidine-1-carboxylate (0.050 g, 50% yield) as colorless oil.1H NMR: (400 MHz, MeOH-d4) δ 4.29 - 4.07 (m, 1H), 3.96 - 3.90 (m, 1H), 3.19 - 2.91 (m, 1H), 2.89 - 2.70 (m, 1H), 2.08 - 1.96 (m, 1H), 1.89 - 1.74(m, 1H), 1.72 - 1.55 (m, 2H), 1.36 (s, 9H). 19F NMR: (376 MHz, MeOH-d4) δ -83.92 (br d, J= 31.5 Hz, 3F), -178.92 - -179.75 (m, 1F). Step B.3-fluoro-3-(trifluoromethyl)piperidine. To a solution of tert-butyl 3-fluoro-3- (trifluoromethyl)piperidine-1-carboxylate (0.050 g, 0.18 mmol) in DCM (0.5 mL) was added 2 M HCl in dioxane (0.092 mL). The mixture was stirred for 2 h and then it was concentrated under reduced pressure to give 3-fluoro-3-(trifluoromethyl)piperidine (0.035 g, 89% yield). Intermediate I75 3,3-difluoro-5-methoxypiperidine Step A.5-methoxypiperidin-3-ol. A solution of 5-methoxypyridin-3-ol (3.0 g, 24 mmol) in HFIP (90 mL) was pumped at a rate of 0.3 mL / min through a fixed bed (FLR1, SS, Fixed bed, 6.350(1 / 4") mm, 1 mL, 85 °C) of 5% Pd(OH)2 / Al2O3 (4.7 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of adjusted to 30 mL / min. The solution was collected and concentrated under reduced pressure to afford 5-methoxypiperidin-3-ol (3.0 g, 95% yield). LCMS (MM-ES+APCI, Pos): 132.0 (M+H). Step B. benzyl 3-hydroxy-5-methoxypiperidine-1-carboxylate. To a solution of 5- methoxypiperidin-3-ol (3.0 g, 23 mmol) in THF (30 mL) at 0 °C was added Na2CO3(7.3 g, 69 mmol) and CbzCl (3.9 mL, 27 mmol). The reaction was stirred at rt for 2 h and then it was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (13 – 43% MeCN in 0.1% aqueous NH4HCO3) to give benzyl 3-hydroxy-5- methoxypiperidine-1-carboxylate (2.3 g, 37% yield) as yellow oil. LCMS (MM-ES+APCI, Pos): 266.0 (M+H). Step C. benzyl 3-methoxy-5-oxopiperidine-1-carboxylate. To a solution of benzyl 3-hydroxy- 5-methoxypiperidine-1-carboxylate (2.0 g, 7.3 mmol) in DCM (20 mL) at 0 °C. was added DMP (3.7 g, 8.7 mmol). The reaction was stirred at rt for 16 h. The mixture was filtered and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-33% EtOAc in hexanes) to give benzyl 3-methoxy-5-oxopiperidine-1-carboxylate (1.8 g, 94% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.42 - 7.31 (m, 5H), 5.17 (br s, 2H), 4.27 - 4.09 (m, 1H), 4.06 - 3.96 (m, 1H), 3.85 (br d, J = 9.6 Hz, 2H), 3.77 - 3.64 (m, 1H), 3.51 - 3.17 (m, 3H), 2.82 - 2.50 (m, 2H). Step D. benzyl 3,3-difluoro-5-methoxypiperidine-1-carboxylate. To a solution of benzyl 3- methoxy-5-oxopiperidine-1-carboxylate (0.50 g, 1.9 mmol) in DCM (5 mL) at 0 °C was added DAST 0.75 mL, 5.7 mmol). The reaction was heated to 40 °C for 16 h and then it was quenched with water (10 mL). The pH of mixture was adjusted to 9 with sat. aq. NaHCO3solution and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0- 14% EtOAc in hexanes). The residue was purified by preparative HPLC (18 – 48% MeCN in 0.1% aqueous TFA) to give benzyl 3,3-difluoro-5-methoxypiperidine-1-carboxylate (0.160 g, 28% yield) as yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.43 - 7.30 (m, 5H), 5.17 (s, 2H), 4.30 - 3.99 (m, 2H), 3.58 - 3.20 (m, 5H), 3.09 - 2.83 (m, 1H), 2.49 (br d, J = 10.4 Hz, 1H), 2.00 - 1.76 (m, 1H).19F NMR: (376 MHz, CDCl3) δ -98.50 - -102.13 (m, 2F). Step E.3,3-difluoro-5-methoxypiperidine. A solution of benzyl 3,3-difluoro-5- methoxypiperidine-1-carboxylate (0.20 g, 0.70 mmol) in THF (5 mL) and MeOH (5 mL) was pumped at a rate of 0.4 mL / min through a fixed bed (FLR1, SS, Fixed bed, 6.35(1 / 4’’) mm, 5mL, 45 °C) of 5% Pd / Al2O3(4.7 g). The H2back pressure regulator was adjusted to 1.5 MPa, and the flow rate of adjusted to 30 mL / min. The solution was collected and concentrated under reduced pressure to afford 3,3-difluoro-5-methoxypiperidine (0.10 g, 94% yield), which was taken onto the next step without further purification. Intermediate I76 2-(3-methoxypyrrolidin-3-yl)acetonitrile Steps A-B were performed with tert-butyl 3-(cyanomethyl)-3-hydroxypyrrolidine-1- carboxylate following the procedures for Intermediate I60. Intermediate I77 2-(3-methoxypiperidin-3-yl)acetonitrile Steps A-B were performed with tert-butyl 3-(cyanomethyl)-3-hydroxypiperidine-1- carboxylate following the procedures for Intermediate I60. Intermediate I78 (R)-2-(morpholin-3-yl)acetonitrile Step A. tert-butyl (R)-3-(2-amino-2-oxoethyl)morpholine-4-carboxylate. To a solution of (R)- 2-(4-(tert-butoxycarbonyl)morpholin-3-yl)acetic acid (0.20 g, 0.82 mmol) in THF (5 mL) was added EDCI (0.31 g, 1.6 mmol), NEt3(1.1 mL, 8.2 mmol), and 1-hydroxy-1H-benzotriazole, ammonium salt (0.50 g, 3.3 mmol). The reaction was stirred for 1 h and then it was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAC in petroleum ether) to give tert-butyl (R)-3-(2-amino-2- oxoethyl)morpholine-4-carboxylate (0.15 g, 75% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ = 7.35 (br s, 1H), 6.83 (br s, 1H), 4.22 - 4.12 (m, 1H), 3.77 (br dd, J = 2.8, 11.6 Hz, 1H), 3.65 - 3.60 (m, 2H), 3.42 (dd, J = 3.2, 11.2 Hz, 1H), 3.21 - 3.07 (m, 2H), 3.04 - 2.95 (m, 1H), 2.27 - 2.12 (m, 1H), 1.39 (s, 9H). Step B. tert-butyl (R)-3-(cyanomethyl)morpholine-4-carboxylate. To a solution of tert-butyl (R)-3-(2-amino-2-oxoethyl)morpholine-4-carboxylate (0.15 g, 0.61 mmol) in DCM (2 mL) was added 1-methoxy-N-triethylammoniosulfonyl-methanimidate azanide (0.29 g, 1.2 mmol). The reaction was stirred for 1 h and then it was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% EtOAC in petroleum ether) to give tert-butyl (R)-3-(cyanomethyl)morpholine-4-carboxylate (0.11 g, 79% yield) as a yellow solid.1H NMR: (400 MHz, DMSO-d6) δ = 4.23 (br s, 1H), 3.78 (br dd, J = 2.8, 11.2 Hz, 1H), 3.69 - 3.58 (m, 2H), 3.47 (dd, J = 3.2, 12.0 Hz, 1H), 3.32 - 3.27 (m, 1H), 3.15 - 2.92 (m, 2H), 2.87 - 2.75 (m, 1H), 1.42 (s, 9H). Step C. (R)-2-(morpholin-3-yl)acetonitrile. To a solution of tert-butyl (R)-3- (cyanomethyl)morpholine-4-carboxylate (0.11 g, 0.49 mmol) in DCM (1.0 mL) was added 2 M HCl in dioxane (1.0 mL). The mixture was stirred for 1 h and then it was concentrated under reduced pressure to give (R)-2-(morpholin-3-yl)acetonitrile (0.060 g, 76% yield). Intermediate I79 3-methoxy-3-(methoxymethyl)pyrrolidine Step A. benzyl 3-methoxy-3-(methoxymethyl)pyrrolidine-1-carboxylate. To a solution of benzyl 3-hydroxy-3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.080 g, 0.32 mmol) in THF (2 mL) at 0 °C was added NaH (60% in mineral oil; 0.032 g, 0.80 mmol). The mixture was stirred for 30 min, then MeI (0.050 mL, 0.80 mmol) was added. The reaction was stirred at rt for 1 h and then it was diluted with H2O (6 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAC in petroleum ether) to give benzyl 3-methoxy-3- (methoxymethyl)pyrrolidine-1-carboxylate (0.080 g, 90% yield) as a colorless oil.1H NMR: (400 MHz, CDCl3) δ 7.41 - 7.28 (m, 5H), 5.19 - 5.08 (m, 2H), 3.65 - 3.35 (m, 9H), 3.30 (d, J = 3.2 Hz, 3H), 2.13 - 2.01 (m, 1H), 1.99 - 1.82 (m, 1H). Step B.3-methoxy-3-(methoxymethyl)pyrrolidine. To a solution of benzyl 3-methoxy-3- (methoxymethyl)pyrrolidine-1-carboxylate (0.080 g, 0.29 mmol) in MeOH (3 mL) was added 10% Pd / C (0.15 g, 0.14 mmol). The flask was evacuated and backfilled with H2three times. The mixture was stirred under an atmosphere of H2for 1 h. The suspension was filtered and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to give 3-methoxy-3-(methoxymethyl)pyrrolidine (0.040 g, 96% yield) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 8.93 - 8.13 (m, 1H), 3.67 - 3.40 (m, 8H), 3.39 - 3.28 (m, 4H), 2.31 - 2.22 (m, 1H), 2.15 - 2.02 (m, 1H). Intermediate I80 3-(2-fluorophenyl)-3-(trifluoromethyl)pyrrolidine Step A.1-fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene. To a solution of (2- fluorophenyl)boronic acid (0.50 g, 3.6 mmol) in THF (10 mL) was added 2-bromo-3,3,3- trifluoroprop-1-ene (1.3 g, 7.2 mmol), Pd(PPh3)2Cl2(0.13 g, 0.18 mmol) and 2 M aq. K2CO3(7.2 mL). The reaction was heated to 60oC for 12 h and then it was diluted with H2O (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-1% EtOAc in hexanes) to give 1-fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.29 g, 43% yield) as a colorless liquid.1H NMR: (400 MHz, CDCl3) δ = 7.41 - 7.33 (m, 2H), 7.19 - 7.11 (m, 2H),6.19 (d, J = 1.2 Hz, 1H), 5.79 (d, J = 0.8 Hz, 1H). 19FNMR: (377 MHz CDCl3) δ = -65.85 - -66.00 (m, 3F), -114.37 (q, J = 4.5 Hz, 1F). Step B.1-benzyl-3-(2-fluorophenyl)-3-(trifluoromethyl)pyrrolidine. To a solution of 1- fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.40 g, 2.1 mmol) in DCM (4 mL) at 0oC was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (2.0 g, 8.4 mmol) and TFA (0.016 mL, 0.21 mmol). The mixture was stirred for 12 h and then it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-2% EtOAc in hexanes) to give 1-benzyl-3-(2-fluorophenyl)-3- (trifluoromethyl)pyrrolidine (0.55 g, 68% yield) as a colorless liquid. LCMS (MM-ES+APCI, Pos): 324.1 (M+H). Step C.3-(2-fluorophenyl)-3-(trifluoromethyl)pyrrolidine. To a solution of 1-benzyl-3-(2- fluorophenyl)-3-(trifluoromethyl)pyrrolidine (0.50 g, 1.3 mmol) in THF (5 mL) was added 10% Pd / C (0.14 g, 0.13 mmol). The mixture was stirred at rt under an atmosphere of H2(30 Psi) for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 3-(2-fluorophenyl)-3-(trifluoromethyl)pyrrolidine (0.35 g, 99 % yield). LCMS (MM-ES+APCI, Pos): 234.0 (M+H). Intermediate I81 4-fluoro-N,N-dimethylpiperidine-4-carboxamide Step A. tert-butyl 4-(dimethylcarbamoyl)-4-fluoropiperidine-1-carboxylate. To a solution of 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid (0.20 g, 0.81 mmol) dimethylamine HCl (0.079 g, 0.97 mmol) in DCM (2 mL) was added EDCI (0.23 g, 1.2 mmol) and DMAP (0.20 g, 1.6 mmol). The reaction was stirred for 1 h and then it was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% EtOAc in petroleum ether) to give tert-butyl 4-(dimethylcarbamoyl)-4- fluoropiperidine-1-carboxylate (0.12 g, 54% yield) as a yellow oil. LCMS (MM-ES+APCI, Pos): 219.2 (M+H-tBu). Step B.4-fluoro-N,N-dimethylpiperidine-4-carboxamide. To a solution of tert-butyl 4- (dimethylcarbamoyl)-4-fluoropiperidine-1-carboxylate (0.12 g, 0.44 mmol) in DCM (1.0 mL) was added 2 M HCl in dioxane (1.0 mL). The mixture was stirred for 1 h and then it was concentrated under reduced pressure to give 4-fluoro-N,N-dimethylpiperidine-4-carboxamide (0.090 g, 98% yield), which was taken onto the next step without further purification. Intermediate I82 2-(4-fluoropiperidin-4-yl)acetonitrile Steps A-B were performed with tert-butyl 4-(cyanomethyl)-4-hydroxypiperidine-1- carboxylate following the procedures for Intermediate I74. Intermediate I83 3,3,3-trifluoro-N-methyl-2-phenylpropan-1-amine Step A. tert-butyl (3,3,3-trifluoro-2-phenylpropyl)carbamate. To a solution of 3-((tert- butoxycarbonyl)amino)-2-phenylpropanoic acid (0.90 g, 3.4 mmol) and 1-trifluoromethyl- 1,2-benziodoxol-3(1H)-one (1.4 g, 4.2 mmol) in EtOAc (10 mL) was (4,4'-di-tert-butyl-2,2'- bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-κN)phenyl-κC]iridium(III) hexafluorophosphate (0.038 g, 0.034 mmol), CuCl2(0.091 g, 0.68 mmol), bis(2- pyridyl)methanone (0.16 g, 0.85 mmol) and 1,1,3,3-tetramethylguanidine (0.21 mL, 1.7 mmol). The vial was sparged with nitrogen for one minute and the reaction was stirred for 16 h. The mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% EtOAc in petroleum ether). The residue was purified by preparative TLC (9% EtOAc in petroleum ether) to give tert-butyl (3,3,3-trifluoro-2- phenylpropyl)carbamate (0.060 g, 6% yield) as yellow oil. LCMS (MM-ES+APCI, Pos): 234.2 (M+H-tBu). Step B. tert-butyl methyl(3,3,3-trifluoro-2-phenylpropyl)carbamate. To a solution of tert- butyl (3,3,3-trifluoro-2-phenylpropyl)carbamate (0.023 g, 0.080 mmol) in THF (1 mL) at 0 °C was added NaH (60% in mineral oil; 0.0070 g, 0.18 mmol). The mixture was stirred at rt for 30 min and then MeI (0.015 mL, 0.24 mmol). The reaction was stirred for 1 h and then it was diluted with H2O (5 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (9% EtOAc in pe...

Claims

Listing of Claims:

1. A compound having the following structure of Formula (I):or a stereoisomer of the compound, salt of the compound or tautomer of the compound thereof; wherein: A is 4-11 membered heterocyclylene, wherein the 4-11 membered heterocyclylene is optionally substituted; B is an arylene or 5-14 membered heteroarylene, wherein the arylene or 5-14 membered heteroarylene is optionally substituted, wherein the 5-14 membered heteroarylene is not indazolylene; R1is a hydrogen or C1-C3alkyl; R2is a hydrogen, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, -(C1-C3alkylene)-heteroaryl, aryl fused to 4-8 membered heterocyclyl, or amine, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, 4-8 membered heterocyclyl, or amine is optionally substituted; L is C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1-C8heteroalkylene. wherein the C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1-C8heteroalkylene is optionally substituted; X is -O-, -NR3-, or a direct bond, wherein R3is a hydrogen or C1-C3alkyl; and Y is C1-C5alkylene, C1-C5deuteroalkylene, or a direct bond, wherein the C1-C5alkylene or C1-C5deuteroalkylene is optionally substituted, wherein: when B is , L is not C2 alkylene, wherein * indicates the locationof a bond to L and indicates the location of a bond to the pyridine group.

2. The compound of claim 1, wherein the 4-11 membered heterocyclylene of A is pyrrolidinylene, piperidinylene, morpholinylene, azepanylene, oxazepanylene, or diazepanylene.

3. The compound of claim 1, wherein the 4-11 membered heterocycloalkylene of A is azepanylene, piperidinylene, or oxazepanylene.

4. The compound of claim 1, wherein the 4-11 membered heterocycloalkylene of A has one of the following structures:wherein * indicates the location of a bond to the carbamate group and indicates the location of a bond to the pyrimidine group.

5. The compound of claim 1, wherein the 4-11 membered heterocycloalkylene of A has one of the following structures:, wherein * indicates the location of a bond to the carbamate group and indicates the location of a bond to the pyrimidine group, wherein the 4-11 membered heterocycloalkylene is optionally substituted.

6. The compound of claim 1, wherein the 4-11 membered heterocyclylene of A is a fused bicyclic heterocyclylene or a bridged bicyclic heterocyclylene.

7. The compound of claim 6, wherein the fused bicyclic heterocyclylene has one of the following structures:* indicates the location of a bond to the carbamate group, and indicates the location of a bond to the pyrimidine group.

8. The compound of claim 6, wherein the bridged bicyclic heterocyclylene has one of the following structures:, wherein m is 1 or 2 and * indicates the location of a bond to a carbamate group, and indicates the location of a bond to the pyrimidine group.

9. The compound of any one of claims 1-8, wherein the 4-11 membered heterocyclylene of A is substituted with one or more substituents each independently selected from C1-C4alkyl, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, C1-C4alkylene-CN, halo, amine, hydroxyl, - and C(=O)CH3.

10. The compound of any one of claims 1-8, wherein the 4-11 membered heterocyclylene of A is substituted with one or more substituents each independently selected from -CH3, - CD3, -D, -F, -CN, -CH3CN, -NH2, -CH2OCH3, -OCH3, -CF2H, -CF3, -OH, -C1-C3alkylalcohol, and C1-C3alkoxyl.

11. The compound of any one of claims 1-8, wherein the 4-11 membered heterocyclylene of A is substituted with one or more substituents each independently selected from -CH3, -F, - OH, -CH2CN, and -CH2OH.

12. The compound of any one of claims 1-8, wherein the 4-11 membered heterocyclylene of A is substituted with one or more substituents each independently selected from -C1-C4alkyl, -OH, -halo and -CN.

13. The compound of claim 1, wherein A is selected from the group consisting of:

14. The compound of any one of claims 1-13, whereincarbamate group and indicates the location of a bond to the pyrimidine group.

15. The compound of claim 1, wherein A is selected from the group consisting of:, wherein * indicates the location of a bond to the carbamate group and indicates the location of a bond to the pyrimidine group.

16. The compound of any one of claims 1-14, wherein B is an arylene or 5-10 membered heteroarylene, wherein the arylene or 5-10 membered heteroarylene is optionally substituted, wherein the 5-10 membered heteroarylene is not indazolylene.

17. The compound of claim 1, wherein the compound has the following structure of Formula (IA):wherein: R4is a hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, halo, amine, hydroxyl, or - C(=O)CH3; and wherein the remaining variables are as defined in claim 1.

18. The compound of claim 14, wherein R4is -H, -CH3, -F, -Cl, -CN, -NH2, -CH2OCH3, - OCH3, -CF2H, -CF3, -OH, -C1-C3alkylalcohol, C1-C3alkoxyl, or -C(=O)CH3.

19. The compound of claim 17 or 18, wherein R4is -CH3.

20. The compound of claim 16, wherein the compound has the following structure of Formula (IA-2):. (IA-2) wherein the variables are as defined in claim 1.

21. A compound having the following structure of Formula (IA-3): ,or a stereoisomer of the compound, tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein: R4is -H; B is an arylene or heteroarylene, wherein the arylene or heteroarylene is optionally substituted; R1is a hydrogen or C1-C3alkyl; R2is a hydrogen, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, -(C1-C3alkylene)-heteroaryl, aryl fused to 4-8 membered heterocyclyl, or amine, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, 4-8 membered heterocyclyl, or amine is optionally substituted; L is C1-C8alkylene, C1-C8alkenylene, C1-C8alkynylene, or C1-C8heteroalkylene. wherein the C1-C8 alkylene, C1-C8 alkenylene, C1-C8 alkynylene, or C1-C8 heteroalkylene is optionally substituted; X is -O-, -NR3-, or a direct bond, wherein R3is a hydrogen or C1-C3alkyl; and Y is C1-C5alkylene, C1-C5deuteroalkylene, or a direct bond, wherein the C1-C5alkylene or C1-C5deuteroalkylene is optionally substituted,or a stereoisomer of the compound, salt of the compound or tautomer of the compound thereof.

22. The compound of claim 21, wherein B is arylene or 5-18 membered heteroarylene.

23. The compound of claim 21, wherein B is arylene or 5-14 membered heteroarylene.

24. The compound of claim 21, whereinwherein * indicates the location of a bond to L and indicates the location of a bond to the pyridine group, wherein RBis selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O- C1-C4alkylene, halo, hydroxyl, -C(=O)CH3, NH2, -NH(CH3), N(CH3)2; R6is selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene- CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2wherein RX1, RX2: are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy can be substituted with: C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, - C(O)NRX3RX4wherein RX3and RX4are each independently H, C1-4 alkyl, C1-4 haloalkyl, C1-4alkylene-C1-4alkoxy, or prodrug moiety R5.

25. The compound of claim 21, whereinwherein * indicates the location of a bond to L and indicates the location of a bond to the pyridine group.

26. The compound of any one of claims 1-25, wherein the arylene of B is a phenylene or naphthylene.

27. The compound of any one of claims 1-25, wherein the heteroarylene of B is a pyridinylene.

28. The compound of any one of claims 1-25, wherein the heteroarylene of B is, wherein * indicates the location of a bond to the carbamate group and indicates the location of a bond to the pyrimidine group.

29. The compound of any one of claims 1-28, wherein the arylene or heteroarylene of B is optionally substituted with one or more substituents each independently selected from H, C1- C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2, alkylene-cyclyl, heterocyclyl, aryl, heteroaryl, and a prodrug functional moiety R5, wherein the alkylene-cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy, wherein the C1-4alkyl, C1-4haloalkyl, or C1-4alkylene- C1-4alkoxy is optionally substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, or -C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4 alkyl, C1-4 haloalkyl, C1-4alkylene-C1-4alkoxy.

30. The compound of any one of claims 1-29, wherein the arylene or heteroarylene of B is optionally substituted with one or more substituents each independently selected from H, C1- C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2, C1-C4alkylene-C6-C10aryl, C1-C4alkylene-(5-10 membered heteroaryl), C1-C4alkylene-C3-C10cycloalkyl, C1-C4alkylene-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, and a prodrug functional moiety R5, wherein the C1-C4alkylene-C6-C10aryl, C1-C4alkylene-(5-10 membered heteroaryl), C1-C4alkylene-C3-C10cycloalkyl, C1-C4alkylene-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, C6-C10 aryl, or 5-10 membered heteroaryl is optionally substituted, wherein RX1, RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy and wherein the C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy is optionally substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl , heterocyclyl, or -C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy.

31. The compound of any one of claims 1-30, wherein the arylene or heteroarylene of B is optionally substituted with one or more substituents each independently selected from C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, CN and a prodrug functional moiety R5.

32. The compound of any one of claims 1-31, wherein the arylene or heteroarylene of B is substituted with one or more substituents each independently selected from C1-C4alkyl, C1- C4heteroalkyl, halo, amine, hydroxyl, and a prodrug functional moiety R5.

33. The compound of any one of claims 1-30, wherein the arylene or heteroarylene of B is substituted with one or more substituents each independently selected from -CH3, -F, -Cl, - CN, -NH2, -CH2OCH3, -OCH3, -CF2H, -CF3, -OH, -C1-C3alkylalcohol, C1-C3alkoxyl, and a prodrug functional moiety R5.

34. The compound of any one of claims 1-33, wherein the prodrug functional moiety R5is selected from the group consisting of, and, wherein: Z1 and Z4 are each independently(i) -NRX1RX2, wherein RX1and RX2are each independently H, C1-4 alkyl, C1-4 haloalkyl, C1-4alkylene-C1-4alkoxy, C1-4heteroalkyl, or aryl wherein the alkyl, haloalkyl, alkoxy, heteroalkyl, aryl is optionally substituted with C1-4alkyl, C1-4haloalkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, or -C(O)NRX3RX4, wherein the heteroaryl is optionally substituted with C1-4alkyl, RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy; (ii) optionally substituted monocyclic, fused or bridged bicyclic 4-11 membered N- containing heterocyclyl or 4-11 membered N-containing heteroaryl, wherein the point ofattachment is on N; (iii) optionally substituted C1-8alkylene, C2-6alkenylene, C2-6alkynylene, or C1-6heteroalkylene; (iv) optionally substituted 4-8 membered cycloalkyl, 4-10 membered aryl; or (v) -OM, wherein M is a metal; Z2is (i) R′′, (R)—O—(R), (R)—S—(R), (R)—O—(R)-X, (R)—S—(R)-X, wherein the X is optionally substituted cycloalkyl, heterocyclyl, aryl, heteroaryl, (R)—O—C(O)—R′, or (R)— O—C(O)—O—R′, wherein R′′is optionally substituted C1-8alkyl, C2-6alkenyl, C2-6alkynyl, or C1-6heteroalkyl, wherein R is optionally substituted C1-8alkylene, C2-6alkenylene, C2-6alkynylene, or C1-6heteroalkylene; wherein R′is optionally substituted -NRX1RX2, C1-8alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-8 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein RX1and RX2are each independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, or C1-4alkylene-C1-4alkoxy;(iv) optionally substituted 4-10 membered aryl, 4-11 membered heteroaryl, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl; Z3is (i) R′′, which is optionally substituted C1-8alkyl, C2-6alkenyl, C2-6alkynyl, or C1-6heteroalkyl; or (ii) amino acid residue; or (iii) optionally substituted 4-10 membered aryl, 4-11 membered heteroaryl, 4-8 membered cycloalkyl or 4-10 membered heterocyclyl; Z5 and Z6 are each independently(i) hydrogen; or (ii) R′′, (R)—O—(R), (R)—S—(R), (R)—O—(R)-X, (R)—S—(R)-X, wherein the X is optionally substituted cycloalkyl, heterocyclyl, aryl, heteroaryl, (R)—O—C(O)—R′, or (R)—O—C(O)—O—R′, wherein R′′is optionally substituted C1-8 alkyl, C2-6 alkenyl, C2-6alkynyl, or C1-6heteroalkyl, wherein R is optionally substituted C1-8alkylene, C2-6alkenylene, C2-6alkynylene, or C1-6heteroalkylene; wherein R′is optionally substituted - NRX1RX2, C1-8alkyl, C2-6alkenyl, C2-6alkynyl, C1-8haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein RX1and RX2are each independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy; or (iii) optionally substituted 4-10 membered aryl, 4-11 membered heteroaryl, 4-8 membered cycloalkyl or 4-10 membered heterocyclyl.

35. The compound of any one of claims 1-34, wherein the prodrug functional moiety R5wherein Z1is monocyclic, fused or bridged bicyclic 4-11 membered N- containing heterocyclyl or 4-11 membered N-containing heteroaryl optionally substituted with 0 to 4 substituents, wherein the point of attachment is on N.

36. The compound of any one of claims 1-34, wherein the prodrug functional moiety R5is, wherein Z1is monocyclic, fused or bridged bicyclic 4-11 membered N- containing heterocyclyl or 4-11 membered N-containing heteroaryl optionally substituted with 2 to 3 substituents, wherein the point of attachment is on N.

37. The compound of any one of claims 1-34, wherein, wherein Z1is optionally substituted.

38. The compound of any one of claims 1-34, wherein the prodrug functional moiety R55555539. The compound of any one of claims 1-34, wherein the prodrug functional moiety R5iswherein Z2is C1-3alkyl, (C1-3alkylene)—O—(C1-3alkyl), (C1-3alkylene)—O—C(O)—X, wherein the alkyl and X are optionally substituted.

40. The compound of any one of claims 1-34, wherein the prodrug functional moiety R541. The compound of any one of claims 1-34, wherein the prodrug functional moiety R5is,wherein Z3is optionally substituted 4-10 membered aryl, 4-11 membered heteroaryl, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl.

42. The compound of any one of claims 1-34, wherein the prodrug functional moiety R5543. The compound of any one of claims 1-34, wherein the prodrug functional moiety R5is , wherein Z4is monocyclic, fused or bridged bicyclic 4-11 membered N- containing heterocyclyl or 4-11 membered N-containing heteroaryl optionally substituted with 0 to 4 substituents, wherein the point of attachment is on N.

44. The compound of any one of claims 1-34, wherein the prodrug functional moiety R5is ,wherein Z4is monocyclic, fused or bridged bicyclic 4-11 membered N- containing heterocyclyl or 4-11 membered N-containing heteroaryl optionally substituted with 2 to 3 substituents, wherein the point of attachment is on N.

45. The compound of any one of claims 1-34, wherein the prodrug functional moiety R546. The compound of any one of claims 1-34, wherein the prodrug functional moiety R547. The compound of any one of claims 1-34, wherein the prodrug functional moiety R548. The compound of any one of claims 1-34, wherein the prodrug functional moiety R549. The compound of any one of claims 1-34, wherein the prodrug functional moiety R5has one of the following structures:82450. The compound of any one of claims 1-49, wherein B has one of the following structures:a to group.

51. The compound of any one of claims 1-50, whereinand indicates the location of a bond to the pyridine group.

52. The compound of any one of claims 1-51, wherein B,substituted, wherein * indicates the location of a bond to L and indicates the location of a bond to the pyridine group.

53. The compound of any one of claims 1-52, wherein B,location of a bond to L and indicates the location of a bond to the pyridine group.

54. The compound of any one of claims 1-53, wherein the C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1-C8heteroalkylene of L is substituted with one or more substituents each independently selected from halo, -D, C1-C4 alkyl, and C3-C5 cycloalkyl.

55. The compound of any one of claims 1-54, wherein the C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1-C8heteroalkylene of L is substituted with one or more substituents each independently selected from -F, -D, -CH3, -CH2CH3, -CF3, and -CF2H; or one or more carbon atoms of the C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, or C1- C8 heteroalkylene are substituted with a substituent each independently selected from56. The compound of any one of claims 1-53, wherein L is selected from the group consisting of: C1-C8alkylene, C2-C8alkenylene, and C2-C8alkynylene, wherein the C1-C8alkylene, C2-C8alkenylene, and C2-C8alkynylene are optionally substituted with one or more substituents each independently selected from halo and -D.

57. The compound of any one of claims 1-53, wherein L is selected from the group consisting of: C1-C6alkylene, C2-C6alkenylene, and C2-C6alkynylene, wherein the C1-C6alkylene, C2-C6alkenylene, and C2-C6alkynylene are optionally substituted with one or more substituents each independently selected from halo and -D.

58. The compound of any one of claims 1-53, wherein L is selected from the group consisting of: C2-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene, wherein the C2-C4alkylene, C2-C4alkenylene, and C2-C4alkynylene are optionally substituted with one or more substituents each independently selected from halo and -D.

59. The compound of any one of claims 1-55, wherein L is selected from the group consisting of: –(CH2)4-, –(CH2)3-, –(CH2)2-, *–CH2CH=CH–**, *–(CH2)2CH=CH–**, *– (CH2)2C≡C–**, *–CH2C≡C–**, –CH2CHFCH2–, –CH2CF2CH2–, *–CH(CH3)CH2CH2–**, *–(CH2)CH(CH2)- **, *–(CH2)2CH(CH2)- **, *–(CH2)C(CH)2-**, and *–(CH2)2C(CH2)-**, wherein * indicates the location of the bond to the carbamate group and ** indicates the location of the bond to B group.

60. The compound of any one of claims 1-55, wherein L is selected from the group consisting of: –(CH2)4-, –(CH2)3-, –(CH2)2-, *–CH2CH=CH–**, *–(CH2)2CH=CH–**, *– (CH2)2C≡C–**, *–CH2C≡C–**, –CH2CHFCH2–, –CH2CF2CH2–, and *–CH(CH3)CH2CH2– **, wherein * indicates the location of the bond to the carbamate group and ** indicates the location of the bond to B group.

61. The compound of any one of claims 1-60, wherein L is –(CH2)3-, –(CH2)2-, *– (CH2)CH(CH2)-**, *–(CH2)2CH(CH2)-**, *–(CH2)C(CH)2-**, or *–(CH2)2C(CH2)-**, wherein * indicates the location of the bond to the carbamate group and ** indicates the location of the bond to B group.

62. The compound of any one of claims 1-61, wherein L is –(CH2)3- or –(CH2)2-.

63. The compound of any one of claims 1-62, wherein L is –(CH2)3-.

64. The compound of any one of claims 1-63, wherein the 4-8 membered cycloalkyl of R2is a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

65. The compound of any one of claims 1-64, wherein the 4-10 membered heterocyclyl of R2is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxanyl, piperazinyl, morpholinyl, dioxanyl, azepanyl, oxepanyl, homopiperazinyl, or oxazepanyl.

66. The compound of any one of claims 1-65, wherein the 4-10 membered heterocyclyl of R2is azetidinyl, pyrrolidinyl, morpholinyl, or piperidinyl.

67. The compound of any one of claims 1-66, wherein the heteroaryl of R2is imidazolyl, pyrazolyl, or pyridinyl.

68. The compound of any one of claims 1-67, wherein the 4-10 membered heterocyclyl of R2is a fused bicyclic heterocyclyl, a spiro bicyclic heterocyclyl, or a bridged bicyclic heterocyclyl.

69. The compound of any one of claims 1-68, wherein the fused bicyclic heterocyclyl of R2is hexahydro-1H-pyrrolizinyl, octahydro-6λ2-pyrrolo[3,4-b]pyridinyl, octahydro-1H- cyclopenta[b]pyridinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, 2- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, or 1,2,3,4-tetrahydroisoquinolinyl.

70. The compound of any one of claims 1-69, wherein the spiro bicyclic heterocyclyl of R2is tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizinyl] or 5-azaspiro[2.4]heptanyl.

71. The compound of any one of claims 1-70, wherein the bridged bicyclic heterocyclyl of R2is 2-oxa-5-azabicyclo[2.2.1]heptanyl.

72. The compound of any one of claims 1-71, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, or amine of R2is substituted with one or more substituents each independently selected from H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4 alkylene-O-C1-C4 alkyl, halo, hydroxyl, -C(=O)-C1-C3 alkyl, NRX1RX2, C1-C4alkylene-C6-C10aryl, C1-C4alkylene-(5-10 membered heteroaryl), C1-C4alkylene-C3- C10cycloalkyl, C1-C4alkylene-(3-10 membered heterocyclyl), 3-10 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, C1-C4alkylene- NRX1RX2, =CH2, =CF2or =CFH, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy.

73. The compound of any one of claims 1-72, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, or amine of R2is substituted with one or more substituents each independently selected from halo, deuterium, C1-C4alkyl, C1-C4alkylene- N(RX)2, C1-C4alkylene-(4-10 membered heterocyclyl), C1-C4heteroalkyl, hydroxyl, =CH2,=CF2, =CFH,and heteroaryl, each RXis independently hydrogen or C1-C4alkyl.

74. The compound of claim 73, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, or amine of R2is substituted with one or more substituents each independently selected from -CH3, -F, -CN, -NH2, -CH2OCH3, -OCH3, -CF2H, -CF3, -OH, =CH2, =CF2, =CFH, heteroaryl, -C1-C3alkylalcohol, C1-C3alkoxyl, and deuterium, - CH2N(CH3)2, and -CH2-(6-membered heterocyclyl).

75. The compound of claim 73, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, or amine of R2is substituted with one or more substituents eachindependently selected from the group consisting of -CH3, -F, =CF2, =CFH, =CH2, and -OH.

76. The compound of any one of claims 1-75, wherein the amine of R2is -NH2, - NH(CH3), or -N(CH3)2.

77. The compound of claim 73, wherein R2is selected from the group consisting of 4-10 membered heterocyclyl, 5-6 membered heteroaryl, and amine, wherein the 4-10 membered heterocyclyl, 5-6 membered heteroaryl, and amine are optionally substituted with one or more substituents each independently selected from the group consisting of -CH3, -F, =CF2,=CFH, =CH2, and -OH.

78. The compound of any one of claims 1-77, wherein R2has one of the following structures: ,79. The compound of any one of claims 1-77, wherein R2is selected from the group consisting of:

80. The compound of any one of claims 1-79, wherein81. The compound of any one of claims 1-79, wherein82. The compound of any one of claims 1-81, wherein R1is a hydrogen, -CH2CH3, or - CH3.

83. The compound of any one of claims 1-82, wherein R1is a hydrogen.

84. The compound of any one of claims 1-83, wherein R3is a hydrogen or -CH3.

85. The compound of any one of claims 1-84, wherein Y is -CH2-, -CD2-, -CH(CH3)-, - CD(CH3)-, -CD(CD3)-, or a direct bond.

86. The compound of any one of claims 1-84, wherein Y is -CH2-, -CD2-, -CH2-CH2-, or a direct bond.

87. The compound of any one of claims 1-86, wherein Y is -CH2-.

88. The compound of any one of claims 1-87, wherein the C1-C5alkyl or C1-C5deuteroalkyl of Y is substituted with methyl, dimethyl, or cyclopropyl.

89. The compound of any one of claims 1-86, wherein X is -O- or a direct bond.

90. The compound of any one of claims 1-86, wherein X is -O-.

91. A compound having the following structure of Formula (III):or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein L is selected from the group consisting of linear C3-C5alkylene and linear C3-C5deuteroalkylene, wherein the linear C3-C5alkylene or linear C3-C5deuteroalkylene is optionally substituted with C1-C2alkyl, C1-C2haloalkyl, CN, halo, OH, NH2, -NH(CH3) or N(CH3)2; RAis selected from the group consisting of alkylenecyclyl, heterocyclyl, aryl, or heteroaryl, H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy, wherein the alkylene-cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted, wherein the C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy is optionally substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl , heterocyclyl, -C(O)NRX3RX4wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, or prodrug moiety R5; RBis selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene- CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the alkyl, haloalkyl, alkoxy can be substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl , heterocyclyl, or -C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy; RCis selected from the group consisting of H, D, C1-C2 alkyl, C1-C2 alkoxy, halo, CN, NH2, -NH(CH3), and N(CH3)2; RDis selected from the group consisting of H, D, C1-C3alkyl, C1-C2deuteroalkyl, C1- C3haloalkyl, C1-C3alkylalcohol, (C1-C3alkylene)-O-(C1-C3alkyl), and CN;REand RFare each independently selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, and NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the alkyl, haloalkyl, alkoxy can be substituted with: C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, - C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy; R1is selected from the group consisting of H, D, C1-C2alkyl, C1-C2alkoxy, halo, CN, NH2, -NH(CH3), and N(CH3)2; Y is selected from the group consisting of C1-C5alkylene, C1-C5deuteroalkylene, or a direct bond, wherein the C1-C5 alkylene or C1-C5 deuteroalkylene is optionally substituted;R2is selected from the group consisting of hydrogen, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, -(C1-C3alkylene)-heteroaryl, aryl fused to 4-8 membered heterocyclyl, and amine, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, 4-8 membered heterocyclyl, or amine is optionally substituted.

92. The compound of claim 91, wherein the compound has one of the following structures of Formula (IIIA), (IIIB) or (IIIC):wherein the variables are as defined in claim 91.

93. The compound of claim 1 or 86, wherein the compound has the following structure of Formula (III-1):wherein L is selected from the group consisting of linear C3-C5alkylene and linear C3-C5deuteroalkylene, wherein the linear C3-C5alkylene or linear C3-C5deuteroalkylene is optionally substituted with C1-C2alkyl, C1-C2haloalkyl, CN, halo, OH, NH2, -NH(CH3) or N(CH3)2;RAis selected from the group consisting of alkylenecyclyl, heterocyclyl, aryl, or heteroaryl, H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, or C1-4alkylene-C1-4alkoxy, wherein the alkylene-cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted, wherein the C1-C4alkyl, C1-C4haloalkyl, C1-4alkylene-C1-4alkoxy is optionally substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl , heterocyclyl, -C(O)NRX3RX4wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, or prodrug moiety R5; RBis selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4 haloalkoxy, C1-C4 deuteroalkyl, -D, C1-C4 heteroalkyl, CN, C1-C4 alkylene- CN, C1-C3 alkylalcohol, C1-C4 alkylene-O-C1-C4 alkyl, halo, hydroxyl, -C(=O)-C1-C3 alkyl, NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the alkyl, haloalkyl, alkoxy can be substituted with C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, or -C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy; RDis selected from the group consisting of H, D, C1-C3alkyl, C1-C2deuteroalkyl, C1- C3haloalkyl, C1-C3alkylalcohol, (C1-C3alkylene)-O-(C1-C3alkyl), and CN; REand RFare each independently selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, and NRX1RX2, wherein RX1and RX2are each independently H, C1-4 alkyl, C1-4 haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the alkyl, haloalkyl, alkoxy can be substituted with: C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, - C(O)NRX3RX4, wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy; R1is selected from the group consisting of H, D, C1-C2alkyl, C1-C2alkoxy, halo, CN, NH2, -NH(CH3), and N(CH3)2; Y is selected from the group consisting of C1-C5alkylene, C1-C5deuteroalkylene, or a direct bond, wherein the C1-C5alkylene or C1-C5deuteroalkylene is optionally substituted;R2is selected from the group consisting of hydrogen, 4-8 membered cycloalkyl, 4-10 membered heterocyclyl, heteroaryl, -(C1-C3alkylene)-heteroaryl, aryl fused to 4-8 membered heterocyclyl, and amine, wherein the 4-8 membered cycloalkyl, 4-10 membered heterocyclyl,heteroaryl, 4-8 membered heterocyclyl, or amine is optionally substituted.

94. The compound of any one of claim 1, 91, 92, or 93, wherein the compound has one of the following structures of Formula (IIIA), (IIIB) or (IIIC):(III-1C) wherein the variables are as defined in claim 91.

95. The compound of any one of claim 91-94, wherein L is selected from the groupconsisting of unsubstituted linear C3-alkylene, unsubstituted linear C4-alkylene, linear C3- alkylene substituted with -CH3,CN, F, or Cl, or linear C4-alkylene substituted with -CH3,CN, F, or Cl.

96. The compound of any one of claim 91-95, wherein RA is selected from the groupconsisting of H, OH, C1-C4alkylalcohol, F, Cl, C1-C2alkyl, C1-C2NH(CH3), N(CH3)2, -NHC(O)NHCH3, -CHF2, R5prodrug moiety,97. The compound of any one of claims 91-96, wherein RB is selected from the groupconsisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4heteroalkyl, halo, NH2, -NH(CH3), N(CH3)2, and OH.

98. The compound of any one of claims 91-97, wherein RB is selected from the group ofH, CH3, F, and Cl.

99. The compound of any one of claims 91-98, whereinstructure of the following:,, wherein * indicates the location of a bond to L andindicates the location of a bond to the pyrimidine group.

100. The compound of any one of claims 91-99, wherein RC is selected from the groupconsisting of H, -CH3, and -OCH3.

101. The compound of any one of claims 91-100, wherein RDis selected from the group consisting of -CH3,C1-haloalkyl, -CF3, -CH2CH2OH, -CH2OH, -CH2CHF2, and -CH2-O-CH3.

102. The compound of any one of claims 91-101, wherein RE and RF are eachindependently selected from the group consisting of H, D, F, Cl, CH3, C1haloalkyl, and - OCH3.

103. The compound of any one of claims 91-102, whereinhas the structure ofindicates the location of a bond to the pyrimidine group.

104. The compound of any one of claims 91-103, wherein R1is selected from the groupconsisting of H, CH3, and C1 haloalkyl.105.The compound of any one of claims 91-104, wherein Y is C1-C3 alkylene optionally substituted with C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, - C(=O)-C1-C3alkyl, cyclopropyl, and NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, or C1-4haloalkyl.

106. The compound of any one of claims 91-105, wherein Y is substituted C3alkylene, wherein the substituted C3alkylene is, whereinrepresents the point of attachment to X and represents the point of attachment to R2.

107. The compound of any one of claims 91-106, wherein R2is selected from the group consisting of, morpholinyl, or pyrrolidinyl, wherein, morpholinyl, or pyrrolidinyl is optionally substituted with C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1- C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, cyclopropyl, or NRX1RX2, wherein RX1and RX2are each independently H, C1-4alkyl, or C1-4haloalkyl.

108. The compound of any one of claims 91-107, where in R2is selected from the group consisting of:

109. A compound having the following structure of Formula (IV):or a stereoisomer of the compound, tautomer of the compound, or salt thereof, wherein L is selected from the group consisting of : C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, C1-C8heteroalkylene, wherein the C1-C8alkylene, C1-C8alkenylene, C1-C8alkynylene, or C1-C8heteroalkylene is optionally substituted, —O-( C1-C8alkylene)—, —O- (C2-C8alkenylene)—, —O-( C2-C8alkynylene)—, —O-(C1-C8heteroalkylene)—, —S-( C1- C8alkylene)—, —S-(C2-C8alkenylene)—, —S-( C2-C8alkynylene)—, —S-(C1-C8heteroalkylene)—, —NR-( C1-C8alkylene)—, —NR-(C2-C8alkenylene)—, —NR-( C2-C8alkynylene)—, and —NR-(C1-C8heteroalkylene)—; RBis selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene-CN, C1-C3alkylalcohol, C1-C4alkylene-O- C1-C4alkylene, halo, hydroxyl, -C(=O)CH3, NH2, -NH(CH3), N(CH3)2; R6is selected from the group consisting of H, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4deuteroalkyl, -D, C1-C4heteroalkyl, CN, C1-C4alkylene- CN, C1-C3alkylalcohol, C1-C4alkylene-O-C1-C4alkyl, halo, hydroxyl, -C(=O)-C1-C3alkyl, NRX1RX2wherein RX1, RX2: are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, and wherein the C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy can be substituted with: C1-4alkyl, halo, OH, CN, aryl, heteroaryl, cycloalkyl, heterocyclyl, - C(O)NRX3RX4wherein RX3and RX4are each independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-C1-4alkoxy, or prodrug moiety R5; X, Y, and R2are as defined in claim 17; REand RFare each independently H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, halo, NRX1RX2, hydroxyl, or CN, wherein RX1and RX2are each independently H or C1-4 alkyl.

110. The compound of claim 109, wherein the compound has the following structure of Formula (IVA):wherein the variables are as defined in claim 109.

111. The compound of claim 109 or 110, wherein L is linear C2-C5 alkylene optionallysubstituted with C1-C4alkyl, C1-C4heteroalkyl, halo, amine, hydroxyl, or CN.

112. The compound of any one of claims 109-111, wherein RBis H, F, Cl, -CH3, -CD3, - CF3, -CH2CH3, OH, CN, or NH2.

113. The compound of any one of claims 109-112, wherein R6is H, F, Cl, -CH3, -CD3, - CF3, -CH2CH3, OH, CN, or NH2.

114. The compound of any one of claims 109-113, wherein RBis CN or Cl.location of a bond to L and indicates the location of a bond to the pyridine group.

116. The compound of any one of claims 109-115, wherein REand RFare each independently H, F, Cl, -CH3, -CD3, -CF3, -CH2CH3, OH, CN, or NH2.

117. The compound of claim 1, wherein the compound is selected from Table 1.

118. A pharmaceutical composition comprising a compound of any one of claims 1-117 and a pharmaceutically acceptable carrier.

119. The pharmaceutical composition of claim 118, further comprising an additional therapeutic agent.

120. The compound of any one of claims 1-117 or the pharmaceutical composition of claim 113 or 114 for use in treating a disease associated with a mutation in KRAS.

121. A method of treating a disease associated with G12D, G12V, G12C, G12S, G12A, G12R, Q61H, G13D mutation in KRAS or a wild-type KRAS mutation in a subject in need thereof, comprising: administering the compound of any one of claims 1-118 or the pharmaceutical composition of claim 118 or 119 to the subject.

122. The method of claim 121, wherein the subject is an animal.

123. The method of claim 121 or claim 122, wherein the subject is a human.

124. The compound for use or the method of any one of claims 120-123, wherein the disease associated with a mutation in KRAS is a cancer.

125. The compound for use or the method of claim 124 , wherein the cancer is pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, endometrial endometrioid adenocarcinoma, rectal adenocarcinoma, gastric cancer, or lung cancer.

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