Macrocyclic compounds as modulators of KRAS and uses thereof

Abstract

Disclosed herein are compounds useful for the inhibition of KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C. The compounds have a general Formula (I) or pharmaceutically acceptable salts thereof, wherein the variables of Formula (I) are as defined herein. Also provided herein are pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C disorder.

Description

MACROCYCLIC COMPOUNDS AS MODULATORS OF KRAS AND USES THEROF. CROSS REFERENCE TO PRIOR APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 640,103, filed April 29, 2024. FIELD

[0002] The present disclosure provides compounds having activity as inhibitors of mutant KRAS proteins. This disclosure also provides pharmaceutical compositions comprising the compounds, uses and methods of treating certain disorders, such as cancer, including but not limited to non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma. BACKGROUND

[0003] From its identification as one of the first human oncogenes in 1982 (Der et al., 1982), KRAS (the Kirsten rat sarcoma viral oncogene homologue) has been the focus of extensive academic and industrial research, as a key node in the MAPK signal transduction pathway, as a transforming factor in a network of parallel effector pathways (e.g., PI3K / AKT) (Vojtek et al., 1998) and as a potential target for anti-cancer agents (Malumbres et al., 2003). Despite progress in the development of inhibitors of upstream and downstream nodes in the MAPK pathway (e.g., EGFR (Sridhar et al., 2003), BRAF (Holderfield et al., 2014) and MEK (Caunt et al., 2015), the KRAS protein has historically proven resistant to direct inhibition.

[0004] KRAS is a G-protein that couples extracellular mitogenic signaling to intracellular, pro- proliferative responses. KRAS serves as an intracellular “on / off” switch. Mitogen stimulation induces the binding of GTP to KRAS, bringing about a conformational change which enables the interaction of KRAS with downstream effector proteins, leading to cellular proliferation. Normally, pro-proliferative signaling is regulated by the action of GTPase-activating proteins (GAPs), which return KRAS to its GDP-bound, non-proliferative state. Mutations in KRAS impair the regulated cycling of KRAS between these GDP- and GTP-bound states, leading to the accumulation of the GTP-bound active state and dysregulated cellular proliferation (Simanshu et al., 2017).

[0005] Attempts to develop inhibitors of mutated KRAS proteins have historically been thwarted by the absence of druggable pockets on the surface of the protein (Cox et al., 2014). In 2013, Shokat and colleagues identified covalent inhibitors of a common (O’Bryan, 2019) oncogenic mutant ofKRAS, KRAS G12C, which bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and prevented its subsequent activation (Ostream et al., 2013). This discovery brought about significant new efforts in the KRAS inhibitor research, which have recently culminated in the entry of KRAS inhibitors in human clinical trials.

[0006] While some progress has been made on KRAS G12C inhibitors, there is a continued interest and effort to develop inhibitors of KRAS, particularly inhibitors of other KRAS such as KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C. Thus, there is a need to develop new inhibitors for KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C for the treatment of disorders, such as cancer. SUMMARY

[0007] One aspect of the disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein; Z is C-H, C-halogen, C-CN, C-C1-4alkyl, C-C1-4haloalkyl, C-C1-4alkoxy, C-C1-4haloalkoxy, C-C3-7cycloalkyl or N; Q is CH, C-halogen, C-C1-4 alkyl, C-C1-4 haloalkyl or N; B is a 4-15 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S and N; p is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4alkyl, C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkylene, 5-7 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2N(Rz)2, -C(O)Rz, -C(O)ORz, -C(O)N(Rz)2, -C1-4alkylene-C(O)-C1-4alkyl, -C1-4alkylene-C(O)N(Rz)2, C1-4alkylene-S(O)2-C1-4alkyl, or -S-C1-4alkyl;R4is hydrogen, hydroxyl, halogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl or cyano; each R6a,R6band R6cindependently is hydrogen, halogen, hydroxyl, cyano, -N(Rz)2, - C(O)Rz, -C(O)ORz, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4alkynyl or C3-6cycloalkyl or R6aand R6b, together with the atom to which they are attached form a fused C3-7cycloalkyl; and each Rzindependently is hydrogen or C1-4alkyl.

[0008] Another aspect of the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.

[0009] Yet another aspect of the disclosure provides method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or salt of Formula (I) or a pharmaceutical composition comprising the compound or salt of Formula (I).

[0010] Still another aspect of the disclosure provides a compound or salt of Formula (I) for use as a medicament. Another aspect of the disclosure provides a compound or salt disclosed herein, or the pharmaceutical composition disclosed herein for use in the treatment of cancer.

[0011] Yet another aspect of the disclosure provides a compound or salt of Formula (I), or the pharmaceutical composition comprising a compound or salt of Formula (I), for the manufacture of a medicament for the treatment of cancer. Another aspect of the disclosure provides the use of a compound or salt disclosed herein, or the pharmaceutical composition of the disclosure, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma, or any combination of the foregoing. In some cases, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.

[0012] Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description. The description hereafter includes specific cases, embodiments, and examples with the understanding that the disclosure is illustrative and is not intended to limit the embodiments of the present disclosure to the specific cases, embodiments, and examples described herein. DETAILED DESCRIPTION

[0013] Disclosed herein are compounds having activity as inhibitors of KRAS such as KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C, pharmaceutical compositions comprising the compounds, and uses and methods of treating disorders, such as cancer (e.g., non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma), with the compounds and pharmaceutical composition described herein. DEFINITIONS

[0014] The following definitions are provided to assist in understanding the scope of this disclosure. Unless defined otherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0015] The term “alkyl” refers to a saturated straight chain hydrocarbon or saturated branched chain hydrocarbon containing the indicated number of carbon atoms. For example, C3alkyl means an alkyl group that has 3 carbon atoms (e.g., n-propyl or isopropyl). For example, a C1-6alkyl refers to an alkyl group having 1 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C1-6alkyl includes alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges)). A “C1-4alkyl” includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Nonlimiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl.

[0016] The term “alkenyl” refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. For example, C3alkenyl means the alkenyl group has 3 carbon atoms (e.g., 1-propenyl or 2-propenyl). For example, a C2-6alkenyl refers to an alkenyl group having 2 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C2-6alkenyl includes alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges). A C2-4alkenyl includes, for example, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or 3-butenyl. Non-limiting examples of alkenyl groups include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2- methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0017] The term “alkynyl” refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds. For example, C3alkynyl means the alkynyl group has 3 carbon atoms. For example, a C2-6alkynyl refers to an alkynyl group having 2 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C2-6alkynyl includes any alkynyl groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges). For illustration, C2-4alkynyl includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl. Nonlimiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0018] The term “cycloalkyl” refers to a saturated, hydrocarbon monocyclic ring, or a saturated, hydrocarbon polycyclic ring system containing the indicated number of carbon atoms as ring members in the ring or ring system. No ring in a cycloalkyl ring or ring system has s double bond, a heteroatom, or is aromatic. When a cycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. For example, C5cycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring or ring system. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C3-7cycloalkyl includes cycloalkyl groups having 3, 4, 5, 6, or 7 carbon atoms in the ring (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 3-4, 3-5, 3-6, 3-7, 4-5, 4-6, 4-7, 5-6, 5-7, or 6-7 carbon atom ring members, or any combination of the foregoing ranges). Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, norbornyl, decalinyl, and 7,7-dimethylbicyclo[2.2.1]heptanyl.

[0019] The term “aryl” refers to a monocyclic aromatic, hydrocarbon ring (i.e., phenyl,or a polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) aromatic hydrocarbon ring system containing the indicated number of carbon atoms. For example, C10aryl refers to an aryl group that has 10 carbon atoms in the ring system (e.g., naphthyl). When an aryl group is a polycyclic ring system, each ring in the ring system is aromatic, and no ring in the ring system contains a heteroatom. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C6-14aryl includes aryl groups having 6-14 (e.g., 6, 10, or 14) carbon atoms in the ring or ring system (or combinations of the foregoing), as well as all subgroups in the indicated range (e.g., 6-10 or 10-14 carbon atom ring members in the ring or ring system, or combinations of the foregoing). Nonlimiting examples of aryl groups include phenyl, naphthyl, and anthracenyl.

[0020] The term “heteroatom,” unless otherwise stated herein, refers to oxygen, sulfur, nitrogen, and phosphorus.

[0021] The term “heterocycloalkyl” refers to a saturated, monocyclic ring or saturated, polycyclic ring system comprising carbon atoms and one or more heteroatoms (e.g., one or more of N, O, and S), and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring). When a heterocycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. No ring in a heterocycloalkyl ring or ring system contains a double bond or is aromatic. For example, a heterocycloalkyl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to a ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heterocycloalkyl group having 5-7 total ring atoms and 1-3 heteroatoms independently selected fromN, O, and S includes rings having 5, 6, or 7 total atoms, or any combination of the foregoing, as well as all subgroups in the indicated range (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom independently is selected from N, O, and S. Thus, a heterocycloalkyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing is independently selected from N, O, and S. Nonlimiting examples of heterocycloalkyl groups include but are not limited to aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene-yl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, oxathiolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, morpholinyl, thiomorpholinyl, azepanyl, hexahydro-1H-pyrrolizinyl, and 1,4- diazepanyl.

[0022] The term “heteroaryl” refers to a monocyclic aromatic ring comprising carbon and one or more heteroatoms, and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring), or a polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) aromatic ring system having one or more heteroatoms and the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring system). When a heteroaryl group is a polycyclic ring system, each ring in the ring system is aromatic. For example, a heteroaryl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to an aromatic ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S refers to an aromatic ring having a total number of ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms, or any combination of the foregoing), as well as encompassing all subgroups (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom is independently selected from N, O, and S. A heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing independently is selected from N, O, and S. Nonlimiting examples of monocyclic heteroaryl groups include: pyrrolyl, furanyl, thiophene-yl (or thienyl), pyrazolyl, imidazolyl,isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (or pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. Nonlimiting examples of bicyclic heteroaryl groups include benzofuranyl, benzothienyl, benzimidazolyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, furopyridinyl (e.g., furo[2,3-b]pyridinyl), imidazopyridinyl (imidazo[4,5-b]pyridinyl), imidazothiazolyl (e.g., imidazo[4,5-d]thiazolyl), indolizinyl, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl (e.g., oxazolo[5,4-b]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (e.g., pyrrolo[2,3-b]pyridyl), quinolinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, cinnolinyl, isoquinolyl, pyrazolopyridinyl (e.g., pyrazolo[3,4-b]pyridinyl), and thiazolopyrindinyl (e.g., thiazolo[5,4-b]pyridinyl). Nonlimiting examples of tricyclic heteroaryl groups include carbazolyl, 4,5-benzindolyl, dibenzofuranyl, dibenzothiophene-yl, phenazinyl, and acridinyl.

[0023] The term “alkylene” refers to a divalent saturated, straight or branched hydrocarbon chain diradical containing the indicated number of carbon atoms. For example, C3alkylene means the alkylene group has 3 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, C1-6alkylene means an alkylene group having a 1, 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). When the number of carbon atoms in an alkylene group is indicated as “C0,” then the alkylene group is not present and the recited substituent is directly attached to the rest of the compound. For example, the term C0-6alkylene-OH indicates that the OH group can be directly attached to the compound or through a C1-6alkylene linker. Examples of alkylene groups include methylene (—CH2—), ethylene (—CH2CH2—), n-propylene (— CH2CH2CH2—), isopropylene (—CH(CH3)CH2—), 1-butylene (—CH2CH2CH2CH2—), 1- methylbutylene (—CH(CH3)CH2CH2—), 2-methylbutylene (—CH2CH(CH3)CH2—), and 3- methylbutylene (—CH2CH2CH2(CH3)—).

[0024] The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0025] The term “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms is replaced by a halogen. The halogen is independently selected at each occurrence. The term includes, for example, monohaloalkyl (e.g., CH2F, CH(CH2F)CH3) dihaloalkyl (e.g., CHF2, CH(CHF2)CH3), trihaloalkyl (e.g., CF3, CH(CF3)CH3), and polyhaloalkyl (e.g., CF(CF3)CH3). A haloalkyl group may or may not be perhalogenated (e.g., perfluorinated, such as CF(CF3)CF3). For example, the term “C1-4haloalkyl” refers to a C1-4alkyl, wherein one or more hydrogen atoms is substituted with a halogen. For illustration, C1-4haloalkyl includes, for example, CH2F, CHF2, CF3, CHFCl, CH2CF3, CFHCF3, CF2CF3, CH(CF3)2, CF(CHF2)2, CH(CH2F)(CF3), CH2Cl, CHCl2, CCl3, CHFCl, CH2CCl3, CClHCCl3, CCl2CCl3, CH(CCl3)2, CCl(CHCl2)2, CH(CH2Cl)CCl3, and CH2CF(CH3)2.

[0026] The term “hydroxyalkylene” or “hydroxylalkylene” refers to a saturated straight chain alkylene or saturated branched chain alkylene containing the indicated number of carbon atoms substituted with one or two hydroxy groups in place of a hydrogen, provided that if two hydroxy groups are present they are not both on the same carbon atom. Nonlimiting examples hydroxyalkylene include but are not limited to, hydroxymethylene, 2-hydroxyethylene, 2-hydroxypropylene, 3- hydroxypropylene, l-(hydroxymethyl)-2- methylpropylene, 2-hydroxybutylene, 3-hydroxybutylene, 4- hydroxybutylene, 2,3-dihydroxypropylene, 1-(hydroxymethyl)-2-hydroxyethylene, 2,3- dihydroxybutyIene, 3,4-dihydroxybutylene and the like.

[0027] The term “oxo” refers to a substituent oxygen atom connected to another atom by a double bond (e.g., =O). For example, an oxo substituent on a cyclopentyl ring can be depicted as: .

[0028] The term “carbonyl” refers to a divalent C=O radical, such as.

[0029] The terms “hydroxy” and “hydroxyl” are interchangeable and refer to a —OH group.

[0030] The terms “alkoxy” and “alkoxyl” are interchangeable and refer to an —O-alkyl group, where the alkyl group is as defined elsewhere herein. For example, a C3alkoxy group means the alkoxy group has 3 carbon atoms (e.g., OCH2CH2CH3). Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C1-6alkoxy includes alkoxy groups having 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing, as well as all subgroups in the indicated range (e.g., 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). Nonlimiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, 1-methylethyloxy (iso-propoxy), n-butoxy, isobutoxy, sec-butoxy, and tert- butoxy.

[0031] The terms “haloalkoxy” and “haloalkoxyl” are interchangeable and refer to an alkoxy group in which one or more of the hydrogen atoms is replaced by a halogen. The halogen is independently selected at each occurrence. The term includes monohaloalkoxy (e.g., OCH2F, OCH(CH2F)CH3) dihaloalkoxy (e.g., OCHF2, OCH(CHF2)CH3), trihaloalkoxy (e.g., OCF3, OCH(CF3)CH3), and polyhaloalkoxy (e.g., OCF(CF3)CH3). A haloalkoxy group may or may not be perhalogenated (e.g., perfluorinated, such as OCF(CF3)CF3). For example, the term “C1-4haloalkoxy” refers to a C1-4alkoxy as defined herein, wherein one or more hydrogen atoms is substituted with a halogen. Representative examples of C1-4haloalkoxy include OCH2F, OCHF2, OCF3, OCHFCl, OCH2CF3, OCFHCF3, OCF2CF3, OCH(CF3)2, OCF(CHF2)2, OCH(CH2F)(CF3), OCH2Cl, OCHCl2, OCF3, OCHFCl, OCH2CCl3, OCClHCCl3, OCCl2CCl3, OCH(CCl3)2, OCCl(CHCl2)2, OCH(CH2Cl)CCl3, and OCH2CF(CH3)2.

[0032] The term “cyano” refers to a —CN group.

[0033] The term “deutero” as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with deuterium (“D” or “2H”). For example, the term “C1-4deuteroalkyl” refers to a C1-4alkyl as defined herein, wherein one or more hydrogen atoms are substituted with D. Representative examples of C1-4deuteroalkyl include, but are not limited to, -CH2D, -CHD2, -CD3, -CH2CD3, -CDHCD3, -CD2CD3, - CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3).

[0034] The term “amino” refers to —NH2.

[0035] The term “alkylamino” refers to a — NRH group in which R is alkyl.

[0036] The term “ether” refers to an oxygen atom bonded to two alkyl or aryl groups (R-O-R). The term “ether bridge” refers to an ether group that forms a bridge on a ring, wherein the bridge has theindicated number of carbon atoms. For example, a C1 ethe cyclohexylenering cyclohexylene ring can be depicted as, for example,

[0037] The term “solvate” refers to a molecular aggregate comprising a compound, or a pharmaceutically acceptable salt thereof as described herein and a stoichiometric or non- stoichiometric amount of one or more pharmaceutically acceptable solvent molecules.

[0038] The term “hydrate” refers to a solvate in which the solvent is water.

[0039] The term “geminal” refers to substituents that are attached to the same atom. Geminal R groups on a chain and ring can be depicted as:respectively.

[0040] The term “vicinal” refers to substituents that are attached to adjacent atoms along a chain orwithin a ring. Vicinal R groups along a chain and within a ring can be depicted as and , respectively.

[0041] The term “non-neighboring” refers to substituents that are attached to atoms along a chain or within a ring that are not attached to adjacent atoms and that are not geminal. Non-neighboring R groups along a chain and within a ring can be depictedrespectively.

[0042] The term “protecting group” refers to a removable moiety that modifies a desired functional group to block the desired functional group from reacting in a subsequent chemical reaction. For example, the term “nitrogen protecting group” refers to a removable moiety that modifies a functional group having a nitrogen atom to block the functional group having a nitrogen atom from reacting in a subsequent chemical reaction (e.g., tert-butyloxycarbonyl). Examples of protecting groups are detailed in Greene, T. W., Wuts, P. G, “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book, such as Wuts, P.G.M. and Greene, T.W. “Greene’s Protective Groups in Organic Synthesis,” Fourth Edition, John Wiley & Sons, Hoboken: 2007).

[0043] As used herein, if any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0044] The term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure or functional group with the radical of a specified substituent. A substituted structure or functional group may have a substituent at any substitutable position of the structure or functional group. When more than one position in a given structure can be substituted with more than one substituent, the substituent may be either the same or different at each position.

[0045] The term “pharmaceutically acceptable” refers to a species or component that is generally safe, non-toxic, and neither biologically nor otherwise undesirable for use in a subject.

[0046] The term “pharmaceutically acceptable salt” refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and that is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or formed with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid). Pharmaceutically acceptable salts also include, for example, salts formed when an acidic proton present in the parent compound either is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) orassociates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N- methylglucamine, dicyclohexylamine). Additionally, the salts of the compounds described herein, can exist in either hydrated or anhydrous form or as solvates with other solvent molecules.

[0047] The term “pharmaceutically acceptable excipient” refers to a broad range of ingredients that may be combined with a compound, solvate, or salt disclosed herein to prepare a pharmaceutically acceptable composition or formulation. Excipients include, for example, vehicles (e.g., solvents, dispersion media), coatings, isotonic and absorption delaying agents, diluents, colorants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, and preservatives (e.g., antibacterial and antifungal agents).

[0048] The term “therapeutically effective amount” as used herein refers to that amount of a compound disclosed herein that elicits a desired biological or medical response in a cell, a tissue, a system, or a subject.

[0049] The term “patient” or “subject” refers to humans and other mammals. The term “mammal” as used herein includes, for example, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), and monkeys. Human subjects include neonates, infants, juveniles, adults, and geriatric subjects.

[0050] For clarity and avoidance of doubt, the divalent structural elements of L1as provided herein are to be inserted into Formula (I) such that the left hand side is attached to the nitrogen-containing hetercycloalkyl group and the right hand side is attached to the aryl ring. For example, if L1isExample 1-001. COMPOUNDS OF FORMULA (I)

[0051] Provided herein as Embodiment 1 are compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein; Z is C-H, C-halogen, C-CN, C-C1-4alkyl, C-C1-4haloalkyl, C-C1-4alkoxy, C-C1-4haloalkoxy, C-C3-7cycloalkyl or N; Q is CH, C-halogen, C-C1-4alkyl, C-C1-4haloalkyl or N; B is a 4-15 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S and N; p is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4alkyl, C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkylene, 5-7 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2N(Rz)2, -C(O)Rz, -C(O)ORz, -C(O)N(Rz)2, -C1-4alkylene-C(O)-C1-4alkyl, -C1-4alkylene-C(O)N(Rz)2, C1-4alkylene-S(O)2-C1-4alkyl, or -S-C1-4alkyl;R4is hydrogen, hydroxyl, halogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl or cyano; each R6a,R6band R6cindependently is hydrogen, halogen, hydroxyl, cyano, -N(Rz)2, - C(O)Rz, -C(O)ORz, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4alkynyl or C3-6cycloalkyl or R6aand R6b, together with the atom to which they are attached form a fused C3-7cycloalkyl; and each Rzindependently is hydrogen or C1-4alkyl.

[0052] Provided herein as Embodiment 2 is the compound or salt of Embodiment 1, wherein the compound or salt is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein; Z is C-H, C-halogen, C-CN, C-C1-4alkyl, C-C1-4haloalkyl, C-C1-4alkoxy, C-C1-4haloalkoxy, C-C3-7cycloalkyl or N; Q is CH, C-halogen, C-C1-4alkyl, C-C1-4haloalkyl or N; B is a 4-15 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S and N; p is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4alkyl, C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkylene, 5-7 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2N(Rz)2, -C(O)Rz, -C(O)ORz, -C(O)N(Rz)2, -C1-4alkylene-C(O)-C1-4alkyl, -C1-4alkylene-C(O)N(Rz)2, C1-4alkylene-S(O)2-C1-4alkyl, or -S-C1-4alkyl; -L2-R1is , , , , , , , , , , , , , , ,R4is hydrogen, hydroxyl, halogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl or cyano; each R6a,R6band R6cindependently is hydrogen, halogen, hydroxyl, cyano, -N(Rz)2, - C(O)Rz, -C(O)ORz, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4alkynyl or C3-6cycloalkyl or R6aand R6b, together with the atom to which they are attached form a fused C3-7cycloalkyl; and each Rzindependently is hydrogen or C1-4alkyl.

[0053] Provided herein as Embodiment 3 is the compound or salt of Embodiment 1, wherein the compound or salt is a compound of Formula (II):or a pharmaceutically acceptable salt of said compound, wherein X is O or S; and Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

[0054] Provided herein as Embodiment 4 is the compound or salt of Embodiment 1, wherein the compound or salt is a compound of Formula (III):or a pharmaceutically acceptable salt of said compound, wherein X is O or S; and Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

[0055] Provided herein as Embodiment 5 is the compound or salt of Embodiment 1, wherein the compound or salt is a compound of Formula (IV):or a pharmaceutically acceptable salt of said compound, wherein Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

[0056] Provided herein as Embodiment 6 is the compound or salt of Embodiment 1, wherein the compound or salt is a compound of Formula (V):or a pharmaceutically acceptable salt of said compound, wherein Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

[0057] Provided herein as Embodiment 7 is the compound or salt of Embodiment 1, wherein the compound or salt is a compound of Formula (VI):or a pharmaceutically acceptable salt of said compound, wherein Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

[0058] Provided herein as Embodiment 8 is the compound or salt of any of Embodiments 1-7, wherein Z is C-H, C-F, C-CN, C-CH3, C-CF3, C-OMe, C-Cl or N. Provided herein as Embodiment 9 is the compound or salt of Embodiment 8, wherein Z is N. Provided herein as Embodiment 10 is the compound or salt of Embodiment 8, wherein Z is CH. Provided herein as Embodiment 11 is the compound or salt of Embodiment 8, wherein Z is CF.

[0059] Provided herein as Embodiment 12 is the compound or salt of any of Embodiments 1-11, wherein Q is CH or N. Provided herein as Embodiment 13 is the compound or salt of Embodiment 12, wherein Q is CH. Provided herein as Embodiment 14 is the compound or salt of Embodiment 12, wherein Q is N.

[0060] Provided herein as Embodiment 15 is the compound or salt of any of Embodiments 1-7, wherein Z is N and Q is CH. Provided herein as Embodiment 16 is the compound or salt of any of Embodiments 1-7, wherein Z is N and Q is N.

[0061] Provided here as Embodiment 17 is the compound or salt of any of Embodiments 1-16, wherein B is a 5-7-membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S and N. Provided herein as Embodiment 18 is the compound or salt of Embodiment 17, wherein p is 0. Provided herein as Embodiment 19 is the compound or salt of Embodiment 18, wherein B is, wherein X is -O- or -S-. Provided herein as Embodiment 20 is the compound or salt of Embodiment 19, whereinProvided herein asEmbodiment 21 is the compound or salt of Embodiment 20, whereinerein as Embodiment 22 is the compound or salt of Embodiment 21, w.

[0062] Provided herein as Embodiment 23 is the compound or salt of Embodiment 19, wherein B iProvided herein as Embodiment 24 is the compound or salt of Embodiment 23, whereinProvided herein as Embodiment 25 is the compound or salt of Embodiment 24, wherein.

[0063] Provided herein as Embodiment 26 is the compound or salt of Embodiment 18, wherein Bd or salt of Embodiment 27, wherein B is. Provided herein as Embodiment 29 is the compound or salt of Embodiment 27, wherein B is.

[0064] Provided herein as Embodiment 30 is the compound or salt of Embodiment 18, wherein B i, wherein X is -O- or -S-. Provided herein as Embodiment 31 is the compound or salt of Embodiment 30, wherein B is. Provided herein as Embodiment 32 is the compound or salt of Embodiment 31, wherein B is. Provided herein as Embodiment 33 is the compound or salt of Embodiment 32, wherein B isas Embodiment 34 is the compound or salt of Embodiment 32, wherein B is.

[0065] Provided herein as Embodiment 35 is the compound or salt of Embodiment 18, wherein Bor salt of Embodiment 36, wherein B is. Provided herein as Embodiment 38 is the compound or salt of Embodiment 36, wherein B is.

[0066] Provided herein as embodiment 39 is the compound or salt of Embodiment 18, wherein B is. Provided herein as Embodiment 40 is the compound or salt of Embodiment 39,whereinProvided herein as Embodiment 41 is the compound or salt of Embodiment 40, wherein. Provided herein as Embodiment 42 is the compound or salt of Embodiment 40, wherein

[0067] Provided herein as Embodiment 43 is the compound or salt of Embodiment 17, wherein p is 1. Provided herein as Embodiment 44 is the compound or salt of Embodiment 43, wherein each Rxindependently is hydroxyl, halogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy. Provided herein as Embodiment 45 is the compound or salt of Embodiment 44, wherein each Rxindependently is hydroxyl, halogen, C1-4alkyl, or C1-4haloalkyl. Provided herein as Embodiment 46 is the compound or salt of Embodiment 45, wherein each Rxindependently is hydroxyl, fluorine, methyl or monofluoromethyl.

[0068] Provided herein as Embodiment 47 is the compound or salt of Embodiment 46, wherein B i, wherein X is -O- or -S-. Provided herein as Embodiment 48 is the compound or salt of Embodiment 47, wherein. Provided herein as Embodiment 49 is the compound or salt of Embodiment 48, wherein. Provided herein as Embodiment 50 is the compound or salt of Embodiment 49, wherein

[0069] Provided herein as Embodiment 51 is the compound or salt of Embodiment 46, wherein B iProvided herein as Embodiment 52 is the compound or salt of Embodiment 51, whereinProvided herein as Embodiment 53 is the compound or salt of Embodiment 52, wherein. Provided herein as Embodiment 54 is the compound or salt of Embodiment 53, wherein. Provided herein as Embodiment 55 is the compound or salt of Embodiment 53, whereinProvided herein as Embodiment 56 is the compound or salt of Embodiment 53, whereinProvided herein as Embodiment 57 is the compound or salt of Embodiment 53, wherein

[0070] Provided herein as Embodiment 58 is the compound or salt of Embodiment 46, wherein B i. Provided herein as Embodiment 59 is the compound or salt of Embodiment 58,whereinProvided herein as Embodiment 60 is the compound or salt ofEmbodiment 59, wherein.Provided herein as Embodiment 61 is the compound or salt of Embodiment 60, wherein B is.

[0071] Provided herein as Embodiment 62 is the compound or salt of Embodiment 46, wherein Bis . Provided herein as Embodiment 63 is the compound or salt of Embodiment 62, wherein B is. Provided herein as Embodiment 64 is the compound or salt ofEmbodiment 63, wherein B is.Provided herein as Embodiment 65 is the compound or salt of Embodiment 64, wherein B is rein as Embodiment 66 is the compound or salt of Embodiment 64,. Provided herein as Embodiment 67 is the compound or salt of Embodiment 64, wherein B is. Provided herein as Embodiment 68 is the compoundor salt of Embodiment 64, wherein B is .

[0072] Provided herein as Embodiment 69 is the compound or salt of any of Embodiments 1-68,,

[0073] Provided herein as Embodiment 70 is the compound or salt of any of Embodiments 1-68,Provided herein as Embodiment 72 is the compound or salt of anycompound or salt of Embodiment 72, wherein -Provided herein as Embodiment 74 is the compound or salt of Embodiment 72, wherein -Provided herein as Embodiment 75 is the compound or salt of Embodiment 72, wherein -L2-R1iswherein -L2-R1is . Provided herein as Embodiment 77 is the compound or salt of odiment 72, wherein -L2Emb -R1is . Provide herein as Embodiment 78 is the compound or salt of Embodiment 72, wherein -Provide herein as Embodiment 79 is the compound or salt of Embodiment 71, wherein -.Provide herein as Embodiment 80 is the compound or salt of Embodiment 71, wherein -L2-R1is. Provide herein as Embodiment 81 is the compound or salt of Embodiment 71,compound or salt of Embodiment 71, wherein -L2-R1is. Provide herein as Embodiment 84 is the compound or salt of Embodiment 71, wherein -Provided herein as Embodiment 85 is the compound or salt of Embodiment 71, wherein -L2-R1is. Provided herein as Embodiment 86 is the compound or salt of Embodiment 71, wherein -

[0074] Provided herein as Embodiment 87 is the compound or salt of any of Embodiments 1-68,Embodiment 88 is the compound or salt of Embodiment 87, wherein -. Provided herein as Embodiment 89 is the compound or salt of Embodiment 88, wherein -Provided herein as Embodiment 90 is the compound or salt of Embodiment 88, wherein -. Provided herein as Embodiment 91 is the compound or salt of Embodiment 88, wherein -L2-R1is. Provided herein as Embodiment 92 is the compound or salt of Embodiment 88, wherein -. Provided herein as Embodiment 93 is the compound or salt of Embodiment 88, wherein -L2-R1. Provided herein as Embodiment 94 is the compound or salt of Embodiment 88, wherein -L2-R1is. Provided herein as Embodiment 95 is the compound or salt of Embodiment 88, wherein -L2-R1is. Provided herein as Embodiment 96 is the compound or salt of Embodiment 88, wherein -L2-R1is wEmbodiment 88, wherein -L2-R1. Provided herein as Embodiment 99 is the compound or salt of Embodiment 88, wherein -L2-R1is. Provided herein as Embodiment 100 is the compound or salt of Embodiment 88, wherein -L2-R1is. Provided herein as Embodiment 101 is the compound or salt of Embodiment 88, wherein -L2-R1is. Provided herein as Embodiment 102 is the compound or salt of Embodiment 88, wherein -L2-R1is. Provided herein as Embodiment 103 is the compound or salt ofEmbodiment 88, wherein -L2-R1. Provided herein as Embodiment 104 is the compound or salt of Embodiment 88, wherein -L2-R1is.

[0075] Provided herein as Embodiment 105 is the compound or salt of any of Embodiments 1-104,

[0076] Provided herein as Embodiment 106 is the compound or salt of any of Embodiments 1-104, wherein. Provided herein as Embodiment 107 is the compound or salt of Embodiment 106, wherein L1is. Provided herein as Embodiment 108 is the compound or salt of Embodiment 106, wherein L1is. Provided herein as Embodiment 109 is the compound or salt of Embodiment 106, wherein L1is. Provided herein as Embodiment 110 is the compound or salt of Embodiment 106, wherein L1is. Provided herein as Embodiment 111 is the compound or salt of Embodiment 106, wherein L1is.

[0077] Provided herein as Embodiment 112 is the compound or salt of any of Embodiments 1-111, wherein R4is hydrogen, hydroxyl, halogen, C1-4alkyl or C1-4alkoxy. Provided herein as Embodiment 113 is the compound or salt of Embodiment 112, wherein R4is halogen or C1-4alkyl. Provided herein as Embodiment 114 is the compound or salt of Embodiment 113, wherein R4is fluorine.

[0078] Provided herein as Embodiment 115 is the compound or salt of any of Embodiments 1-114, wherein R6a,R6band R6care each independently hydrogen, halogen, C1-4alkyl, C1-4alkoxy or C1-4haloalkyl. Provided herein as Embodiment 116 is the compound or salt of Embodiment 115, wherein R6a,R6band R6care each hydrogen. Provided herein as Embodiment 117 is the compound or salt of Embodiment 115, wherein R6band R6care each hydrogen and R6ais halogen (e.g., fluorine orchlorine). Provided herein as Embodiment 118 is the compound or salt of Embodiment 117, wherein R6band R6care each hydrogen and R6ais chlorine. Provided herein as Embodiment 119 is the compound or salt of Embodiment 115, wherein R6band R6care each hydrogen and R6ais C1-4alkyl (e.g., methyl or ethyl). Provided herein as Embodiment 120 is the compound or salt of Embodiment 119, wherein R6band R6care each hydrogen and R6ais methyl.

[0079] Provided herein as Embodiment 121 is the compound or salt of Embodiment 1, wherein the compound is: Table 1

[0080] Provided herein as Embodiment 122 is the compound or salt of Embodiment 1, wherein the compound i. Provided herein as Embodiment 123 is thecompound or salt of Embodiment 1, wherein the compound i. Provided herein as Embodiment 124 is the compound or salt of Embodiment 1, wherein the compound isProvided herein as Embodiment 125 is the compound or salt of Embodiment 1, wherein the compound is sherein as Embodiment 127 is the compound or salt of Embodiment 1, wherein the compound is. Provided herein as Embodiment 128 is the compound or salt of Embodiment 1, wherein the compound iProvided herein as Embodiment 129 is the compound or salt of Embodiment 1, wherein the compound is. Provided herein as Embodiment 130 is the compound or salt of Embodiment 1, wherein the compound i. Provided herein as Embodiment 131 is the compound or salt of Embodiment 1, wherein the compound is . Provided herein as Embodiment 132 is the compound or saltof Embodiment 1, wherein the compound iProvided herein as Embodiment 133 is the compound or salt of Embodiment 1, wherein the compound isEmbodiment 135 is the compound or salt of Embodiment 1, wherein the compound is. Provided herein as Embodiment 136 is the compound or salt of Embodiment 1, wherein the compound iProvided herein asEmbodiment 137 is the compound or salt of Embodiment 1, wherein the compound is oEmbodiment 139 is the compound or salt of Embodiment 1, wherein the compound is.

[0081] In another aspect of the disclosure, Embodiment 140 provides a compound from the Table below: Table 2

[0082] Provided herein as Embodiment 141 is the compound or salt of Embodiment 1, wherein the compound isProvided herein as Embodiment 142 is thecompound or salt of Embodiment 1, wherein the compoundProvided herein as Embodiment 143 is the compound or salt of Embodiment 1, wherein the compound isProvided herein as Embodiment 144 is the compound or salt of Embodiment 1, wherein the compoundProvided herein as Embodiment 145 is the compound or salt of Embodiment 1, wherein the compound isProvided herein as Embodiment 146 is thecompound or salt of Embodiment 1, wherein the compound i. Provided herein as Embodiment 147 is the compound or salt of Embodiment 1, wherein the cProvided herein as Embodiment 148 is the cProvided herein as Embodiment 149 is the compound or salt of Embodiment 1, wherein the compound isProvided herein as Embodiment 150 is the compound or salt of Embodiment 1, wherein the compound i

[0083] It is understood that selections of values of each variable are those that result in the formation of stable or chemically feasible compounds. Stereoisomers

[0084] The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropoisomers. Accordingly, the scope of the present disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.

[0085] If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of the structure. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated, unless otherwise noted. Forexample,representsSimilarly, for example, the chemicalname (4R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole represents (4R,5R)-4-methoxy-5- methyl-4,5,6,7-tetrahydro-2H-isoindole and (4R,5S)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H- isoindole. A bond drawn with a wavy line may be used to indicate that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.

[0086] The term “stereoisomer” or “stereoisomerically pure” compound refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of thecompound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.

[0087] This disclosure also encompasses the pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein. Further, this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGrawHill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). Tautomers

[0088] As known by those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes other tautomers of said structural formula.represents. Similarly, for example, the chemical name (4R,5R)-4- methoxy-5-methyl-4,5,6,7-tetrahydro-1H-indazole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7- tetrahydro-1H-indazole and (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-indazole. Accordingly, the scope of the present disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein. Isotopically-Labeled Compounds

[0089] In some cases, the scope of the present disclosure includes pharmaceutically acceptable isotopically-labeled compounds of the compounds disclosed herein, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusionin the compounds disclosed herein include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labelled compounds of the compounds disclosed herein, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium (2H or D) 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 advantageous in some circumstances. As such, the term “deuterated” refers to the substitution of one or more hydrogen atoms with one or more deuterium atoms on a particular structure or functional group. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. Isotopically- labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying GENERAL SYNTHETIC PROCEDURES and EXAMPLES sections using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. BIOLOGICAL ACTIVITY

[0090] In some cases, the compounds or salts disclosed herein (such as compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-150, or a pharmaceutically acceptable salt of any of the foregoing), have an IC50value of less than 5 µM, or less than 4 µM, or less than 3 µM, or less than 2 µM, or less than 1 µM, or less than 0.9 µM, or less than 0.7 µM, or less than 0.6 µM, or less than 0.5 µM, or less than 0.4 µM, or less than 0.3 µM, or less than 0.2 µM, or less than 0.1 µM, or less than 0.09 µM, or less than 0.08 µM, or less than 0.07 µM, or less than 0.06 µM, or less than 0.05 µM, or less than 0.04 µM, or less than 0.03 µM, or less than 0.02 µM, or less than 0.01 µM in the G12D Coupled Exchange assay, AsPC-1 p-ERK assay, AsPC-1 CTG assay or the SW620 CTG assay, described in “SECTION 3: Biochemical and Cellular Assays.” In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50value of between 0.001 to 0.200 µM. FORMULATION AND ROUTE OF ADMINISTRATION

[0091] While it may be possible to administer a compound disclosed herein alone in the uses described, the compound administered normally will be present as an active ingredient in a pharmaceutical composition. Thus, further provided herein is a pharmaceutical composition comprising a compound or salt disclosed herein (such as compounds of Formula (I), Formula (II),Formula (III), Formula (IV), Formula (V) or Formula (VI), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-150, or a pharmaceutically acceptable salt of any of the foregoing), in combination with one or more pharmaceutically acceptable excipients and, if desired, other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol.1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In some cases, the pharmaceutical composition described herein comprises a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0092] The compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended. The compounds and compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0093] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. In some cases, the pharmaceutical composition is made in the form of a dosage unit containing a particular amount of the active ingredient.

[0094] Thus, a further aspect of the disclosure is a pharmaceutical composition comprising one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Further provided herein is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, for use as a medicament.

[0095] Provided herein as Embodiment 151 is pharmaceutical composition comprising the compound or salt of any one of Embodiments 1 to 150, and a pharmaceutically acceptable excipient. METHODS OF USE

[0096] The compounds described herein (such as compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI), or compounds listed in Table 1, Table 2or compounds of Embodiments 1-150, or a pharmaceutically acceptable salt of any of the foregoing) can competitively bind to KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C or a mutated KRAS comprising one or more mutations selected from G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R and G12C. In some cases, the compounds described herein can act as inhibitors of KRAS G12D. In some cases, the compounds described herein can act as inhibitors of KRAS G12V. In some cases, the compounds described herein can act as inhibitors of KRAS G12A. In some cases, the compounds described herein can act as inhibitors of KRAS G12S. In some cases, the compounds described herein can act as inhibitors of KRAS G13D. In some cases, the compounds described herein can act as inhibitors of KRAS Q61H. In some cases, the compounds described herein can act as inhibitors of KRAS Q61R. In some cases, the compounds described herein can act as inhibitors of KRAS Q61L. In some cases, the compounds described herein can act as inhibitors of KRAS G12R. In some cases, the compounds described herein can act as inhibitors of KRAS G12C. Without intending to be bound by any particular theory, the compounds of the disclosure can, in some cases, inhibit KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C, leading to an improvement in conditions or symptoms mediated by a KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutation (e.g., reduction in tumor size).

[0097] Besides being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats may be treated with compounds provided herein.

[0098] In several embodiments, as disclosed elsewhere herein, a method of treating a patient is provided. In several embodiments, the method comprises administering a therapeutic amount of a compound or salt disclosed herein (such as compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-150, or a pharmaceutically acceptable salt of any of the foregoing) to a patient.

[0099] Another aspect of the disclosure provides methods of using the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present disclosure to treat disease conditions, including but not limited to conditions mediated by a KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutation.

[0100] Another aspect of the disclosure provides a compound or salt disclosed herein (such as compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-150, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein, for use in treating cancer.

[0101] Yet another aspect of the disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, in the preparation of a medicament for treating cancer.

[0102] A further aspect provided by the disclosure is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0103] In some cases, the cancer disclosed herein is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In some cases, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is colorectal cancer. In some cases, the cancer is pancreatic cancer.

[0104] Provided herein as Embodiment 152 is a method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of Embodiments 1 to 150, or the composition of Embodiment 151.

[0105] Provided herein as Embodiment 153 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS G12D mutant protein.

[0106] Provided herein as Embodiment 154 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS G12V mutant protein.

[0107] Provided herein as Embodiment 155 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS G12A mutant protein.

[0108] Provided herein as Embodiment 156 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS G12S mutant protein.

[0109] Provided herein as Embodiment 157 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS G13D mutant protein.

[0110] Provided herein as Embodiment 158 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS Q61H mutant protein.

[0111] Provided herein as Embodiment 159 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS Q61L mutant protein.

[0112] Provided herein as Embodiment 160 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS Q61R mutant protein.

[0113] Provided herein as Embodiment 161 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS G12R mutant protein.

[0114] Provided herein as Embodiment 162 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 150, or the composition of Embodiment 151, wherein one or more cells express KRAS G12C mutant protein.

[0115] Provided herein as Embodiment 163 is the method according to any one of embodiments 134-144, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferativeneoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0116] Provided herein as Embodiment 164 is the method according to Embodiment 163, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma. Provided herein as Embodiment 165 is the method according to Embodiment 164, wherein the cancer is non-small cell lung cancer. Provided herein as Embodiment 166 is the method according to Embodiment 164, wherein the cancer is colorectal cancer. Provided herein as Embodiment 167 is the method according to Embodiment 164, wherein the cancer is pancreatic cancer.

[0117] Provided herein as Embodiment 168 is the compound or salt of any one of Embodiments 1 to 150, or the pharmaceutical composition of Embodiment 151 for use as a medicament.

[0118] Provided herein as Embodiment 169 is the compound or salt of any one of Embodiments 1 to 150, or the pharmaceutical composition of Embodiment 151 for use in the treatment of cancer.

[0119] Provided herein as Embodiment 170 is the use of the compound or salt of any one of Embodiments 1 to 150, or the pharmaceutical composition of Embodiment 151, for the manufacture of a medicament for the treatment of cancer.

[0120] Provided herein as Embodiment 171 is the use of the compound or salt of any one of Embodiments 168 to 170, wherein the cancer is cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma, or any combination of the foregoing.

[0121] Provided herein as Embodiment 172 is the method according to Embodiment 171, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma. Provided herein as Embodiment 173 is the method according to Embodiment 172, wherein the cancer is non-small cell lung cancer. Provided herein as Embodiment 174 is the method according to Embodiment 172, wherein the cancer is colorectal cancer. Provided herein as Embodiment 175 is the method according to Embodiment 172, wherein the cancer is pancreatic cancer.Combination therapy

[0122] The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound or salt disclosed herein (such as compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-150, or a pharmaceutically acceptable salt of any of the foregoing). In one aspect, such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect. See, e.g., See, e.g., U.S. Patent No.10,519,146 B2, issued December 31, 2019; specifically, the sections from column 201 (line 37) to column 212 (line 46) and column 219 (line 64) to column 220 (line 39), which are herewith incorporated by reference.

[0123] The compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound in any of the methods described herein. In some cases, the second compound is wherein the second compound is an Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK4 / 6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF18A inhibitor, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PI3K inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agent. In some cases, the second compound is administered as a pharmaceutically acceptable salt. In some cases, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0124] Aurora Kinase A Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.

[0125] Exemplary Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2- fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2- methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H- pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8- dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2- chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13- yl]morpholine), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4- methylthiophen-2-yl)phthalazin-1-amine), MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4- (cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca- 2(7),3,5-trien-11-yl]-2-oxoethyl]acetamide), SNS-314 (1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2- d]pyrimidin-4-ylamino)ethyl]-1,3-thiazol-2-yl]urea), CYC116 (4-methyl-5-[2-(4-morpholin-4- ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607.

[0126] AKT Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0127] Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1- aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1- aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1- aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10-diethyl ester), ONC201 (11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ 751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3- chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0128] Arginase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an Arginase inhibitor. Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidargistat and CB 280.

[0129] CDK4 / 6 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an CDK4 / 6 inhibitor. The term “CDK 4 / 6” as used herein refers to cyclin dependent kinases (“CDK”) 4 and 6, which are members of the mammalian serine / threonine protein kinases. The term “CDK 4 / 6 inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of CDK 4 and / or 6.

[0130] Exemplary CDK 4 / 6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin- 7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfony1)- 4-piperidinyl]amino]).

[0131] ErbB Family Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an ErbB Family inhibitor. The term “ErbB family” as used herein refers to a member of a mammalian transmembrane protein tyrosine kinase familyincluding: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). The term “ErbB family inhibitor” as used herein refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one member of the ErbB family. The modulation or inhibition of one or more ErbB tyrosine kinase may occur through modulating or inhibiting kinase enzymatic activity of one or more ErbB family member or by blocking homodimerization or heterodimerization of ErbB family members.

[0132] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, e.g., an anti-EGFR antibody. Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab.

[0133] In another embodiment the ErbB family inhibitor is a HER2 inhibitor, e.g., an anti-HER2 antibody. Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.

[0134] In yet another embodiment the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti- HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).

[0135] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody.

[0136] In one embodiment, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7- [3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide)), PF 6274484 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4- (dimethylamino)but-2-enamide).

[0137] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3- (trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3- methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3- fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate), and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2- methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

[0138] ERK Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0139] Exemplary ERK inhibitors for use in the methods provided herein include, but are not limited to, ulixertinib, ravoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6-dimethyl- 2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4- one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7- one), ASTX029, LTT462, and JSI-1187.

[0140] FAK Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an FAK inhibitor.

[0141] Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4- yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5- yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), VS- 4718 (2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N- methylbenzamide), and APG-2449.

[0142] FGFR Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0143] Exemplary FGFR inhibitors for use in the methods provided herein include, but are not limited to, futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5- dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5- dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), debio 1347 ([5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl- methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453, and HGS1036.

[0144] Glutaminase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

[0145] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0146] IGF-1R Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0147] Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS-754807 ((2S)-1-[4- [(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2- methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2- [(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.

[0148] KIF18A Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0149] Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, the inhibitors disclosed in US 2020 / 0239441, WO 2020 / 132649, WO 2020 / 132651, and WO 2020 / 132653, each of which is herewith incorporated by reference in its entirety.

[0150] MCL-1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0151] Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro- 2,3,24,33-tetramethyl-22H-9,4,8-(metheniminomethyno)-14,20:26,23-dimetheno-10H,20H- pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 ((αR)-α-[[(5S)-5-[3-Chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4- pyrimidinyl]methoxy]benzenepropanoic acid), and ABBV-467.

[0152] MEK Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an MEK inhibitor.

[0153] Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3- dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4- iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide), GDC-0623 (5-(2- fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4- difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)- 8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4- difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N- (cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodophenylamino)benzamide), PD98059 (2-(2-amino-3-methoxyphenyl)-4H- chromen-4-one), PD334581 (N-[5-[3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-1,3,4- oxadiazol-2-yl]-4-morpholineethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554. .

[0154] mTOR Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0155] Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, vistusertib, dactolisib, Torin-1 (1-(4-(4-propionylpiperazin-1-yl)-3- (trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin- 2-yl)phenyl)urea), and VS-5584 (SB2343, (5-(8-methyl-2-rnorpholin-4-yl-9-propan-2-ylpurin-6- yl)pyrimidin-2-amine).

[0156] PD-1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0157] Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR- 042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and the anti-PD-1 antibody as described in US 10,640,504 B2 (the “Anti-PD-1 Antibody A,” column 66, line 56 to column 67, line 24 and column 67, lines 54-57), which is incorporated herein by reference.

[0158] PD-L1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.

[0159] Exemplary PD-L1 inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR-1316, MSB2311, MDX- 1105, KN035, IMC-001, HLX20, FAZ053, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167.

[0160] PI3K Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0161] Exemplary PI3K inhibitors for use in the methods provided herein include, but are not limited to, idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolisib, tenalisib, serabelisib, acalisib, CUDC-907 (N-hydroxy-2- [[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl- methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4- yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2- amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2- phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 ((2S)-2-[[(2S)-3- carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2- yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]- 3-hydroxypropanoate), XL147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4- methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3- thiazolidine-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H- purin-6-amine).

[0162] Raf Kinase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a Raf Kinase inhibitor. The term “RAF kinase” as used herein refers to a member of a mammalian serine / threonine kinases composed of three isoforms (C-Raf, B-Raf and A- Raf) and includes homodimers of each isoform as well as heterodimers between isoforms, e.g., C- Raf / B-Raf heterodimers. The term “Raf kinase inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Raf family kinases or is capable of disrupting Raf homodimer or heterodimer formation to inhibit activity.

[0163] Exemplary Raf kinase inhibitors include, but is not limited to, encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a- dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1- sulfonamide), Raf-709 (N-(2-methyl-5,-morpholino-6’-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'- bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3- dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6- yl)phenyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3- (trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP- 32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), CCT196969 (1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3- oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea), and RO5126766 (N-[3-fluoro-4-[[4- methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl- sulfamide).

[0164] SHP2 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.

[0165] Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6- (2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TNO155, (3S,4S)-8-[6-amino-5-(2-amino-3- chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and vociprotafib (RMC-4630 - Revolution Medicine).

[0166] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3- dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2- oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3- hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7), and 6- [(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5- methyl-2-pyrazinemethanol (CAS 2172652-48-9).

[0167] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4- methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5- a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3- dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]- 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2- oxa-8-azaspiro[4.5]dec-8-yl]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2), and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0168] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3- dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decan-1-amine (CAS 2238840- 62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2- pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]- 8-azaspiro[4.5]decan-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2-[(2,3- dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2- [(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]- 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2- pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8- yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-amino-3-chloro- 4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2- pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)- 5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4- amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS 2238840-72-5), 5-[(2-amino-3-chloro-4- pyridinyl)thio]-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-3- pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8- yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 3-[(3S,4S)-4-amino- 3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8), and 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3- methyl-2-oxa-8- azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyridin-3-ol.

[0169] In one embodiment, the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1- amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5). In one embodiment, the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in US 10,590,090 B2, US 2020 / 017517 A1, US 2020 / 017511 A1, or WO 2019 / 075265 A1.

[0170] SOS1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a SOS1 inhibitor.

[0171] Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6- [(3S)-oxolan-3-yl]oxyquinazolin-4-amine), and BI 1701963.

[0172] Src Kinase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a Src Kinase inhibitor. The term “Src kinase” as used herein refers to a member of a mammalian nonreceptor tyrosine kinase family including: Src, Yes, Fyn, and Fgr (SrcA subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily), and Frk subfamily. The term “Src kinase inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Src kinases.

[0173] Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7- tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4- methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide).

[0174] Chemotherapeutic Agents. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agents.

[0175] Exemplary chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folinate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate. GENERAL SYNTHETIC PROCEDURES

[0176] The compounds provided herein can be synthesized according to the procedures described in this and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. It should be appreciated that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner.

[0177] Generally, the compounds of Formula (I) can be synthesized according to the following schemes. Variables used in the following schemes are the variables as defined for Formula (I), unless otherwise noted. All starting materials are either commercially available, for example, from Sigma- Aldrich, Combi-Blocks, Strem, Oakwood, TCI America, Fisher, Arcos, Alfa Aesar or known in the art and may be synthesized by employing known procedures using ordinary skill. Starting materials may also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such assolvent, reaction temperature, and reagents, for the Schemes discussed in this section, may be found in the examples provided herein.

[0178] In general, the compounds of Formula (I) can be synthesized according to Schemes I-V as shown below:Scheme I

[0179] Compounds of Formula (I) and I-1 can be prepared according to Scheme I. In step A, compound (I-2) is treated m-CPBA to give compound (I-3). In step B, compound (I-3) undergoes SNAr reaction with R1-L2-H in the presence of a base such as DBU, NaH, DIEA or triethyl amine in a solvent such as CH3CN, THF, DMF or DMSO. This is followed by step C wherein the product from Step B is treated with an acid C such as HCl or TFA in a solvent such as 1,4-dioxane or DCM to give compounds of Formula (I-1).Scheme II

[0180] Compounds of Formula (I) and (II-1) can be prepared according to Scheme II. In step A, compound (II-2) undergoes SNAr reaction with R1-L2H in the presence of a base such as NaH, DBU, DIEA or TEA in a solvent such as 1,4-dioxane, THF or 2-MeTHF to give compound (II-3). In step B, compound (II-3) is coupled with an organometallic reagent or a boronic acid (ester) attached to an aryl or heteroaryl ring bearing a terminal ester (II-4) to give compound (II-5). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-MeTHF, THF, dioxane, 1,2-DME and water, and a catalyst such as cataCXium A Pd G3, with or without base such as potassium phosphate or sodium carbonate. In step C, compound (II-5) undergoes hydrolysis with a reagent such as LiOH in solvents such as THF, 2-MeTHF and water to give compound (II-6). In step D, compound (II-6) is coupled with an optionally substituted cyclic amine (II-7) using a coupling agent such as HATU or T3P in the presence of a base such as DIEA or TEA in a solvent such as DCM, DMF, THF or 2- MeTHF to give compound (II-8). In step E, compound (II-8) is treated with an acid such as HCl or TFA in a solvent such as 1,4-dioxane or DCM to give compound (II-9). In step F, compound (II-9) is cyclized under conditions such as BrOP or PyBOP in the presence of a base such as DIEA in a solvent such as CH3CN and DMSO to give compounds of Formula (II-1).Scheme III

[0181] Compounds of Formula (I) and (III-1) can be prepared according to Scheme III, wherein m and n are independently 0, 1 or 2. In step A, compound (III-2) undergoes SNAr reaction with with R1- L2H in the presence of a base such as NaH, DBU, DIEA or TEA in a solvent such as 1,4-dioxane, THF or 2-MeTHF to give compound (III-3). In step B, compound (III-3) is coupled with an organometallic reagent or a boronic acid (ester) attached to an aryl or heteroaryl ring and an optionally substituted cyclic amine (III-4) to give compound (III-5). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-MeTHF, THF, dioxane, 1,2-DME and water, and a catalyst such as cataCXium A Pd G3, with or without base such as potassium phosphate or sodium carbonate. In step C, compound (III-5) is treated with an acid such as HCl or TFA in a solvent such as 1,4-dioxane or DCM to give compound (III-6). In step D, compound (III-6) is cyclized under conditions such as BrOP or PyBOP in the presence of a base such as DIEA in a solvent such as CH3CN and DMSO to give compounds of Formula (III-1).Scheme IV

[0182] Compounds of Formula (I) and (IV-1) can be prepared according to Scheme IV, wherein m and n are independently 0, 1 or 2. In step A, compound (IV-2) undergoes SNAr reaction with an optionally substituted cyclic amine or aliphatic amine (IV-3) bearing an alcohol in a solvent such as acetonitrile and in the presence of a base such as DIEA to give compound (IV-4). In step B, compound (IV-4) undergoes SNAr reaction with a nucleophile having the formula R1-L2-H in the presence of a base such as NaH, DBU, DIEA or TEA in a solvent such as 1,4-dioxane, THF or 2- MeTHF to give compound (IV-5). In step C, compound (IV-5) is coupled with an organometallic reagent or a boronic acid (ester) attached to an aryl or hetereoaryl bearing a terminal TBS protected alcohol (IV-6) to give compound (IV-7). This coupling reaction proceeds in a solvent or mixture of solvents such as THF, 2-MeTHF, 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (IV-7) is reacted with CDI, followed by treatment with a desilyating reagent such as TBAF in solvent such as THF to give compound (IV-8). In step E, compound (IV-8) is treated with acid such as HCl or TFA in solvent such as 1,4-dioxane or DCM to give compounds of Formula (IV-1).Scheme V

[0183] Compounds of Formula (I) and (V-1) can also be prepared according to Scheme V, wherein k, i, m and n are independently 0, 1 or 2. In step A, compound (V-2) undergoes SNAr reaction with an optionally substituted cyclic amine or aliphatic amine (V-3) bearing an terminal alkene in a solvent such as acetonitrile or THF and in the presence of a base such as DIEA to give compound (V-4). In step B, compound (V-4) undergoes SNAr reaction with a nucleophile having the formula R1-L2-H in the presence of a base such as NaH, DBU, DIEA or TEA in a solvent such as 1,4-dioxane, THF or 2- MeTHF to give compound (V-5). In step C, compound (V-5) is coupled with an organometallic reagent or a boronic acid (ester) attached to a aryl or hetereoaryl bearing a terminal alkene (V-6) to give compound (V-7). This coupling reaction proceeds in a solvent or mixture of solvents such as THF, 2-MeTHF, 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (V-7) undergoes ring closing metathesis (RCM) using a catalyst such as Grubbs G2 in a solvent such as DCM or 1,2-DCE to give compound (V-8). In step E, compound (V-8) undergoes hydrogenation using a catalyst such as palladium oncharcoal in a solvent such as ethanol under an atmosphere of hydrogen gas to give compound (V- 9). In step F, compound (V-9) is treated with acid such as HCl or TFA in a solvent such as 1,4- dioxane or DCM to give compounds of Formula (V-1).

[0184] As can be appreciated by the skilled artisan, the above synthetic scheme and representative examples are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds.

[0185] Purification methods for the compounds described herein are known in the art and include, for example, crystallization, chromatography (for example, liquid, gas phase, and supercritical fluid), filtration, sublimation, lyophilization, extraction, distillation, trituration, and reversed phase HPLC.

[0186] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. One skilled in the art will appreciate readily that the present disclosure is well-adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends, and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art. EXAMPLES

[0187] This section provides specific examples of compounds of Formula (I) and methods of making the same. List of Abbreviations

[0188] Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific examples provided herein.

[0189] Chromatography: Unless otherwise indicated, product-containing residues were purified by passing the material or concentrate through (a) Biotage High Capacity D column or (b) ISCO RediSep Gold High Performance column or (c) ISCO RediSep Rf HP C18 Gold column or (d) Biotage Isolute SCX-2 column; and eluting the product off the column with a solvent gradient as indicated.

[0190] Preparative HPLC Method: Where indicated, the compounds described herein were purified via reversed phase HPLC using Waters FractionLynx or Gilson semi-preparative HPLC-MS system using one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run through the instrument included: eluting at 45 mL / min with a linear gradient of 10% (v / v) to 100% MeCN(0.1% v / v formic acid) in water (0.1% formic acid) over 10 minutes. Conditions can be varied to achieve improved separations.

[0191] Proton NMR Spectra: Unless otherwise indicated, all1H NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz. All observed protons are reported as parts-per- million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as reference. Some1H signals may be missing due to exchange with D from MeOD, or due to signal suppression.

[0192] Mass Spectra (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or exemplary compounds are reported as mass / charge (m / z), having an [M+H]+molecular ion. The molecular ion reported was obtained by electrospray detection method (commonly referred to as an ESI MS) utilizing a Waters Acquity UPLC / MS system. Compounds having an isotopic atom, such as bromine and the like, are generally reported according to the detected isotopic pattern, as appreciated by those skilled in the art.

[0193] Fluorine NMR Spectra: Unless otherwise indicated, all19F NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz. SECTION 1: Synthesis of Intermediates

[0194] Provided in this section is the synthesis of various intermediates used to prepare compounds of Formula (I). All starting materials are either commercially available from Sigma-Aldrich, Combi- Blocks, Enamine, PharmaCore, PharmaBlock, Synnovator, Chemscene, AA blocks, Oakwood or Ambeed, or similar vendors, unless otherwise noted, or known in the art and may be synthesized by employing known procedures using ordinary skill.

[0195] Intermediate A: 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.

[0196] Step 1.3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanal. To a 40 mL vial was charged with 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (3.00 g, 6.80 mmol, Lab Network), sodium bicarbonate (1.43 g, 17.0 mmol), TBACl (1.95 g, 6.82 mmol), and N,N-dimethylformamide (14 mL). The solution was degassed by nitrogen bubbling for 10 min. Then palladium(II) acetate (77 mg, 0.34 mmol) and allyl alcohol (0.7 mL, 10 mmol) were added at 50 °C. The reaction mixture was stirred at 50 °C for 18 h. After cooling to room temperature, the reaction was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–50% 3:1 EtOAc / EtOH in heptane, to provide 3-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)propanal (2.12 g, 5.70 mmol, 84% yield). m / z (ESI): 371.0 (M+H)+.

[0197] Step 2.3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1- ol. To a 100-mL round-bottom flask was added 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)propanal (1.06 g, 2.86 mmol) in tetrahydrofuran (5 mL) / methanol (5 mL). The reaction mixture was cooled to 0 °C and sodium borohydride (0.11 g, 2.9 mmol) was slowly added in portion. The reaction mixture was stirred at 0 °C for 30 minutes, then was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 3-(4-bromo-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)propan-1-ol (1.03 g, 2.76 mmol, 97% yield). m / z (ESI): 289.0 (M- THP+H)+.

[0198] Step 3.4-Bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole. To a stirred solution of 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)propan-1-ol (1.03 g, 2.76 mmol) and Hünig’s base (0.53 mL, 3.0 mmol) in dichloromethane (10 mL) in a 40-mL vial was added tert-butyldimethylsilyl chloride (0.46 g, 3.03 mmol) and 4-(dimethylamino)pyridine (34 mg, 0.28 mmol) at 0 °C. After stirring at 0 °C for 2 h, the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0– 30% 3:1 EtOAc / EtOH in heptane, to provide 4-bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.12 g, 2.3 mmol, 83% yield). m / z (ESI): 487.1 (M+H)+.

[0199] Step 4.5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. To a solution of 4-bromo-5-(3- ((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.40 g, 7.00 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.85 g, 34.8 mmol) in 1,4- dioxane (80 mL) and water (10 mL) was added Pd(dppf)Cl2(0.51 g, 0.70 mmol) and Cs2CO3(6.81 g, 20.9 mmol) under N2. The reaction mixture was heated at 120 ℃ for 5 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 10–100% EtOAc in petroleum ether, to give 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran- 2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (3.30 g, 6.20 mmol, 88% yield). m / z (ESI): 535.3 / 537.2 (M+H)+.

[0200] Intermediate B: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine.

[0201] Step 1.4-(tert-Butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 198 mmol, Lab Network) in tetrahydrofuran (1.5 L) was added t-BuOK (1 M in THF, 190 mL, 190 mmol) dropwise at -60 ℃ and the reaction mixture was stirred at -60 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was triturated with petroleum ether at room temperature for 1 h. The suspension was filtered, and the cake was concentrated under reduced pressure to give 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (30.0 g, 103 mmol, 54% yield).1H NMR (400 MHz, CDCl3) δ ppm 9.08 (s, 1 H), 1.74 (s, 9 H).

[0202] Step 2.4-(tert-Butoxy)-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-(tert-butoxy)-2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 172 mmol) and 4Å MS (10 g) in 1,4-dioxane (1 L) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (30.2 g, 190 mmol) and DIPEA (60.0 g, 431 mmol) in sequence. Then the mixture was stirred at 80 °C for 5 h. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE at room temperature for 1 h. The suspension was filtered, and the cake was concentrated under reduced pressure to give 4-(tert- butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine (40 g, 97 mmol, 56% yield). m / z (ESI): 413.2 / 415.2 (M+H)+.

[0203] Intermediate C: rac-tert-Butyl (3R,5S)-3-((4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)butoxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate.

[0204] Step 1.4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal. To a solution of 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (25.0 g, 56.6 mmol, Lab Network) in N,N-dimethylformamide (300 mL) was added NaHCO3(11.9 g, 142 mmol) and TBACl (14.8 g, 56.6 mmol) under N2. Then the mixture was stirred at room temperature for 15 min, then but-3-en-1-ol (8.17 g, 113 mmol) and Pd(OAc)2(1.27 g, 5.66 mmol) was added under N2. The mixture was stirred at 80 °C for 12 h. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% ethyl acetate in petroleum ether, to give 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal (15 g, 39 mmol, 70% yield). m / z (ESI): 385.1 / 387.1 (M+H)+.

[0205] Step 2.4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butan-1- ol. To a solution of 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal (15 g, 39 mmol) in EtOH (300 mL) was added NaBH4 (4.41 g, 117 mmol) portionwise at 0 °C. The mixture was stirred at room temperature for 2 h, then was quenched by addition of saturated NH4Cl and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% ethyl acetate in petroleum ether, to give 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butan-1-ol (11 g, 28 mmol, 73% yield). m / z (ESI): 387.0 / 389.0 (M+H)+.

[0206] Step 3.4-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)butan-1-ol. A vial was charged with tris(4-methoxyphenyl)phosphine (1.45 g, 4.13 mmol, Ambeed, Inc.), palladium acetate (0.46 g, 2.06 mmol, Combi-Blocks Inc.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.93 g, 15.48 mmol, Ambeed, Inc.), cesium carbonate (6.72 g, 20.63 mmol), 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-5-yl)butan-1-ol (4.00 g, 10.32 mmol) and ethyl acetate (10 mL), then sparged with nitrogen and heated to 80 °C for 12 h. The reaction mixture was cooled to room temperature and the crude material was filtered through a plug of celite and concentrated. It was purified by chromatography on silica gel, eluting with a gradient of 0-20% (3:1 EtOAc / EtOH with 2% TEA) / heptane, to provide provide 4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)butan-1-ol (3.05 g, 7.03 mmol, 68% yield). m / z (ESI): 435.1 (M+H)+.

[0207] Step 4.4-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)butyl methanesulfonate. A 40-mL vial was charged with 4-(6- chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)butan-1-ol (1.16 g, 2.67 mmol), dichloromethane (15 mL), and triethylamine (0.75 mL, 5.34 mmol). Methanesulfonyl chloride (0.31 mL, 4.0 mmol) was then added dropwise, and the reaction mixture was stirred at room temperature for 3 h. The crude mixture was purified by flash column chromatography on silica gel, eluting with a gradient of 0–85% ethyl acetate in heptane, to give 4-(6- chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)butyl methanesulfonate (0.80 g, 1.56 mmol, 58% yield). m / z (ESI): 513.2 (M+H)+.

[0208] Step 5. rac-1-(tert-Butyl) 3-methyl (3R,5S)-5-(methoxymethoxy)piperidine-1,3- dicarboxylate. A vial was charged with rac-1-(tert-butyl) 3-methyl (3R,5S)-5-hydroxypiperidine-1,3- dicarboxylate (1.00 g, 3.9 mmol, eNovation), N-ethyl-N-isopropylpropan-2-amine (2.0 mL, 11.6 mmol) and dichloromethane (13 mL). The reaction mixture was cooled to 0oC with an ice-water bath. Bromo(methoxy)methane (0.63 mL, 7.7 mmol) was added slowly, and the reaction mixture was stirred at 0oC for 5 h. The reaction was carefully quenched with saturated aqueous sodium bicarbonate then the organic phase was separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide rac-1-(tert-butyl) 3-methyl (3R,5S)-5- (methoxymethoxy)piperidine-1,3-dicarboxylate (1.00 g, 3.30 mmol, 100% yield). m / z (ESI): 326.2 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 4.68 (s, 2 H) 4.02 - 4.44 (m, 2 H) 3.70 (s, 3 H) 3.48 - 3.61 (m, 1 H) 3.38 (s, 3 H) 2.30 - 2.82 (m, 4 H) 1.50 - 1.63 (m, 1 H) 1.46 (s, 9 H).

[0209] Step 6. rac-tert-Butyl (3R,5S)-3-(hydroxymethyl)-5-(methoxymethoxy)piperidine-1- carboxylate. A vial was charged with rac-1-(tert-butyl) 3-methyl (3R,5S)-5- (methoxymethoxy)piperidine-1,3-dicarboxylate (1.00 g, 3.30 mmol) and tetrahydrofuran (11 mL), then cooled to 0oC. Lithium borohydride (2.0 M in THF, 3.6 mL, 7.2 mmol) was added and the reaction mixture was stirred and warmed to room temperature for 30 minutes. The reaction mixturewas carefully quenched with saturated aqueous ammonium chloride. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to provide rac-tert-butyl (3R,5S)-3-(hydroxymethyl)-5- (methoxymethoxy)piperidine-1-carboxylate (0.92 g, 3.30 mmol, 100% yield). m / z (ESI): 298.2 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 4.70 (d, J=3.76 Hz, 2 H) 3.86 - 4.40 (m, 2 H) 3.50 - 3.68 (m, 3 H) 3.40 (s, 3 H) 2.49 - 3.07 (m, 2 H) 2.06 - 2.17 (m, 1 H) 1.75 - 1.88 (m, 1 H) 1.48 (s, 9 H) 1.25 - 1.37 (m, 1 H).

[0210] Step 7. rac-tert-Butyl (3R,5S)-3-((4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)butoxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate. A vial was charged with rac-tert-butyl (3R,5S)-3- (hydroxymethyl)-5-(methoxymethoxy)piperidine-1-carboxylate (2.15 g, 7.80 mmol), sodium hydride (60 wt% in mineral oil, 0.31 g, 7.80 mmol) and tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 15 min, then a solution of 4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)butyl methanesulfonate (2.00 g, 3.90 mmol) in THF (5 mL) was added. The reaction mixture was heated to 50oC for 3 h. After cooling to room temperature, the reaction mixture was carefully quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0– 50% (3:1 EtOAc / EtOH with 2% TEA) / heptane, to provide rac-tert-butyl (3R,5S)-3-((4-(6-chloro-1- (tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)butoxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (2.30 g, 3.30 mmol, 85% yield). m / z (ESI): 692.2 (M+H)+.

[0211] Intermediate D: 2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)ethan-1-ol.

[0212] 2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethan-1-ol. A vial was charged with (E)-1-ethoxyethene-2-boronic acid pinacol ester (2.02 g, 10.2 mmol, Aurum Pharmatech), 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3.00 g, 6.80 mmol, LabNetwork), tripotassium phosphate (5.05 g, 23.8 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium dichloride (0.50 g, 0.68 mmol), water (4 mL) and 1,4-dioxane (19 mL). The reaction mixture was heated to 100 °C for 1.5 h. After cooling to room temperature, the crude material was diluted with EtOAc and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc, and the combined organics were dried (Na2SO4) and concentrated. This crude product was then diluted with 1,4-dioxane (18 mL) and water (1 mL) and to it was added trifluoroacetic acid (7.8 mL, 102 mmol) dropwise. The reaction mixture was stirred at 40 °C for 6 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by column chromatography on silica gel, eluting with 0–100% (3:1 EtOAc:EtOH + 2% triethylamine) in heptane, to provide 2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)acetaldehyde (2.40 g, 6.71 mmol, 99% yield), which was treated with triethyl amine and filtered to neutralize the remaining TFA. m / z (ESI): 357.0 (M+H)+.

[0213] To a 250 mL round-bottom flask was charged with the above aldehyde (2.40 g, 6.71 mmol) and ethanol (70 mL). The reaction mixture was cooled to 0 °C and sodium borohydride (0.53 g, 14 mmol) was added portionwise. The solution was allowed to warm to room temperature with stirring for 30 min. The reaction mixture was then carefully quenched by the addition of methanol, water, and saturated aqueous ammonium chloride. The resulting solution was extracted with EtOAc, and the combined organics were dried (Na2SO4) and concentrated. The residue was purified by reversed phase chromatography using a 50 g C18 column, eluting with 0–100% acetonitrile with 0.1% TFA in water with 0.1% TFA, to give 2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethan-1- ol (0.20 g, 0.56 mmol, 8% yield). m / z (ESI): 359.0 (M+H)+.

[0214] Intermediate E: rac-tert-Butyl (3R,5S)-3-(hydroxymethyl)-5- (methoxymethoxy)piperidine-1-carboxylate.

[0215] Step 1. rac-1-(tert-Butyl) 3-methyl (3R,5S)-5-(methoxymethoxy)piperidine-1,3- dicarboxylate. A vial was charged with rac-1-(tert-butyl) 3-methyl (3R,5S)-5-hydroxypiperidine-1,3- dicarboxylate (1.00 g, 3.90 mmol, eNovation), N-ethyl-N-isopropylpropan-2-amine (2.0 mL, 11.6 mmol) and dichloromethane (13 mL). The reaction mixture was cooled to 0oC. Bromo(methoxy)methane (0.63 mL, 7.70 mmol) was added slowly, and the reaction mixture was stirred at 0oC for 5 h. The reaction was carefully quenched with saturated aqueous sodium bicarbonate then the organic phase was separated, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide rac-1-(tert-butyl) 3-methyl (3R,5S)-5- (methoxymethoxy)piperidine-1,3-dicarboxylate (1.00 g, 3.30 mmol, 100% yield). m / z (ESI): 326.2(M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 4.68 (s, 2 H) 4.02 - 4.44 (m, 2 H) 3.70 (s, 3 H) 3.48 - 3.61 (m, 1 H) 3.38 (s, 3 H) 2.30 - 2.82 (m, 4 H) 1.50 - 1.63 (m, 1 H) 1.46 (s, 9 H).

[0216] Step 2. rac-tert-Butyl (3R,5S)-3-(hydroxymethyl)-5-(methoxymethoxy)piperidine-1- carboxylate. A vial was charged with rac-1-(tert-butyl) 3-methyl (3R,5S)-5- (methoxymethoxy)piperidine-1,3-dicarboxylate (1.00 g, 3.30 mmol) and tetrahydrofuran (11 mL), then cooled to 0oC. Lithium borohydride (2.0 M in THF, 3.6 mL, 7.2 mmol) was added and the reaction mixture was allowed to warm to room temperature with stirring for 30 min. The reaction mixture was carefully quenched with saturated aqueous ammonium chloride. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide rac-tert-butyl (3R,5S)-3-(hydroxymethyl)-5-(methoxymethoxy)piperidine-1-carboxylate (0.92 g, 3.30 mmol, 100% yield). m / z (ESI): 298.2 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 4.70 (d, J=3.76 Hz, 2 H) 3.86 - 4.40 (m, 2 H) 3.50 - 3.68 (m, 3 H) 3.40 (s, 3 H) 2.49 - 3.07 (m, 2 H) 2.06 - 2.17 (m, 1 H) 1.75 - 1.88 (m, 1 H) 1.48 (s, 9 H) 1.25 - 1.37 (m, 1 H).

[0217] Intermediate F: 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.

[0218] Step 1.2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 198 mmol) in tetrahydrofuran (750 mL) cooled to -60oC was added 2,2,2-trifluoroethan-1-ol (18.82 g, 188 mmol), followed by t- BuOK (1 M in THF, 188 mL, 188 mmol) dropwise. The mixture was stirred at -60 °C for 2 h. The reaction mixture was quenched by addition of water (1 L) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was washed with petroleum ether (50 mL), then filtered. The filter cake was concentrated under reduced pressure to give 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50 g, 158 mmol, 84% yield).1H NMR (400 MHz, CDCl3) δ ppm 9.18 (s, 1 H), 5.06 – 5.12 (m, 2 H).

[0219] Step 2.7-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 (28 g, 89 mmol) in 1,4-dioxane (280 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (16.93 g, 106 mmol) and DIPEA (46 mL, 266 mmol) in sequence. Then the mixture was stirred at 80 °C for 10 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water andextracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–100% EtOAc in petroleum ether, to provide 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 (28 g, 63.8 mmol, 72% yield). m / z (ESI): 439.1 / 441.1 (M+H)+.

[0220] Intermediate G: 5-(3-((tert-Butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.

[0221] The title compound was prepared in an analogous fashion to Intermediate A using tert- butyl(chloro)diphenylsilane (CAS#: 58479-61-1, Aldrich) and imidazole in DCM and THF in Step 3.1H NMR (400 MHz, CDCl3) δ ppm 8.33 (s, 1 H), 7.71 - 7.74 (m, 5 H), 7.38 - 7.42 (m, 6 H), 5.66 (dd, J =8.8, 2.4 Hz, 1 H), 3.99 - 4.02 (m, 1 H), 3.74 - 3.83 (m, 3 H), 3.19 - 3.23 (m, 2 H), 2.48 - 2.56 (m, 1 H), 2.14 - 2.17 (m, 1 H), 2.03-2.05 (m, 1 H), 1.86 - 1.90 (m, 2 H), 1.73 - 1.76 (m, 2 H), 1.68 (s, 1 H), 1.34 (s, 12 H), 1.09 (s, 9 H). m / z (ESI): 659.3 / 660.3 / 661.3 (M+H)+.

[0222] Intermediate H: tert-Butyl (3S,5R)-3-(methoxymethoxy)-5 (((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate.

[0223] Step 1.1-(tert-Butyl) 3-methyl (3R,5S)-5-(methoxymethoxy)piperidine-1,3- dicarboxylate. A round-bottom flask was charged with 1-(tert-butyl) 3-methyl (3R,5S)-5- hydroxypiperidine-1,3-dicarboxylate (3.00 g, 11.6 mmol, PharmaBlock), N-ethyl-N-isopropylpropan- 2-amine (6.1 mL, 34.7 mmol) and dichloromethane (40 mL). Bromo(methoxy)methane (1.9 mL, 23 mmol) was added slowly, and the reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 5 h. The reaction was carefully quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with DCM and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material purified bycolumn chromatography on silica gel, eluting with 0–100% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to provide 1-(tert-butyl) 3-methyl (3R,5S)-5-(methoxymethoxy)piperidine-1,3- dicarboxylate (2.67 g, 8.80 mmol, 76% yield). m / z (ESI): 326.2 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 4.69 (s, 2 H) 3.99 - 4.44 (m, 2 H) 3.71 (s, 3 H) 3.46 - 3.62 (m, 1 H) 3.38 (s, 3 H) 2.67 - 2.84 (m, 1 H) 2.35 - 2.61 (m, 3 H) 1.51 - 1.64 (m, 1 H) 1.46 - 1.48 (m, 9 H).

[0224] Step 2. tert-Butyl (3R,5S)-3-(hydroxymethyl)-5-(methoxymethoxy)piperidine-1- carboxylate. A vial was charged with 1-(tert-butyl) 3-methyl (3R,5S)-5- (methoxymethoxy)piperidine-1,3-dicarboxylate (1.5 g, 4.9 mmol) and tetrahydrofuran (15 mL), then cooled to 0 °C. Lithium borohydride (2.0 M in THF, 5.4 mL, 10.8 mmol) was added dropwise and then the reaction mixture was allowed to slowly warm to room temperature with stirring for 30 min. The reaction mixture was carefully quenched with half-saturated aqueous ammonium chloride and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated aqueous bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl (3R,5S)-3-(hydroxymethyl)-5-(methoxymethoxy)piperidine-1- carboxylate (1.2 g, 4.4 mmol, 88% yield). m / z (ESI): 298.2 (M+Na)+.1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 - 4.66 (m, 3 H) 4.04 - 4.17 (m, 1 H) 3.91 - 4.01 (m, 1 H) 3.37 - 3.46 (m, 1 H) 3.21 - 3.34 (m, 6 H) 2.28 - 2.46 (m, 2 H) 1.99 (s, 1 H) 1.54 (br s, 1 H) 1.40 (s, 9 H).

[0225] Step 3. tert-Butyl (3S,5R)-3-(methoxymethoxy)-5- (((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate. A vial was charged with tert-butyl (3R,5S)-3-(hydroxymethyl)-5-(methoxymethoxy)piperidine-1-carboxylate (1.2 g, 4.4 mmol), triethylamine (0.75 mL, 5.2 mmol) and dichloromethane (15 mL). The contents were cooled to 0 °C and methanesulfonyl chloride (0.37 mL, 4.8 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature with stirring for 15 minutes, was then diluted with water, and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl (3S,5R)-3- (methoxymethoxy)-5-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (1.47 g, 4.16 mmol, 95% yield). m / z (ESI): 376.2 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 4.65 - 4.73 (m, 2 H) 4.13 - 4.21 (m, 2 H) 3.81 - 4.05 (m, 2 H) 3.55 - 3.67 (m, 1 H) 3.39 (s, 3 H) 3.05 (s, 3 H) 2.83 - 3.00 (m, 2 H) 1.97 - 2.16 (m, 2 H) 1.48 (s, 10 H).

[0226] Intermediate I: Methyl 5-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate.

[0227] Step 1.4-Bromo-6-chloro-1-(triisopropylsilyl)-1H-indazole. To a solution of 4-bromo-6- chloro-1H-indazole (50 g, 216 mmol) in tetrahydrofuran (500 mL) was added LiHMDS (1 M in THF, 259 mL, 259 mmol) dropwise under nitrogen at -78 °C. The reaction mixture was stirred for 1 h. Then TIPSCl (55 mL, 259 mmol) was added dropwise at -78 °C under N2. The reaction mixture was stirred at -78 °C for 0.5 h, then at room temperature for 3.5 h. The reaction mixture was poured into water at 0 °C and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–100% EtOAc in petroleum ether, to give 4-bromo-6-chloro-1- (triisopropylsilyl)-1H-indazole (50 g, 60% yield).1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (s, 1 H), 7.48 (s, 1 H), 7.32 (s, 1 H), 1.71 – 1.80 (m, 3 H), 1.13 – 1.17 (d, J=1.6 Hz, 6 H).

[0228] Step 2.4-Bromo-6-chloro-1H-indazole-5-carbaldehyde. To a solution of 4-bromo-6- chloro-1-(triisopropylsilyl)-1H-indazole (50 g, 129 mmol) in tetrahydrofuran (500 mL) was added LDA (2 M in THF, 97 mL, 194 mmol) dropwise at -78 °C. The reaction mixture was stirred at -78 °C under N2for 1 h. Then the solution of DMF (50 mL, 645 mmol) in tetrahydrofuran (50 mL) was added dropwise to the above mixture under N2. The reaction mixture was stirred at -78 °C for 0.5 h, then at 0 °C for 2.5 h. The reaction mixture was quenched by addition of saturated NH4Cl at 0 °C, then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with a mixed solvent (petroleum ether / EtOAc = 15:1) at room temperature for 1 h. The suspension was filtered, and the filter cake was washed with 30:1 petroleum ether / EtOAc and concentrated under reduced pressure to give 4-bromo- 6-chloro-1H-indazole-5-carbaldehyde (30 g, 116 mmol, 90% yield).1H NMR (400 MHz, DMSO-d6) δ ppm 13.87 (s, 1 H), 10.36 (s, 1 H), 8.32 (s, 1 H), 7.82 (s, 1 H).

[0229] Step 3.4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carbaldehyde. To a solution of 4-bromo-6-chloro-1H-indazole-5-carbaldehyde (50 g, 193 mmol) in dichloromethane (700 mL) was added DHP (53 mL, 578 mmol) and TsOH.H2O (6.64 g, 38.5 mmol). The reaction mixture was stirred at room temperature for 2 h, was then diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with a mixed solvent (petroleum ether / EtOAc = 30:1) at room temperature for 1 h. The suspension was filtered, and the filter cake was washed with petroleum ether, and concentrated under reduced pressure to give 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole-5-carbaldehyde (50 g, 75% yield).

[0230] Step 4. Methyl (E)-4-(diethoxyphosphoryl) but-2-enoate. In a 3-L round-bottom flask was charged with methyl (E)-4-bromobut-2-enoate (150 g, 838 mmol). The contents were heated to 120 °C and triethyl phosphite (167 g, 1.00 mol) was added dropwise. The resulting mixture was stirred at 120 °C under N2atmosphere for 4 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product containing methyl (E)- 4-(diethoxyphosphoryl) but-2-enoate (150 g) was used in the next step without further purification.

[0231] Step 5. Methyl (2E, 4E)-5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl) penta-2, 4-dienoate. To a solution of LDA (2 M in THF, 175 mL, 350 mmol) in tetrahydrofuran (360 mL) was added the solution of methyl (E)-4-(diethoxyphosphoryl)but-2-enoate (82.0 g, 349 mmol) in tetrahydrofuran (600 mL) dropwise at -78 °C under N2. The reaction mixture was stirred at -78 °C for 30 min, then the solution of 4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole-5-carbaldehyde (100 g, 291 mmol) in tetrahydrofuran (600 mL) was added dropwise at - 78 °C. Then the mixture was stirred at 0 °C for 1.5 h. The mixture was quenched by addition of water at 0 °C, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–100% EtOAc in petroleum ether, to give methyl (2E, 4E)-5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) penta-2, 4- dienoate (91 g, 214 mmol, 73% yield).

[0232] Step 6. Methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) pentanoate. In a hydrogenation reactor was charged with PtO2(7.47 g, 32.9 mmol) in tetrahydrofuran (1.4 L). Methyl (2E, 4E)-5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) penta- 2, 4-dienoate (70 g, 164 mmol) was added under argon and the suspension was degassed and purged with hydrogen 3 times. The mixture was hydrogenated under hydrogen (15 psi) at room temperature for 72 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 2–100% EtOAc in petroleum ether, to give methyl 5-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) pentanoate (37.5 g, 87 mmol, 53% yield). m / z (ESI): 429.1 / 431.1 (M+H)+.

[0233] Step 7. Methyl 5-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate. To a solution of methyl 5-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) pentanoate (25 g, 58.2 mmol) in 1,4-dioxane (250 mL) was added bis(pinacolato)diboron (44.3 g, 175 mmol) and Cs2CO3(56.9 g, 175 mmol) under nitrogen. Pd(dppf)Cl2(4.26 g, 5.82 mmol) was added, and the reaction mixture was stirred at 120 °C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 10–35% EtOAc in petroleum ether, to give methyl 5-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate (12 g, 25 mmol, 43% yield). m / z (ESI): 477.2 (M+H)+.

[0234] Intermediate J: 4-(tert-Butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidine.

[0235] To a solution of 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate B, 34 g, 82 mmol) in 1,4- dioxane (680 mL) was added PCy3Pd G2 (19.5 g, 32.9 mmol) and LiCl (17.5 g, 412 mmol). Then bis(tributyltin) (177 g, 305 mmol) was added in one portion under N2. The mixture was stirred at 80 °C for 36 h under nitrogen. After cooling to room temperature, the reaction was filtered, and the filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 0–7% ethyl acetate in petroleum ether, to provide 4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (tributylstannyl)pyrido[4,3-d]pyrimidine (29.8 g, 44.7 mmol, 54% yield). m / z (ESI): 667.4 / 669.4 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.21 (s, 1H), 5.21–5.36 (m, 1H), 4.20–4.29 (m, 2H), 3.24–3.28 (m, 2H), 2.05–2.30 (m, 3H), 1.80–2.05 (m, 4H), 1.34–1.60 (m, 9H), 1.20–1.32 (m, 18H), 0.86–0.93 (m, 9H).

[0236] Intermediate K: tert-Butyl (3R)-3-(6-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)-1-(methoxymethoxy)-2-oxohexyl)piperidine-1-carboxylate.

[0237] Step 1. tert-Butyl (3R)-3-(2-methoxy-1-(methoxymethoxy)-2-oxoethyl)piperidine-1- carboxylate. A mixture of tert-butyl (3R)-3-(1-hydroxy-2-methoxy-2-oxoethyl)piperidine-1- carboxylate (2.30 g, 8.41 mmol, Advanced ChemBlocks), 1,2-dichloroethane (28 mL), and DIPEA (5.9 mL, 34 mmol) was cooled to 0 °C and bromomethyl methyl ether (2.3 mL, 25 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and then heated at 50 °C for 16 h. Aqueous saturated NaHCO3solution was added, and the reaction stirred for 1 h. The aqueous phase was extracted with DCM and the combined organic layers were dried over Na2SO4,filtered and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–55% EtOAc in heptane, to give tert-butyl (3R)-3-(2-methoxy-1- (methoxymethoxy)-2-oxoethyl)piperidine-1-carboxylate (1.30 g, 4.10 mmol, 49% yield). m / z (ESI): 340.0 (M+Na)+.

[0238] Step 2. tert-Butyl (3R)-3-(2-hydroxy-1-(methoxymethoxy)ethyl)piperidine-1- carboxylate. To a 250-mL round-bottom flask was added tert-butyl (3R)-3-(2-methoxy-1- (methoxymethoxy)-2-oxoethyl)piperidine-1-carboxylate (1.30 g, 4.10 mmol) in DCM (10 mL) and methanol (1 mL). At 0 °C, lithium borohydride (2.0 M in tetrahydrofuran, 7.2 mL, 14.4 mmol) was added. The reaction mixture was stirred at room temperature for 4 h, then was diluted with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with saturated NaCl and dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–80% EtOAc in heptane, to give tert-butyl (3R)-3-(2-hydroxy-1- (methoxymethoxy)ethyl)piperidine-1-carboxylate (0.95 g, 3.30 mmol, 80% yield). m / z (ESI): 312.0 (M+Na)+.

[0239] Step 3. tert-Butyl (3R)-3-(1-(methoxymethoxy)-2-oxoethyl)piperidine-1-carboxylate. To a solution of tert-butyl (3R)-3-(2-hydroxy-1-(methoxymethoxy)ethyl)piperidine-1-carboxylate (0.83 g, 2.90 mmol) in DCM (8 mL) cooled to 0 °C was added Dess-Martin periodinane (1.46 g, 3.44 mmol). The reaction mixture was stirred at room temperature for 2 h, then was diluted with saturated Na2S2O3and saturated NaHCO3solutions. The aqueous layer was extracted with EtOAc, and thecombined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0– 80% EtOAc in heptane, to give tert-butyl (3R)-3-(1-(methoxymethoxy)-2-oxoethyl)piperidine-1- carboxylate (0.70 g, 2.40 mmol, 85% yield). m / z (ESI): 310.0 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 9.32 - 9.75 (m, 1 H), 4.56 - 4.89 (m, 2 H), 3.60 - 4.21 (m, 3 H), 3.40 (s, 3H), 2.56 - 3.02 (m, 2 H), 1.55 - 2.10 (m, 4 H), 1.30 - 1.50 (m, 10 H).

[0240] Step 4. tert-Butyl (3R)-3-(2-hydroxy-1-(methoxymethoxy)hex-5-en-1-yl)piperidine-1- carboxylate. To a 100-mL round-bottom flask was added tert-butyl (3R)-3-(1-(methoxymethoxy)-2- oxoethyl)piperidine-1-carboxylate (0.65 g, 2.30 mmol) in THF (6.5 mL). The mixture was cooled to - 78 °C, and 3-butenylmagnesium bromide (0.5 M in THF, 11.2 mL, 5.61 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was diluted with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with saturated NaCl, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–80% EtOAc in heptane, to give tert-butyl (3R)-3-(2-hydroxy-1- (methoxymethoxy)hex-5-en-1-yl)piperidine-1-carboxylate (0.59 g, 1.70 mmol, 76% yield). m / z (ESI): 366.0 (M+Na)+.

[0241] Step 5. tert-Butyl (3R)-3-(6-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)-1-(methoxymethoxy)-2-oxohexyl)piperidine-1-carboxylate. To a vial was charged with 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.29 g, 0.66 mmol), tetrabutylammonium chloride (0.12 g, 0.44 mmol), tert-butyl (3R)-3-(2-hydroxy-1- (methoxymethoxy)hex-5-en-1-yl)piperidine-1-carboxylate (0.15 g, 0.44 mmol), sodium bicarbonate (92 mg, 1. mmol) and palladium(II) acetate (4.9 mg, 0.022 mmol) in DMA (1.7 mL). The mixture was degassed by sparging with nitrogen and was placed on a 65°C hot plate and stirred for 7 h. After cooling to , the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–70% EtOAc in heptane, to give tert-butyl (3R)-3-(6-(4-bromo-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)-1-(methoxymethoxy)-2-oxohexyl)piperidine-1-carboxylate (0.10 g, 0.15 mmol, 35% yield). m / z (ESI): 677.8 / 679.8 (M+Na)+.

[0242] tert-Butyl (R)-3-(1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (Intermediate L)

[0243] Step 1. tert-Butyl 3-(1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate. To a stirred 0 °C solution of 3-(1H-1,2,3-triazol-4-yl)piperidine dihydrochloride (10.0 g, 44.4 mmol, Enamine) andtriethylamine (22.5 g, 31.2 mL, 222 mmol) in DCM (75 mL) was added a solution of di-tert-butyl dicarbonate (9.69 g, 44.4 mmol, TCI America) in DCM (25 mL). The resulting mixture was stirred at 0 °C for 30 minutes and at room temperature for 22 h. To the crude was added silica gel. The volatiles were removed in vacuo and purified by column chromatography on silica gel, eluting with (20% MeOH / DCM with 1% TEA) / DCM (30 min from 0 to 5%) to provide tert-butyl 3-(1H-1,2,3-triazol-4- yl)piperidine-1-carboxylate (12.5 g, 49.5 mmol, >100% yield). m / z (ESI): 275.0 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 7.56 (s, 1H), 4.1-4.4 (m, 1H), 3.8-4.0 (m, 1H), 2.8-3.3 (m, 3H), 2.1-2.2 (m, 1H), 1.5-1.9 (m, 4H), 1.48 (s, 9H).

[0244] Step 2. tert-Butyl (R)-3-(1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate. tert-Butyl-3- (1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (12.5 g) was separated via SFC using a ChiralPak AD, 2 x 25 cm, 5 µm column with a mobile phase of 15% MeOH with 0.2% DEA using a flowrate of 80 mL / min to provide tert-butyl (R)-3-(1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (4.97 g, retention time = 1.0 min) with an ee of >99%. m / z (ESI): 253.1 (M+H)+.

[0245] rac-2-((1S,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethan-1-ol (Intermediate M).

[0246] Step 1. rac-Ethyl (1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropane-1-carboxylate. A vial was charged with 4-bromo-6-chloro-5-iodo-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (0.75 g, 1.70 mmol, Lab Network), rac-ethyl (1R,2S)-2- (tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (0.49 mL, 2.04 mmol, Enamine), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.12 g, 0.17 mmol), potassium phosphate tribasic (1.26 g, 5.95 mmol) in toluene (5 mL) and water (1 mL). The reaction mixture was flushed with nitrogen and heated at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by column chromatography on silica gel, eluting with a gradient of 0–60% EtOAc / heptane to provide rac-ethyl (1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1-carboxylate (0.24 g, 0.56 mmol, 33% yield). m / z (ESI): 448.8 (M+Na)+.

[0247] Step 2. rac-((1R,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)methanol. To a stirred solution of rac-ethyl (1R,2S)-2-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1-carboxylate (0.95 g, 2.23 mmol) in tetrahydrofuran (6 mL) at -78 °C was added diisobutylaluminum hydride (1.0 M in DCM, 5.6 mL, 5.6 mmol) slowly. The resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was poured slowly into Rochelle's salt aqueous solution in an ice bath and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–60% EtOAc / heptane to afford rac-((1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)methanol (0.69 g, 1.78 mmol, 80% yield). m / z (ESI): 384.8 (M+H)+.

[0248] Step 3. rac-(1R,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropane-1-carbaldehyde. To a solution of rac-((1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methanol (Intermediate D, 5.00 g, 13 mmol) in dichloromethane (75 mL) was added Dess-Martin periodinane (11.0 g, 25.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% EtOAc in petroleum ether, to give rac-(1R,2S)-2-(4-bromo-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1-carbaldehyde (4.16 g, 10.9 mmol, 85% yield).

[0249] Step 4. rac-4-Bromo-6-chloro-5-((1S,2R)-2-((Z)-2-methoxyvinyl)cyclopropyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole. To the mixture of (methoxymethyl)triphenylphosphonium (24.0 g, 78.0 mmol) in tetrahydrofuran (200 mL) was added t-BuOK (1 M in THF, 78 mL, 78 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then the solution of rac- (1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1- carbaldehyde (10.0 g, 26.1 mmol) in tetrahydrofuran (200 mL) was added dropwise at 0 °C to the mixture. The reaction mixture was stirred at room temperature for 30 minutes, then was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% EtOAc in petroleum ether, to give rac-4-bromo-6-chloro-5-((1S,2R)- 2-((Z)-2-methoxyvinyl)cyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (9.62 g, 23.0 mmol, 90% yield).

[0250] Step 5. rac-2-((1S,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)acetaldehyde. To the mixture of rac-4-bromo-6-chloro-5-((1S,2R)-2-((Z)-2-methoxyvinyl)cyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (33 g, 80 mmol) in 1,4- dioxane (790 mL) and water (130 mL) was added pyridine 4-methylbenzenesulfonate (32.4 g, 128 mmol). The reaction mixture was stirred at 70 °C for 12 h. After cooling to room temperature, the reaction mixture was quenched by addition of water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% EtOAc in petroleum ether, to give rac-2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)acetaldehyde (20.0 g, 50.3 mmol, 63% yield).

[0251] Step 6. rac-2-((1S,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethan-1-ol (Intermediate M). To the mixture of rac-2-((1S,2S)-2-(4-bromo-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)acetaldehyde (20.0 g, 50.3 mmol) in ethanol (200 mL) was added NaBH4(3.23 g, 85 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, was then quenched by addition of saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 20–35% EtOAc in petroleum ether, to give rac-2-((1S,2S)-2-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (19.1 g, 48.0 mmol, 95% yield). m / z (ESI): 401.0 / 399.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (s, 1 H), 7.99 (s, 1 H), 5.87 (dd, J = 9.6, 2.4 Hz, 1 H), 4.29 - 4.33 (m, 1 H), 3.85 - 3.88 (m, 1 H), 3.76 - 3.77 (m, 1 H), 3.36 - 3.41(m, 2 H), 2.29 - 2.38 (m, 1 H), 1.97 – 2.03 (m, 3 H), 1.84 - 1.86 (m, 1 H), 1.69 - 1.73 (m, 1 H), 1.54 - 1.60 (m, 2 H), 1.38 - 1.48 (m, 1 H), 1.31 - 1.37 (m, 1 H), 0.80 - 0.92 (m, 1 H), 0.20 - 0.26 (m, 1 H).

[0252] tert-Butyl (3R)-3-(2-(2-((1RS,2RS)-2-(4-((R)-4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethyl)-2H-1,2,3-triazol-4-yl)piperidine- 1-carboxylate (Intermediate N).

[0253] Step 1. rac-2-((1R,2R)-2-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol. To a stirred mixture of rac-2-((1R,2R)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethan-1-ol (Intermediate M, 1.87 g, 4.68 mmol) in ethyl acetate (30 mL) at room temperature, was added caesium carbonate (3.05 g, 9.36 mmol), B2Pin2(2.38 g, 9.36 mmol, Ambeed, Inc.), palladium diacetate (0.11 g, 0.47 mmol, Sigma-Aldrich Corporation) and tris(4- methoxyphenyl)phosphine (0.20 g, 0.56 mmol, AA BLOCKS LLC). The reaction mixture was sparged with nitrogen and stirred at 75 °C for 1 h. The reaction mixture was filtered through celite and concentrated. The crude material was purified by column chromatography on silica gel, eluting with 0-100% EtOAc / heptane to provide rac-2-((1R,2R)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (2.09 g, 4.68 mmol, 100% yield). m / z (ESI): 447.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 8.16 (br s, 1H), 7.71 – 7.69 (m, 1H), 5.67 (dd, J = 9.2, 2.7 Hz, 1H), 4.19 – 4.10 (m, 1H), 4.05 – 3.99 (m, 1H), 3.87 – 3.70 (m, 2H), 3.69 – 3.57 (m, 2H), 2.56 – 2.47 (m, 1H), 2.40 – 2.33 (m, 1H), 2.18 – 2.11 (m, 1H), 2.09 – 2.03 (m, 1H), 1.92 – 1.69 (m, 5H), 1.50 – 1.43 (m, 12H), 0.64 – 0.53 (m, 1H), 0.52 – 0.31 (m, 1H).

[0254] Step 2.2-((1RS,2RS)-2-(4-((R)-4-(tert-Butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol. To a stirred mixture of 4- (tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate B, 1.93 g, 4.68 mmol) and rac-2-((1R,2R)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethan-1-ol (2.09 g, 4.68 mmol) in 2-methyltetrahydrofuran (40 mL) at room temperature, was added potassium phosphate (2.48 g, 11.69 mmol), catacXium A Pd G3 (0.34 g, 0.47 mmol, Sigma-Aldrich) and water (4 mL). The reaction mixture was sparged with nitrogen and stirred at 80 °C for 2 h. The organic phase was separated and concentrated. The crude material was purified by column chromatography on silica gel, eluting with 0-100% [3:1 EtOAc / EtOH with 2% Et3N] / heptane to provide 2-((1RS,2RS)-2-(4-((R)-4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (1.71 g, 2.45 mmol, 52% yield). m / z (ESI): 697.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.24 – 9.20 (m, 1H), 7.89 – 7.77 (m, 2H), 5.73 (ddd, J = 13.8, 9.0, 2.7 Hz, 1H), 5.41 – 5.23 (m, 1H), 4.36 – 4.27 (m, 2H), 4.11 – 4.01 (m, 1H), 3.83 – 3.75 (m, 1H), 3.57 – 3.49 (m, 2H), 3.28 (br d, J = 9.4 Hz, 2H), 3.20 (s, 1H), 3.02 (br d, J = 5.2 Hz, 1H), 2.61 – 2.45 (m, 1H), 2.34 – 2.26 (m, 2H), 2.25 – 2.09 (m, 4H), 2.03 – 1.91 (m, 4H), 1.85 – 1.83 (m, 9H), 1.83 – 1.67 (m, 5H), 0.81 – 0.63 (m, 1H), 0.58 – 0.38 (m, 1H), -0.39 (br s, 1H).19F NMR (376 MHz, CDCl3) δ ppm -136.32 – -136.63 (m, 1F), -172.93 – -173.07 (m, 1F).

[0255] Step 3. tert-Butyl (3R)-3-(2-(2-((1RS,2RS)-2-(4-((R)-4-(tert-butoxy)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethyl)-2H-1,2,3-triazol-4- yl)piperidine-1-carboxylate. To a 40-mL vial was added triphenylphosphine (0.49 g, 1.86 mmol, Combi-Blocks Inc.), tert-butyl (R)-3-(1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (0.43 g, 1.69 mmol, Step 2) and 2-((1RS,2RS)-2-(4-((R)-4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (1.18 g, 1.69 mmol) in tetrahydrofuran (16 mL). Diisopropyl azodicarboxylate (0.38 g, 0.37 mL, 1.86 mmol, Oakwood Products, Inc.) was added dropwise upon vigorous stirring at room temperature. The mixture was stirred at room temperature for 2 h before it was concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) + 2% Et3N in heptane followed by reversed phase chromatography on a C18 D column, eluting with a gradient of 0-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to provide tert-butyl (3R)-3-(2-(2-((1RS,2RS)-2-(4-((R)-4-(tert- butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethyl)-2H- 1,2,3-triazol-4-yl)piperidine-1-carboxylate (1.30 g, 1.40 mmol, 82% yield). m / z (ESI): 931.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.23 (d, J = 2.7 Hz, 1H), 7.87 – 7.75 (m, 2H), 7.32 – 7.30 (m, 1H), 5.77 – 5.66 (m, 1H), 5.49 – 5.19 (m, 1H), 4.45 – 4.19 (m, 4H), 4.14 (d, J = 7.1 Hz, 5H), 4.17 – 4.11 (m, 1H), 4.09 – 3.92 (m, 3H), 3.85 – 3.72 (m, 1H), 3.43 – 3.11 (m, 3H), 3.09 – 2.95 (m, 1H), 2.94 – 2.76 (m, 3H), 2.58 – 2.44 (m, 1H), 2.44 – 2.21 (m, 4H), 2.19 – 2.12 (m, 2H), 1.84 (s, 9H), 1.80– 1.74 (m, 2H), 1.65 – 1.51 (m, 3H), 1.46 (s, 9H), 1.22 – 1.06 (m, 1H), 0.88 – 0.59 (m, 2H), -0.37 – - 0.57 (m, 1H).19F NMR (376 MHz, CDCl3) δ ppm -136.17 – -136.71 (m, 1F), -172.78 – -173.12 (m, 1F).

[0256] (6S)-4-(7-(5-(3-((tert-Butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-ol (Intermediate O). C

[0257] Step 1. (S)-4-(7-Bromo-2-chloroquinazolin-4-yl)-1,4-oxazepan-6-ol. A 40-mL vial was charged with 7-bromo-2,4-dichloroquinazoline (1.20 g, 4.32 mmol, Pharmablock Inc.) and acetonitrile (17.3 mL). The reaction mixture was cooled to 0 °C. To the stirred solution, under nitrogen, (S)-1,4-oxazepan-6-ol hydrochloride (0.63 g, 4.10 mmol, LabNetwork Inc.) and DIPEA (2.26 mL, 12.95 mmol) were added, and the reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel, eluting with 0–100% ethyl acetate in heptane. The final product was triturated using dichloromethane:heptane to yield (S)-4-(7-bromo-2-chloroquinazolin-4-yl)-1,4-oxazepan-6-ol (0.50 g, 1.39 mmol, 32% yield). m / z (ESI): 382.0 (M+Na)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.25 – 8.17 (m, 1H), 7.89 – 7.84 (m, 1H), 7.67 – 7.59 (m, 1H), 4.40 – 4.33 (m, 1H), 4.26 – 4.17 (m, 2H), 4.15 – 4.04 (m, 2H), 4.03 – 3.87 (m, 3H), 3.72 (dd, J = 12.8, 5.6 Hz, 1H).

[0258] Step 2. (S)-4-(7-Bromo-2-chloroquinazolin-4-yl)-6-((tert-butyldimethylsilyl)oxy)- 1,4-oxazepane. A 40 mL vial was charged with (S)-4-(7-bromo-2-chloroquinazolin-4-yl)-1,4- oxazepan-6-ol (0.63 g, 1.76 mmol), dichloromethane (11.7 mL), DMAP (20 mg, 0.17 mmol), imidazole (0.29 g, 4.39 mmol) and tert-butyldimethylsilyl chloride (0.32 g, 2.11 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched via the addition of saturated aqueous sodium bicarbonate (10 mL). The layers were separated, and the aqueous layerwas extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield (S)-4-(7-bromo- 2-chloroquinazolin-4-yl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane (0.77 g, 1.62 mmol, 92% yield). m / z (ESI): 474.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 8.02 – 7.96 (m, 1H), 7.95 – 7.87 (m, 1H), 7.53 – 7.44 (m, 1H), 4.36 – 4.28 (m, 2H), 4.13 – 3.92 (m, 5H), 3.81 – 3.74 (m, 1H), 3.59 – 3.54 (m, 1H), 0.94 – 0.89 (m, 9H), 0.21 – 0.13 (m, 6H).

[0259] Step 3. (S)-4-(7-Bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane. A 40-mL vial was charged with (S)-4-(7-bromo-2-chloroquinazolin-4-yl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane (0.77 g, 1.62 mmol), N,N-dimethylformamide (0.9 mL) and tetrahydrofuran (7.2 mL). To the stirred solution, under nitrogen, 1,4-diazabicyclo[2.2.2]octane (3.6 mg, 0.32 mmol, AstaTech Inc.) and Cs2CO3(1.58 g, 4.86 mmol, Ambeed Inc.) were added, and the reaction mixture was stirred at 50 °C for 22 h. The reaction mixture was warmed to room temperature and diluted with water (15 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with 0–60% ethanol / ethyl acetate (1:3) with 2% triethylamine in heptane to yield (S)-4-(7-bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-6-((tert-butyldimethylsilyl)oxy)-1,4-oxazepane (0.94 g, 1.58 mmol, 97% yield). m / z (ESI): 595.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.86 – 7.83 (m, 2H), 7.29 – 7.27 (m, 1H), 5.37 – 5.18 (m, 1H), 4.36 – 4.10 (m, 6H), 4.04 – 3.85 (m, 4H), 3.85 – 3.63 (m, 2H), 3.31 – 3.21 (m, 2H), 2.99 (br d, J = 5.4 Hz, 1H), 2.27 (d, J = 2.9 Hz, 1H), 2.25 – 2.12 (m, 2H), 2.06 (s, 2H), 1.99 – 1.88 (m, 3H), 1.28 (t, J = 7.1 Hz, 3H), 0.91 (s, 7H), 0.13 (d, J = 4.2 Hz, 5H),19F NMR (376 MHz, CDCl3) δ ppm -172.29 – -174.25 (m, 1F).

[0260] Step 4. (S)-4-(7-Bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-ol. A 40 mL vial was charged with (S)-4-(7-bromo-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-((tert- butyldimethylsilyl)oxy)-1,4-oxazepane (1.10 g, 1.85 mmol) and tetrahydrofuran (11.7 mL). To the stirred reaction mixture, tetrabutylammonium fluoride solution (1.0 M in THF, 2.77 mL, 2.77 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched via the addition of saturated aqueous sodium bicarbonate (15 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel eluting with 0–100% ethanol / ethyl acetate (1:3) with 2% triethylamine in heptane to yield (S)-4-(7-bromo-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-ol (0.84 g, 1.75 mmol, 95% yield). m / z (ESI): 481.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.09 – 8.01(m, 1H), 7.77 – 7.68 (m, 1H), 7.45 – 7.33 (m, 1H), 5.45 – 5.18 (m, 1H), 4.36 – 4.30 (m, 1H), 4.25 – 4.14 (m, 4H), 4.11 – 4.02 (m, 1H), 4.02 – 3.87 (m, 4H), 3.66 (dd, J = 12.6, 6.4 Hz, 1H), 3.27 – 3.16 (m, 3H), 3.07 – 3.00 (m, 1H), 2.33 – 2.10 (m, 3H), 2.05 – 1.91 (m, 3H).19F NMR (376 MHz, METHANOL-d4) δ ppm -170.98 – -175.88 (m, 1F).

[0261] Step 5. (6S)-4-(7-(5-(3-((tert-Butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-ol (Intermediate O). A 40 mL vial was charged with potassium phosphate (1.12 g, 5.24 mmol, Combi-Blocks Inc.), (S)-4-(7-bromo-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-ol (0.84 g, 1.75 mmol), 5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate G, 1.60 g, 2.45 mmol), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2’-amino-1,1’-biphenyl)]palladium(II) (0.25 g, 0.35 mmol, Combi-Blocks Inc.). The vial was purged with nitrogen, and the reactants were suspended in dry 2-methyltetrahydrofuran (15.5 mL) and water (1.6 mL). The vial was then sealed, and the reaction mixture was heated to 75 °C for 3 h. After cooling to room temperature, the solution was fully concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield (6S)-4-(7-(5-(3- ((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepan-6-ol (1.31 g, 1.41 mmol, 81% yield). m / z (ESI): 933.2 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.20 (d, J = 8.6 Hz, 1H), 7.85 (s, 1H), 7.62 – 7.53 (m, 2H), 7.53 – 7.48 (m, 5H), 7.36 (br d, J = 6.5 Hz, 3H), 7.33 – 7.29 (m, 4H), 7.24 (br d, J = 8.2 Hz, 1H), 5.80 (dd, J = 9.5, 2.2 Hz, 1H), 5.37 – 5.16 (m, 1H), 4.42 – 4.18 (m, 5H), 4.05 – 3.80 (m, 8H), 3.69 – 3.61 (m, 1H), 3.60 – 3.52 (m, 2H), 3.31 – 3.19 (m, 2H), 3.19 – 3.17 (m, 1H), 3.06 – 2.84 (m, 3H), 2.50 – 2.40 (m, 1H), 2.32 – 2.07 (m, 4H), 2.02 – 1.94 (m, 3H), 1.89 – 1.60 (m, 6H), 0.82 (s, 9H).19F NMR (376 MHz, METHANOL-d4) δ ppm -172.78 – -174.74 (m, 1F).

[0262] (6S)-4-(7-(5-(3-((tert-Butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5- methylpyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (Intermediate P).

[0263] Step 1. (S)-4-(2,7-Dichloro-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol. To a stirred mixture of 2,4,7-trichloro-5-methylpyrido[4,3-d]pyrimidine (3.23 g, 13.0 mmol, Frontier Scientific 3225393-1) and (S)-1,4-oxazepan-6-ol hydrochloride (1.90 g, 12.4 mmol) in acetonitrile (10 mL) at room temperature under nitrogen was added diisopropylethylamine (5.04 g, 6.81 mL, 39.0 mmol). The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) with 2% TEA in heptane to provide (S)-4-(2,7-dichloro-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (1.85 g, 5.62 mmol, 43% yield). m / z (ESI): 329.05 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.44 (s, 1H), 4.95 – 4.64 (m, 1H), 4.42 – 4.21 (m, 2H), 4.03 – 3.81 (m, 4H), 3.80 – 3.66 (m, 1H), 3.48 (br s, 1H), 3.30 – 3.10 (m, 1H), 2.78 (s, 3H).

[0264] Step 2. (S)-4-(7-Chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol. To a stirred mixture of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (0.20 g, 1.24 mmol, Pharmablock Inc.) in tetrahydrofuran (4 mL) at 0 °C under nitrogen, was added lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 1.24 mL, 1.24 mmol). The resulting mixture was stirred at 0 °C for 20 minutes. To this mixture was added (S)-4-(2,7-dichloro-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (0.34 g, 1.03 mmol) as a suspension in tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature for 2 h. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) with 2% TEA in heptane to provide (S)- 4-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (95 mg, 0.21 mmol, 20% yield). m / z (ESI): 452.2 (M+H)+.

[0265] Step 3. (6S)-4-(7-(5-(3-((tert-Butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol. To a stirred mixture of (S)- 4-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (0.90 g, 1.99 mmol) and 5-(3-((tert- butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazole (Intermediate G, 1.84 g, 2.79 mmol) in 2-methyltetrahydrofuran (10 mL) and water (2 mL) at room temperature under nitrogen, was added mesylate[(di(1-adamantyl)-n- butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.29 g, 0.40 mmol, Combi-Blocks Inc.) and potassium phosphate tribasic (1.27 g, 5.97 mmol, Combi-Blocks Inc.). The resulting mixture was stirred at 75 °C for 4 h. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) with 2% TEA in heptane to provide (6S)- 4-(7-(5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (1.37 g, 1.44 mmol, 73% yield). m / z (ESI): 948.3 (M+H)+.

[0266] (6S)-4-(7-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (Intermediate Q).

[0267] Step 1.4-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (15.0 g, 59.4 mmol) in acetonitrile (50 mL) was added the solution of (S)-1,4-oxazepan-6-ol hydrochloride (8.67 g, 56.4 mmol) and N,N- diisopropylethylamine (31 mL, 177 mmol) in acetonitrile (50 mL) at 0 °C. Then the mixture was stirred at 0 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAC (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel, eluting with a gradient of 5-100% ethyl acetate in petroleum ether to provide 4-(2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (13.0 g, 39.0 mmol, 65% yield). m / z (ESI): 333.0 (M+H)+.

[0268] Step 2. (S)-4-(7-Chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-ol. To a solution of (S)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-ol (1.00 g, 3.00 mmol) in tetrahydrofuran (6 mL) was added NaSMe (1.15 g, 3.30 mmol) at 0 °C. After addition, the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by addition of 50 mL water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to provide (S)-4-(7-chloro-8-fluoro- 2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (1.00 g, 2.90 mmol, 97% yield). m / z (ESI): 345.0 (M+H)+.

[0269] Step 3. (6S)-4-(7-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-ol. A mixture of 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate G, 9.98 g, 18.65 mmol), (S)-4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol(5.36 g, 15.55 mmol), K3PO4(9.90 g, 46.6 mmol) and CataCXium A Pd G3 (2.26 g, 3.11 mmol) in 2- methyltetrahydrofuran (60 mL) and water (12 mL) was degassed with nitrogen, and the mixture was stirred at 110 °C for 5 h under nitrogen. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel, eluting with a gradient of 0-10% methanol in dichloromethane to provide (6S)-4-(7-(5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (10.7 g, 12.44 mmol, 80% yield). m / z (ESI): 717.0 (M+H)+.

[0270] tert-Butyl 3-(3-(2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)ethoxy)propyl)piperidine-1-carboxylate (Intermediate R).

[0271] Step 1. tert-Butyl 3-(3-((methylsulfonyl)oxy)propyl)piperidine-1-carboxylate. A 40-mL vial was charged with tert-butyl 3-(3-hydroxypropyl)piperidine-1-carboxylate (0.68 mL, 2.81 mmol, Enamine), triethylamine (0.79 mL, 5.61 mmol) and 1,2-dichloroethane (18.7 mL). To the stirred reaction mixture, methanesulfonyl chloride (0.24 mL, 3.09 mmol, Sigma-Aldrich Corporation) was added dropwise. The resulting mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with agradient of 0-60% ethyl acetate in heptane to provide tert-butyl 3-(3- ((methylsulfonyl)oxy)propyl)piperidine-1-carboxylate (0.90 g, 2.80 mmol, 100%). m / z (ESI): 344.0 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 4.25 – 4.18 (m, 2H), 3.98 – 3.86 (m, 1H), 3.04 – 2.95 (m, 3H), 2.86 – 2.74 (m, 1H), 2.58 – 2.39 (m, 1H), 1.86 – 1.75 (m, 3H), 1.73 – 1.59 (m, 1H), 1.51 – 1.41 (m, 11H), 1.39 – 1.20 (m, 3H), 1.18 – 1.00 (m, 1H).

[0272] Step 2. tert-Butyl 3-(3-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)ethoxy)propyl)piperidine-1-carboxylate. A 40 mL vial was charged with 2-(4- bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethan-1-ol (Intermediate D, 0.36 g, 1.00 mmol), tetrahydrofuran (3.35 mL) and sodium hydride (60 wt% in mineral oil, 80 mg, 2.00 mmol). After 30 minutes, tert-butyl 3-(3-((methylsulfonyl)oxy)propyl)piperidine-1-carboxylate (0.49 g, 1.50 mmol) in 1.5 mL THF was added and the resulting mixture was stirred at 65 °C for 24 h. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-70% ethanol / ethyl acetate (1:3) with 2% triethylamine in heptane to yield tert-butyl 3- (3-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethoxy)propyl)piperidine-1- carboxylate (0.49 g, 0.84 mmol, 84% yield). m / z (ESI): 606.0 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 8.05 – 7.94 (m, 1H), 7.68 – 7.64 (m, 1H), 5.70 – 5.63 (m, 1H), 4.03 – 3.90 (m, 3H), 3.80 – 3.73 (m, 1H), 3.65 – 3.58 (m, 2H), 3.55 – 3.47 (m, 2H), 3.42 – 3.35 (m, 2H), 2.82 – 2.72 (m, 1H), 2.52 – 2.40 (m, 2H), 2.21 – 2.11 (m, 1H), 2.11 – 2.07 (m, 1H), 1.85 – 1.74 (m, 3H), 1.68 – 1.61 (m, 3H), 1.50 – 1.38 (m, 12H), 1.31 – 1.22 (m, 2H), 1.12 – 1.02 (m, 1H).

[0273] Step 3. tert-Butyl 3-(3-(2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)ethoxy)propyl)piperidine-1-carboxylate. To a 6-mL vial was added cesium carbonate (0.41 g, 1.26 mmol), 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.25 g, 1.00 mmol, Combi-Blocks Inc.) and tert-butyl 3-(3-(2-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethoxy)propyl)piperidine-1-carboxylate (0.49 g, 0.84 mmol) in ethyl acetate (1.7 mL). The reaction was flushed with nitrogen for 5 minutes. To this was added Pd(OAc)2(90 mg, 0.042 mmol, Sigma-Aldrich Corporation) and tris(4- methoxyphenyl)phosphine (30 mg, 0.08 mmol, Ambeed, Inc.). The vial was sealed under nitrogen and the reaction mixture was heated to 80 °C for 16 h. The reaction cooled to room temperature and filtered through a short pad of celite, rinsed with EtOAc (30 mL). The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-90% ethyl acetate in heptane to provide tert-butyl 3-(3-(2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)ethoxy)propyl)piperidine-1-carboxylate (0.29 g, 0.46 mmol, 55% yield). m / z (ESI): 654.2 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 8.40 – 8.25 (m, 1H), 7.80 – 7.70 (m, 1H), 5.70 – 5.64 (m, 1H), 4.04 – 3.89 (m, 3H), 3.61 – 3.55 (m, 2H), 3.53 – 3.44 (m, 4H),2.79 – 2.70 (m, 1H), 2.55 – 2.41 (m, 2H), 2.20 – 2.11 (m, 1H), 1.84 – 1.67 (m, 4H), 1.49 – 1.46 (m, 10H), 1.45 – 1.43 (m, 12H), 1.33 – 1.21 (m, 9H).

[0274] Step 4. tert-Butyl 3-(3-(2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)ethoxy)propyl)piperidine-1-carboxylate. A 20-mL vial equipped was charged with tert-butyl 3-(3-(2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)ethoxy)propyl)piperidine-1-carboxylate (0.30 g, 0.46 mmol), 4- (tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate B, 0.21 g, 0.51 mmol), potassium phosphate tribasic (0.30 g, 1.39 mmol), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino- 1,1'-biphenyl)]palladium(II) (50 mg, 0.070 mmol, Combi-Blocks Inc.) and degassed 2- methyltetrahydrofuran (4.20 mL) / water (0.42 mL), then heated to 80 °C for 3 h. The reaction was cooled to room temperature. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) with 2% triethylamine in heptane to yield tert-butyl 3-(3-(2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)ethoxy)propyl)piperidine-1-carboxylate (0.21 g, 0.24 mmol, 51% yield). m / z (ESI): 882.2 (M+H)+.

[0275] 1-((6R)-6-Fluoro-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)propan-1-ol (Intermediate S).

[0276] Step 1.1-Benzyl 2-methyl (4R)-4-fluoro-2-((E)-hex-3-en-1-yl)pyrrolidine-1,2- dicarboxylate. To a stirred mixture of 1-benzyl 2-methyl (2s,4r)-4-fluoropyrrolidine-1,2- dicarboxylate (1.65 g, 5.87 mmol, AstaTech, Inc) in THF (16 mL) at -78 °C under nitrogen, was added lithium bis(trimethylsilyl)amide solution (1.0 M THF, 8.80 mL, 8.80 mmol). The resulting mixture was stirred at -78 °C for 0.5 h. (E)-1-Bromohex-3-ene (1.91 g, 11.73 mmol, Aurum Pharma) was added. The reaction mixture was stirred for 20 h. The reaction mixture was diluted with sat. aq. solution of ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-70% heptane in ethyl acetate. A fraction with desired product was collected. The material was further purified by reversed phase chromatography on a C18 column, eluting with a gradient of 10-90% acetonitrile (0.1% formic acid) in water (0.1% formic acid) to provide 1-benzyl 2-methyl (4R)-4-fluoro-2-((E)-hex-3-en-1-yl)pyrrolidine-1,2-dicarboxylate (1.09 g, 3.00 mmol, 51% yield) as colorless oil. m / z (ESI): 364.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.50 -7.30 (m, 5H), 5.54 – 5.34 (m, 1H), 5.32 – 4.99 (m, 4H), 4.20 – 3.88 (m, 1H), 3.79 – 3.43 (m, 4H), 2.71 – 2.19 (m, 3H), 2.09 – 1.71 (m, 5H), 0.96 (m, 3H).19F NMR (376 MHz, CDCl3) δ ppm -172.85 - -175.20 (m, 1F).

[0277] Step 2.1-Benzyl 2-methyl (4R)-2-(2-(3-ethyloxiran-2-yl)ethyl)-4-fluoropyrrolidine-1,2- dicarboxylate. To a stirred mixture of 1-benzyl 2-methyl (4R)-4-fluoro-2-((E)-hex-3-en-1- yl)pyrrolidine-1,2-dicarboxylate (1.00 g, 2.75 mmol) in DCM (10 mL) at 0 °C under ambient atmosphere, was added 3-chloroperoxybenzoic acid (77 wt%, 1.54 g, 6.88 mmol, Sigma-Aldrich Corporation) slowly. The mixture was further stirred for addtional 2 h while allowing the reaction mixture was warm to room temperature slowly. The reaction mixture was diluted with 10 wt% aq. solution of sodium thiosulfate and sat. sodium bicarbonate solution and extracted with MTBE. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-70% heptane in ethyl acetate to provide 1-benzyl 2-methyl (4R)-2-(2-(3-ethyloxiran-2- yl)ethyl)-4-fluoropyrrolidine-1,2-dicarboxylate (0.70 g, 1.85 mmol, 67% yield) as colorless oil. m / z (ESI): 380.20 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.42 – 7.31 (m, 5H), 5.25 – 5.05 (m, 3H), 5.44 – 4.97 (m, 1H), 4.09 – 3.93 (m, 1H), 3.79 – 3.40 (m, 3H), 2.74 – 2.45 (m, 3H), 2.40 – 2.08 (m, 2H), 1.60 – 1.36 (m, 5H), 1.06 – 0.89 (m, 3H).19F NMR (376 MHz, CDCl3) δ ppm -172.66 - -173.25 (m, 1F).

[0278] Step 3. Methyl (2R)-2-fluoro-5-(1-hydroxypropyl)tetrahydro-1H-pyrrolizine-7a(5H)- carboxylate. A stirred mixture of 1-benzyl 2-methyl (4R)-2-(2-(3-ethyloxiran-2-yl)ethyl)-4- fluoropyrrolidine-1,2-dicarboxylate (0.72 g, 1.90 mmol) and 10 wt% palladium on carbon (0.40 g, 0.38 mmol, Sigma-Aldrich Corporation) in EtOH (5 mL) at room temperature was stirred under hydrogen (45 psi) for 16 h. The solution was filtered through celite and the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-20% dichloromethane in methanol to provide two fractions with the desired mass to provide methyl (2R)-2-fluoro-5-(1- hydroxypropyl)tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate as colorless oil. m / z (ESI): 246.3 (M+H)+. Fraction 1 (185 mg).1H NMR (400 MHz, CDCl3) δ ppm 5.47 – 5.15 (m, 1H), 3.79 – 3.69 (m, 3H), 3.64 – 3.41 (m, 2H), 2.94 – 2.76 (m, 2H), 2.40 – 2.28 (m, 1H), 2.17 – 1.72 (m, 4H), 1.55 – 1.44 (m, 2H), 1.42 – 1.19 (m, 2H), 1.03 (s, 3H).19F NMR (376 MHz, CDCl3) δ ppm -174.12 – - 177.90 (m, 1F). Fraction 2: The material was further purified by reversed phase chromatography on a C18 column, eluting with a gradient of 10-90% acetonitrile (0.1% formic acid) in water (0.1% formic acid) to collect 182 mg of the desired product.1H NMR (400 MHz, CDCl3) δ ppm 5.36 – 5.00 (m, 1H), 3.90 (dt, J = 8.3, 4.0 Hz, 1H), 3.80 – 3.73 (m, 3H), 3.45 – 3.25 (m, 3H), 2.93 – 2.82 (m, 1H), 2.31 – 2.26 (m, 1H), 2.19 – 2.10 (m, 1H), 2.06 – 1.85 (m, 4H), 1.68 (ddd, J = 14.0, 7.5, 4.4 Hz, 1H),1.52 (ddd, J = 14.2, 8.3, 7.4 Hz, 1H), 1.08 – 0.97 (m, 3H).19F NMR (376 MHz, CDCl3) δ ppm - 171.99 -176.55 (m, 1F).

[0279] Step 4.1-((6R)-6-Fluoro-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)propan-1- ol. To a stirred mixture of methyl (2R)-2-fluoro-5-(1-hydroxypropyl)tetrahydro-1H-pyrrolizine- 7a(5H)-carboxylate (0.19 g, 0.75 mmol, fraction 1) in DCM (2.7 mL) and methanol (0.27 mL) at 0 °C under ambient atmosphere, was added lithium borohydride solution (2.0 M in THF, 0.94 mL, 1.89 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at 0 °C for 1 h and then room temperature for 16 h. The mixture was quenched with water, concentrated and the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-20% dichloromethane in methanol to provide 1-((6R)-6-fluoro-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)propan-1- ol (0.14 g, 0.64 mmol, 85% yield) as colorless oil. m / z (ESI): 218.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 5.50 – 5.18 (m, 1H), 3.60 – 3.27 (m, 4H), 3.07 – 2.89 (m, 1H), 2.80 – 2.66 (m, 1H), 2.38 (s, 1H), 2.19 – 1.77 (m, 6H), 1.64 – 1.29 (m, 4H), 1.01 (t, J = 7.5 Hz, 3H).19F NMR (376 MHz, CDCl3) δ ppm -173.09 - -173.23 (m, 1F).

[0280] Methyl (2R)-2-fluoro-5-(1-hydroxypropyl)tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (Fraction 2) was converted to the desired product in a similar fasion. m / z (ESI): 218.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 5.30 – 5.07 (m, 1H), 3.70 (br s, 1H), 3.22 – 3.11 (m, 1H), 3.07 – 2.90 (m, 2H), 2.48 – 2.28 (m, 2H), 2.13 – 1.94 (m, 1H), 1.89 – 1.76 (m, 4H), 1.76 – 1.60 (m, 5H), 1.50 (dt, J = 15.4, 7.3 Hz, 1H), 1.04 (t, J = 7.5 Hz, 3H).19F NMR (376 MHz, CDCl3) δ ppm -172.90 - -173.28 (m, 1F).

[0281] ((2R,7aR)-2-Fluoro-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl)methanol (Intermediate T).

[0282] Step 1. ((2R,6R,7aS)-2-Fluoro-6-hydroxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl pivalate. A 40-mL vial was charged with (2R,6R,7aS)-6-fluoro-7a-(hydroxymethyl)hexahydro-1H- pyrrolizin-2-ol (0.25 g, 1.43 mmol, Pharmablock Inc.) and dichloromethane (9.5 mL). The reaction mixture was cooled to 0 °C. To the stirred solution, under nitrogen, pivaloyl chloride (0.18 mL, 1.43 mmol, Sigma-Aldrich Corporation) and triethylamine (0.40 mL, 2.85 mmol) were added, and the reaction mixture was stirred at 0 °C for 2 h. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield ((2R,6R,7aS)-2-fluoro-6-hydroxytetrahydro-1H-pyrrolizin-7a(5H)- yl)methyl pivalate (0.21 g, 0.81 mmol, 57% yield). m / z (ESI): 260.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 5.37 – 5.15 (m, 1H), 4.55 – 4.49 (m, 1H), 4.15 – 4.01 (m, 2H), 3.38 – 3.27 (m, 1H),3.27 – 3.19 (m, 2H), 3.14 – 3.05 (m, 1H), 2.20 – 2.08 (m, 3H), 2.04 – 1.94 (m, 1H), 1.28 – 1.13 (m, 9H).19F NMR (376 MHz, CDCl3) δ ppm -171.49 – -172.28 (m, 1F).

[0283] Step 2. ((2R,7aR)-2-Fluoro-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl)methyl pivalate. A 40 mL vial was charged with ((2R,6R,7aS)-2-fluoro-6-hydroxytetrahydro-1H-pyrrolizin-7a(5H)- yl)methyl pivalate (0.22 g, 0.85 mmol), and toluene (8.1 mL). To the stirred reaction mixture Martin’s Sulfurane (1.08 g, 1.61 mmol, Combi-Blocks Inc.) was added and the reaction mixture was stirred at room temperature. After 4 h, additional Martin’s Sulfurane (0.57 g, 0.85 mmol, Combi-Blocks Inc.) was added. The reaction mixture was stirred at 100 °C for 8 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude material. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane. The material was further purified by column chromatography on silica gel eluting with a gradient of 0–100% ethyl acetate in heptane to yield ((2R,7aR)-2-fluoro-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl)methyl pivalate (77 mg, 0.32 mmol, 38%). m / z (ESI): 242.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 5.84 – 5.80 (m, 1H), 5.74 – 5.67 (m, 1H), 5.31 – 5.13 (m, 1H), 4.11 – 4.06 (m, 1H), 3.89 (d, J = 10.9 Hz, 1H), 3.73 – 3.67 (m, 1H), 3.33 – 3.18 (m, 2H), 2.22 – 2.10 (m, 1H), 2.03 – 1.94 (m, 1H), 1.92 – 1.84 (m, 1H), 1.23 – 1.18 (m, 9H).19F NMR (376 MHz, CDCl3) δ ppm -177.73 – -178.53 (m, 1F).

[0284] Step 3. ((2R,7aR)-2-Fluoro-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl)methanol. A 40 mL vial was charged with ((2R,7aR)-2-fluoro-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl)methyl pivalate (58 mg, 0.24 mmol), and tetrahydrofuran (1.60 mL). The resulting reaction mixture was cooled to -78 °C and lithium aluminum hydride solution (2.0 M in THF, 0.12 mL, 0.24 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was slowly quenched with water (10 mL) and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with 0–30% methanol in dichloromethane to yield ((2R,7aR)-2-fluoro-2,3-dihydro-1H-pyrrolizin-7a(5H)-yl)methanol (25 mg, 0.16 mmol, 66% yield). m / z (ESI): 158.2 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 5.96 – 5.91 (m, 1H), 5.89 – 5.82 (m, 1H), 5.59 – 5.39 (m, 1H), 4.64 – 4.56 (m, 2H), 4.23 – 4.17 (m, 1H), 3.91 – 3.89 (m, 1H), 3.89 – 3.82 (m, 1H), 3.27 – 3.19 (m, 2H), 2.53 – 2.50 (m, 1H), 2.49 – 2.38 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -176.89 – -179.34 (m, 1F). SECTION 2: Synthesis of Example Compounds

[0285] Provided in this section is the synthesis of examples described herein. It would be understood that compounds described herein (such as compounds of Formula (I), Formula (II) or Formula (III), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-xxx, or apharmaceutically acceptable salt of any of the foregoing) whose preparation is not specifically described in this section could be prepared in an analogous manner.

[0286] (26S)-18-Chloro-4-(((7aS)-2-(difluoromethylidene)tetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-32-fluoro-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one bis(2,2,2-trifluoroacetate) (Example 1-007).

[0287] Step 1. (S)-4-(7-Chloro-2-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol. To a 40-mL vial was charged with 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.40 g, 1.58 mmol, LabNetwork Inc.), acetonitrile (8 mL), and N,N-diisopropylethylamine (1.3 mL, 7.1 mmol). The reaction mixture was cooled to 0 °C and (S)-1,4-oxazepan-6-ol hydrochloride (0.24 g, 1.60 mmol) was added. The solution was stirred for 15 min, and then [(8S)-6-(difluoromethylene)-2,3,5,7-tetrahydro-1H-pyrrolizin-8- yl]methanol (0.90 g, 4.80 mmol, Pharmablock, Inc.) was added. The solution was heated to 80 °C for 18 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purifed by column chromatography on silica gel, eluting with 0–85% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield (S)-4-(7-chloro-2-(((S)-2-(difluoromethylene)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (0.37 g, 0.76 mmol, 48% yield). m / z (ESI): 486.0 (M+H)+.

[0288] Step 2. (6S)-4-(7-(5-(3-((tert-Butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol. In a 40-mL vial was charged with potassium phosphate (0.49 g, 2.30 mmol), (S)-4-(7-chloro-2-(((S)-2- (difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4- yl)-1,4-oxazepan-6-ol (0.37 g, 0.76 mmol), 5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate A, 0.65 g, 0.99 mmol), palladium acetate (34 mg, 0.15 mmol), and (S)-(-)-2- (diphenylphosphino)-2-methoxy-1-,1-binaphthyl (0.14 g, 0.31 mmol). The vial was purged with nitrogen and then the reactants were suspended in degassed 2-methyltetrahydrofuran (4.6 mL) and water (0.46 mL). The reaction mixture was heated to 80 °C for 3 h. After cooling to room temperature, the crude mixture was purified by column chromatography on silica gel, eluting with 0– 65% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane to yield (6S)-4-(7-(5-(3-((tert- butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-2- (difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4- yl)-1,4-oxazepan-6-ol (0.54 g, 0.55 mmol, 73% yield). m / z (ESI): 982.2 (M+H)+.

[0289] Step 3. (26S)-18-Chloro-4-(((7aS)-2-(difluoromethylidene)tetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-N-(tetrahydro-2H-pyran-2-yl)-32-fluoro-23,25,28-trioxa- 1,3,5,9,14,15-hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one. In a round-bottom flask was charged with (6S)-4-(7-(5- (3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2- (((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (0.54 g, 0.55 mmol), tetrahydrofuran (7 mL), and 1,1'- carbonyldiimidazole (0.22 g, 1.40 mmol). The reaction mixture was stirred at room temperature for 45 min, was then diluted with tetrahydrofuran (72 mL). To the reaction mixture was added tetrabutylammonium fluoride (1 M in THF, 1.4 mL, 1.4 mmol) and the reaction was stirred at room temperature for 3 h. The mixture was concentrated and the residue was purifed by column chromatography on silica gel, eluting with 0–80% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield (26S)-18-chloro-4-(((7aS)-2-(difluoromethylidene)tetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-N-(tetrahydro-2H-pyran-2-yl)-32-fluoro-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (0.31 g, 0.40 mmol, 73% yield). m / z (ESI): 769.8 (M+H)+.

[0290] Step 4. (26S)-18-Chloro-4-(((7aS)-2-(difluoromethylidene)tetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-32-fluoro-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one bis(2,2,2-trifluoroacetate). To a 40-mL vial was chargedwith (26S)-18-chloro-4-(((7aS)-2-(difluoromethylidene)tetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)- yl)methoxy)-N-(tetrahydro-2H-pyran-2-yl)-32-fluoro-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (0.31 g, 0.40 mmol), dichloromethane (4 mL), and then trifluoroacetic acid (1.1 mL, 14 mmol) dropwise. The reaction mixture was stirred at room temperature for 40 min and then heated to 30 °C for 10 min. After cooling to 0 °C, the reaction mixture was diluted with dichloromethane and quenched with saturated aqueous sodium bicarbonate solution. The dichloromethane layer was decanted, concentrated, and the residue was purified by reversed phase column chromatography to give (26S)-18-chloro-4-(((7aS)-2- (difluoromethylidene)tetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-32-fluoro-23,25,28- trioxa-1,3,5,9,14,15-hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one bis(2,2,2-trifluoroacetate) (0.16 g, 0.17 mmol, 42% yield). m / z (ESI): 685.8 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.45 (s, 1 H), 7.85 (s, 1 H), 7.78 (s, 1 H), 5.52 (d, 1 H), 5.05 – 4.85 (m, 4 H), 4.49 (d, 1 H), 4.34 – 4.23 (m, 1 H), 4.18 – 4.01 (m, 4 H), 3.91 – 3.78 (m, 3 H), 3.68 – 3.57 (m, 1 H), 3.50 – 3.36 (m, 3 H), 3.14 (d, 1 H), 3.07 – 2.99 (m, 1 H), 2.92 (d, 1 H), 2.70 – 2.56 (m, 1 H), 2.40 (d, 1 H), 2.32 – 2.18 (m, 3H ), 1.89 (s, 2 H).19F NMR (376 MHz, METHANOL-d4) δ ppm -77.33 (TFA), -88.37 (d), -89.25 (d), -141.57 (s). (26S)-18-Chloro-32-fluoro-4-(((2S,7aR)-2-(2-propyn-1-yloxy)tetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6(32),7,9,11,13,16,18-nonaen-24-one (Example 2-017).

[0291] Step 1: (S)-4-(7-Chloro-8-fluoro-2-(methylthio) pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-ol. To a solution of (S)-4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-ol (5.50 g, 16.5 mmol) in tetrahydrofuran (35 mL) was added NaSMe (6.65 g, 19 mmol) dropwise at 0 °C. After addition, the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by addition of water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to (S)-4-(7-chloro-8-fluoro-2-(methylthio) pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (5.30 g, 15.4 mmol, 93% yield). m / z (ESI): 345.0 [M+H]+.

[0292] Step 2. (6S)-4-(7-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4- oxazepan-6-ol. A mixture of 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate A, 9.98 g, 18.7 mmol), (S)-4-(7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (5.30 g, 15.4 mmol), K3PO4(9.90 g, 46.6 mmol) and CataCXium A Pd G3 (2.26 g, 3.11 mmol) in 2- methyltetrahydrofuran (60 mL) and water (12 mL) was degassed and purged with N2, and then the mixture was stirred at 110 °C for 5 h. The mixture was combined with another 1 g batch and was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 1–10% DCM in methanol, to provide (6S)-4-(7-(5-(3-((tert- butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2- (methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (10.7 g, 14.9 mmol, 82% yield). m / z (ESI): 717.2 [M+H]+.

[0293] Step 3. (16S)-36-Chloro-28-fluoro-22-(methylthio)-31-(tetrahydro-2H-pyran-2-yl)- 31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan- 8-one. To a solution of (6S)-4-(7-(5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan- 6-ol (3.00 g, 4.18 mmol) in tetrahydrofuran (15 mL) was added CDI (3.39 g, 20.9 mmol) under nitrogen. The reaction mixture was stirred at 45 °C for 5 h. After cooling to room temperature, the solution of TBAF (1 M in THF, 6.3 mL, 6.3 mmol) was added the mixture was diluted with tetrahydrofuran (180 mL) and stirred at 45 °C for 5 h. The reaction mixture was combined with two other 3 g batches and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 1–100% EtOAc in petroleum ether, to give (16S)-36-chloro-28-fluoro-22-(methylthio)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)- oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (3.00 g, 4.77 mmol, 38% yield). m / z (ESI): 629.2 [M+H]+.

[0294] Step 4. (16S)-36-Chloro-28-fluoro-22-(methylsulfinyl)-31-(tetrahydro-2H-pyran-2-yl)- 31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan- 8-one. To a solution of (16S)-36-chloro-28-fluoro-22-(methylthio)-31-(tetrahydro-2H-pyran-2-yl)- 31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8- one (1.50 g, 2.40 mmol) in dichloromethane (15 mL) was added m-CPBA (0.53 g, 2.60 mmol) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 1 h, was then combined another 1.5 g batch and concentrated. The residue was purified by column chromatography on silica gel, elutingwith a gradient of 30–90% EtOAc in petroleum ether, mixed with 0–100% EtOH, to give (16S)-36- chloro-28-fluoro-22-(methylsulfinyl)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)- oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (2.2 g, 3.4 mmol, 72% yield). m / z (ESI): 645.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ ppm 9.42 (d, J=3.6 Hz, 1 H), 7.87 (d, J=10.0 Hz, 1 H), 7.72 (t, J=5.2 Hz, 1 H), 5.68 - 5.80 (m, 1 H), 5.49 (d, J=16.8 Hz, 1 H), 4.93 - 5.10 (m, 2 H), 4.11 - 4.27 (m, 3 H), 3.92 - 4.10 (m, 2 H), 3.68 - 3.85 (m, 3 H), 3.44 - 3.56 (m, 1 H), 3.11 - 3.21 (m, 1 H), 2.97 - 3.10 (m, 4 H), 2.46 - 2.71 (m, 2 H), 2.06 - 2.23 (m, 2 H), 1.84 - 1.95 (m, 2 H), 1.71 - 1.83 (m, 3 H).19F NMR (376 MHz, CDCl3) δ ppm -134.99 (s, 1 F).

[0295] Step 5. (16S)-36-Chloro-28-fluoro-22-(((2S,7aR)-2-(prop-2-yn-1-yloxy)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana- 2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one. A solution of ((2S,7aR)-2- (prop-2-yn-1-yloxy)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.55 g, 2.80 mmol) in tetrahydrofuran (15 mL) was cooled to -65 °C under nitrogen and to the mixture was added NaOtBu (2 M in THF, 0.7 mL, 1.4 mmol) slowly at -65 °C. The mixture was stirred at -65 °C for 20 min, then (16S)-36-chloro-28-fluoro-22-(methylsulfinyl)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)- oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.46 g, 0.71 mmol) was added. The reaction mixture was stirred at -65 °C for 40 min, was then filtered, and the filtrate concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane / EtOH = 7 / 1) to give (16S)-36-chloro-28-fluoro-22-(((2S,7aR)-2-(prop-2-yn-1- yloxy)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa- 1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.19 g, 0.25 mmol, 35% yield). m / z (ESI): 776.4 [M+H]+.

[0296] Step 6. (26S)-18-Chloro-32-fluoro-4-(((2S,7aR)-2-(2-propyn-1-yloxy)tetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6(32),7,9,11,13,16,18-nonaen-24-one. To (16S)-36-chloro-28-fluoro-22-(((2S,7aR)-2-(prop-2-yn- 1-yloxy)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa- 1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.19 g, 0.25 mmol) in dichloromethane (5 mL) was added TFA (1.5 mL, 20 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, was then combined with another 80 mg batch and basified with aqueous NaHCO3solution to pH=7–8. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, dichloromethane / EtOH = 7 / 1) to give (26S)-18-chloro-32-fluoro-4-(((2S,7aR)-2-(2-propyn-1- yloxy)tetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta-2,4,6(32),7,9,11,13,16,18- nonaen-24-one (0.16 g, 0.23 mmol, 64% yield). m / z (ESI): 692.3 [M+H]+.1H NMR (400 MHz,CDCl3) δ ppm 9.25 (s, 1 H), 7.79 (s, 1 H), 7.71 (s, 1 H), 5.41 (d, J=17.6 Hz, 1 H), 4.90 - 5.99 (m, 1 H), 4.81 (d, J=12.4 Hz, 1 H), 4.28 - 4.53 (m, 3 H), 4.11 - 4.23 (m, 5 H), 3.84 - 3.92 (m, 1 H), 3.78 - 3.84 (m, 2 H), 3.32 - 3.49 (m, 2 H), 3.15 - 3.24 (m, 1 H), 2.90 - 3.14 (m, 3 H), 2.62 - 2.75 (m, 1 H), 2.39 - 2.51 (m, 2 H), 1.96 - 2.24 (m, 5 H), 1.84 - 1.95 (m, 3 H).

[0297] (17R,19S)-9-Chloro-30-fluoro-24-(((7aS)-2-methylidenetetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-15-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-19-ol and (17R,19S)-9-Chloro-30-fluoro-24-(((7aS)-2- methylidenetetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-15-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-19-ol (Example 1-003 and 1-006).

[0298] Step 1. (S)-4-(tert-Butoxy)-7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin- 7a(5H)yl)methoxy)pyrido [4,3-d]pyrimidine. To a round-bottom flask was added a solution of (S)- (2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (0.53 g, 3.50 mmol, Chemscene) in tetrahydrofuran (10 mL). t-BuOLi (0.55 g, 6.90 mmol) and 4-(tert-butoxy)-2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidine (1.00 g, 3.45 mmol, Step 1 of Intermediate B) were added subsequently at 0 °C. The reaction mixture was stirred at room temperature for 12 h, was then quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–100% ethyl acetate in petroleum ether, to provide (S)-4-(tert-butoxy)-7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a (5H)yl)methoxy)pyrido [4,3-d]pyrimidine (2.00 g, 4.90 mmol, 71% yield). m / z (ESI): 407.3 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 8.85 (s, 1 H), 4.94 (s, 2 H), 4.17 - 4.39 (m, 2 H), 3.76 (d, J=13.6Hz, 1 H), 3.29 (d, J=14.4 Hz, 1 H), 3.21 (s, 1 H), 2.77 (d, J=15.6 Hz, 1 H), 2.61 - 2.72 (m, 1 H), 2.42 (d, J=16.0 Hz, 1 H), 2.08 - 2.21 (m, 1 H), 1.90 - 1.99 (m, 2 H), 1.76 (s, 10 H).

[0299] Step 2. tert-Butyl (3R,5S)-3-((4-(4-(4-(tert-butoxy)-8-fluoro-2-(((S)-2- methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butoxy)methyl)-5-(methoxymethoxy)piperidine- 1-carboxylate. In a sealed tube, a mixture of (S)-4-(tert-butoxy)-7-chloro-8-fluoro-2-((2- methylenetetrahydro-1H-pyrrolizin-7a (5H)yl)methoxy)pyrido [4,3-d]pyrimidine (0.50 g, 1.20 mmol), tert-butyl (3R,5S)-3-((4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)butoxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (Intermediate C, 0.94 g, 1.40 mmol), cataCXium A Pd G3 (0.18 g, 0.25 mmol) and K3PO4(0.78 g, 3.7 mmol) in 2-MeTHF (10 mL) and water (1 mL) was degassed and purged with N2. The reaction mixture was stirred at 110 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a gradient of 5–100% ethyl acetate in petroleum ether, to provide tert-butyl (3R,5S)-3-((4-(4-(4-(tert-butoxy)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)butoxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (0.80 g, 0.85 mmol, 69% yield). m / z (ESI): 936.5 (M+H)+.

[0300] Step 3.7-(6-Chloro-5-(4-(((3R,5S)-5-hydroxypiperidin-3-yl)methoxy)butyl)-1H- indazol-4-yl)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. To a solution of tert-butyl (3R,5S)-3-((4-(4-(4-(tert- butoxy)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butoxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate (0.20 g, 0.21 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 5 h, was then combined with other four batches (4 x 0.2 g scale) and adjusted to pH 8 by addition of aqueous NH4OH solution. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um; mobile phase: [A: H2O (0.05% NH4OH + 10 mM NH4HCO3), B: ACN]; gradient: 20–50%) to provide 7-(6-chloro-5-(4-(((3R,5S)-5-hydroxypiperidin-3-yl)methoxy)butyl)- 1H-indazol-4-yl)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.12 g, 0.18 mmol, 22% yield). m / z (ESI): 652.3 (M+H)+.

[0301] Step 4. (17RS,19SR)-9-Chloro-30-fluoro-24-(((7aS)-2-methylidenetetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-15-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-19-ol. To a solution of 7-(6-chloro-5-(4-(((3R,5S)-5- hydroxypiperidin-3-yl)methoxy)butyl)-1H-indazol-4-yl)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (30 mg, 0.046 mmol) in CH3CN (10 mL) and DMSO (1 mL) was added DIPEA (40 µL, 0.23 mmol) and BrOP (54 mg, 0.14 mmol). Then the mixture was stirred at room temperature for 2 h, was then combined with other four batches (3 x 30 mg scale) and concentrated under reduced pressure to remove acetonitrile. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 x 40 mm x 10 um; mobile phase: [A: H2O (0.05% NH3H2O + 10 mM NH4HCO3), B: ACN]; gradient: 30–60%) to provide (17RS,19SR)-9- chloro-30-fluoro-24-(((7aS)-2-methylidenetetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)- 15-oxa-5,6,21,23,25,29-hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-19-ol (35 mg, 0.055 mmol, 30% yield). m / z (ESI): 634.1 (M+H)+.

[0302] Step 5. SFC purification. (17RS,19SR)-9-chloro-30-fluoro-24-(((7aS)-2- methylidenetetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-15-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-19-ol (35 mg, 0.055 mmol) was separated by SFC (Column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 um); Mobile phase: A for CO2and B for MeOH (0.1% NH4OH); Gradient: B%= 55% isocratic elution mode; Flow rate: 80 g / min) to give Peak 1 as (17R,19S)-9-chloro-30-fluoro-24-(((7aS)-2-methylidenetetrahydro-1H-pyrrolo[1,2-a]pyrrol- 7a(5H)-yl)methoxy)-15-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-19-ol (18 mg, 0.028 mmol). m / z (ESI): 634.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.09 (s, 1 H), 7.80 (s, 1 H), 7.56 (s, 1 H), 5.12 (d, J=14.4 Hz, 1 H), 4.88 - 5.04 (m, 3 H), 4.43 (d, J=9.6 Hz, 1 H), 4.31 (d, J=10.8 Hz, 1 H), 4.12 (s, 1 H), 3.92 - 4.08 (m, 1 H), 3.86 (d, J=14.0 Hz, 1 H), 3.62 (d, J=12.4 Hz, 1 H), 3.32 - 3.39 (m, 1 H), 3.27 (d, J=14.4 Hz, 1 H), 3.16 (d, J=13.2 Hz, 1 H), 3.03 - 3.08 (m, 1 H), 2.69 - 3.02 (m, 1 H), 2.91 - 2.96 (m, 1 H), 2.84 - 2.90 (m, 1 H), 2.64 - 2.79 (m, 2 H), 2.31 - 2.47 (m, 3 H), 2.07 - 2.15 (m, 1 H), 1.82 - 1.97 (m, 4 H), 1.65 - 1.81 (m, 2 H), 1.17 - 1.21 (m, 2 H), 1.14 (d, J=6.0 Hz, 3 H).19F NMR (376 MHz, CDCl3) δ ppm -140.25 (s, 1 F).

[0303] Peak 2, (17S,19R)-9-Chloro-30-fluoro-24-(((7aS)-2-methylidenetetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-15-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-19-ol (17 mg, 0.027 mmol). m / z (ESI): 634.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.08 (s, 1 H), 7.81 (s, 1 H), 7.53 (s, 1 H), 4.94 - 5.07 (m, 2 H), 4.90 (s, 2 H), 4.30 (d, J=10.4 Hz, 1 H), 4.19 (d, J=10.8 Hz, 1 H), 4.08 (s, 1 H), 3.72 (d, J=14.0 Hz, 1 H), 3.61 (d, J=12.8 Hz, 1 H), 3.25 (d, J=14.4 Hz, 1 H), 3.12 - 3.21 (m, 2 H), 3.02 - 3.07 (m, 1 H), 2.90 - 2.99 (m, 2 H), 2.58 - 2.76 (m, 3 H), 2.31 - 2.45 (m, 3 H), 2.12 - 2.21 (m, 1 H), 1.80 - 2.02 (m, 5 H), 1.65 - 1.78 (m, 2 H), 1.25 - 1.35 (m, 2 H), 1.16 - 1.23 (m, 3 H).19F NMR (376 MHz, CDCl3) δ ppm -140.49 (s, 1 F).

[0304] (17RS,19SR)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-19-hydroxy-13,15-dioxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-14-one bis(2,2,2-trifluoroacetate) (Example 2-012).

[0305] Step 1. rac-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl (((3R,5S)-5-(methoxymethoxy)piperidin-3-yl)methyl) carbonate. To a stirred solution of 2-(4- bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethan-1-ol (Intermediate D, 0.50 g, 1.39 mmol) in tetrahydrofuran (2.5 mL) was added 1,1'-carbonyldiimidazole (0.27 g, 1.70 mmol). The reaction mixture was then stirred at room temperature. In a separate vial a solution of rel-tert-butyl (3R,5S)-3-(hydroxymethyl)-5-(methoxymethoxy)piperidine-1-carboxylate (Intermediate E, 0.57 g, 2.10 mmol) in tetrahydrofuran (4.5 mL) was cooled to 0 °C and sodium hydride (60 wt% in mineral oil, 0.14 g, 3.5 mmol) was added. The resulting mixture was stirred at 0 °C for 1 h. The solution containing 2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethan-1-ol was then added and the resulting mixture was stirred at 0 °C for 1.5 h. The reaction mixture quenched via the slow addition of saturated aqueous ammonium chloride solution and extracted with CH2Cl2. The combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 5–40% ethyl acetate in heptane, to provide rel-2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)ethyl (((3R,5S)-5-(methoxymethoxy)piperidin-3-yl)methyl) carbonate (0.72 g, 1.10 mmol, 79% yield). m / z (ESI, +ve ion): 561.8 (M+H-Boc)+.

[0306] Step 2. rel-tert-Butyl (3R,5S)-3-((((2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)ethoxy)carbonyl)oxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate. A 40 mL vial was charged with rel-tert-butyl (3R,5S)- 3-((((2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)ethoxy)carbonyl)oxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (0.72 g, 1.10 mmol),bis(pinacalato)diboron (0.33 g, 1.3 mmol), tris(4-methoxyphenyl)phosphine (39 mg, 0.11 mmol), palladium(II) acetate (12 mg, 0.06 mmol), and cesium carbonate (0.54 g, 1.6 mmol). The solids were suspended in ethyl acetate (2.2 mL), and the reaction mixture was sparged with nitrogen before being heated to 80 °C for 5.5 h. After cooling to room temperature, the reaction mixture was filtered through a pad celite, and the filtrate was concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–40% ethyl acetate in heptane, to provide rel-tert-butyl (3R,5S)-3-((((2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)ethoxy)carbonyl)oxy)methyl)-5-(methoxymethoxy)piperidine-1- carboxylate (0.54 g, 0.76 mmol, 70% yield). m / z (ESI): 708.2 (M+H)+.

[0307] Step 3. rel-tert-Butyl (3R,5S)-3-((((2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethoxy)carbonyl)oxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate. A 40 mL vial was charged with rel-tert-butyl (3R,5S)- 3-((((2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazol-5-yl)ethoxy)carbonyl)oxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (0.30 g, 0.42 mmol), cataCXium A Pd G3 (36 mg, 0.050 mmol), potassium phosphate (0.21 g, 0.99 mmol), and 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate B, 0.14 g, 0.33 mmol). The vial was purged with nitrogen and then the reactants were suspended in degassed 2-methyltetrahydrofuran (3.0 mL) and water (0.3 mL). The reaction mixture was stirred at 80 °C for 2.5 h. After cooling to room temperature, the reaction was concentrated and the residue was purified by column chromatography on silica gel, eluting with a gradient of 0–60% of a 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to provide rel-tert-butyl (3R,5S)-3-((((2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethoxy)carbonyl)oxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate (0.19 g, 0.20 mmol, 62% yield). m / z (ESI): 958.2 (M+H)+.

[0308] Step 4. rel-2-(6-Chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)ethyl (((3R,5S)-5- hydroxypiperidin-3-yl)methyl) carbonate. A 20-mL vial was charged with rel-tert-butyl (3R,5S)-3- ((((2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)ethoxy)carbonyl)oxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (0.19 g, 0.20 mmol) and acetonitrile (2 mL). Hydrogen chloride (4 N solution in 1,4-dioxane, 1.0 mL, 4.0 mmol) was added and the reaction was stirred at room temperature for 30 min, then concentrated under reduced pressure. The resultant solid was then redissolved in methanol and free-based using a PL-HCO3tube.The fractions collected were concentrated to provide rel-2-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H- indazol-5-yl)ethyl (((3R,5S)-5-hydroxypiperidin-3-yl)methyl) carbonate (0.11 g, 0.16 mmol, 78% yield). m / z (ESI): 674.2 (M+H)+.

[0309] Step 5. (17R,19S)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-19-hydroxy-13,15-dioxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-14-one bis(2,2,2-trifluoroacetate) and (17S,19R)-9-chloro-30- fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-19- hydroxy-13,15-dioxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-14-one bis(2,2,2-trifluoroacetate). A vial was charged with rel-2- (6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)ethyl (((3R,5S)-5-hydroxypiperidin-3- yl)methyl) carbonate (0.11 g, 0.16 mmol), dimethyl sulfoxide (2 mL), acetonitrile (30 mL) and DIPEA (0.3 mL, 1.6 mmol). Bromotris(dimethylamino)phosphonium hexafluorophosphate (0.31 g, 0.79 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and the crude material was purified via HPLC to provide a mixture of (17R,19S)-9-chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)- yl)methoxy)-19-hydroxy-13,15-dioxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-14-one bis(2,2,2-trifluoroacetate) and (17S,19R)-9-chloro-30- fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-19- hydroxy-13,15-dioxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-14-one bis(2,2,2-trifluoroacetate) (12 mg, 0.014 mmol, 9% yield). m / z (ESI): 656.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.27 – 9.37 (m, 1 H), 7.81 – 7.95 (m, 2 H), 5.50 – 5.72 (m, 1 H), 5.26 – 5.45 (m, 1 H), 5.05 – 5.20 (m, 1 H), 4.82 – 4.89 (m, 1 H), 4.49 – 4.71 (m, 2 H), 4.15 – 4.24 (m, 1 H), 3.70 – 4.13 (m, 7 H), 3.37 – 3.58 (m, 3 H), 3.07 – 3.19 (m, 1 H), 2.55 – 2.90 (m, 2 H), 2.55 – 2.98 (m, 3 H), 2.33 – 2.55 (m, 3 H), 2.09 – 2.30 (m, 3 H), 1.69 – 1.82 (m, 1 H).19F NMR (376 MHz, METHANOL-d4) δ ppm -77.32 (s, 6 F), -143.11 – -142.87 (m, 1 F), -174.16 – -173.98 (m, 1 F).

[0310] (26R)-18-Chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol- 7a(5H)-yl)methoxy)-23,25-dioxa-28-thia-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (Example 2-048) and (26S)-18-chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25-dioxa-28-thia- 1,3,5,9,14,15-hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (Example 2-019).

[0311] Step 1.1,4-Thiazepan-6-ol hydrochloride. A 40-mL vial was charged with tert-butyl 6- hydroxy-1,4-thiazepane-4-carboxylate (2.62 g, 11.2 mmol, LabNetwork Inc.) and 1,4-dioxane (14 mL). To the stirred solution was added HCl (4 M in 1,4-dioxane, 42.0 mL, 168 mmol). The reaction mixture was stirred at room temperature for 2 h, was then fully concentrated to give 1,4-thiazepan-6- ol hydrochloride (1.90 g, 11.2 mmol, 100% yield). m / z (ESI): 134.0 (M+H-HCl)+.1H NMR (400 MHz CDCl3) δ ppm 3.83 – 3.61 (m, 12 H).

[0312] Step 2.4-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepan-6-ol. A 250-mL round-bottom flask was charged with 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 (Intermediate F, 4.00 g, 9.12 mmol) and acetonitrile (36 mL). To the stirred solution, 1,4-thiazepan-6-ol hydrochloride (1.93 g, 11.4 mmol) and N,N- diisopropylethylamine (8.7 mL, 50 mmol) were added then the solution was heated to 60 °C for 10 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by column chromatography on silica gel, eluting with 0–80% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepan-6-ol (2.50 g, 5.30 mmol, 5% yield). m / z (ESI): 471.8 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.13 – 8.97 (m, 1H), 4.58 – 4.05 (m, 6 H), 3.82 – 3.75 (m, 1 H), 3.28 – 3.19 (m, 2 H), 3.21 – 2.99 (m, 4 H), 2.94 – 2.68 (m, 2 H), 2.42 – 1.90 (m, 6 H), 1.34 – 1.23 (m, 2 H).19F NMR (376 MHz, METHANOL-d4) δ ppm - 135.3 – -138.1 (m, 1 F), -173.7 (br d, J =3.5 Hz).

[0313] Step 3.4-(7-(5-(3-((tert-Butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepan-6-ol. A 100-mL round-bottom flask was charged with potassium phosphate (1.35 g, 6.36 mmol), 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepan-6-ol (1.00 g, 2.13 mmol), 5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate G, 2.10 g, 3.18 mmol,), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2’-amino-1,1’-biphenyl)]palladium(II) (0.31 g, 0.42 mmol). The flask was purged with nitrogen, and then the reactants were suspended in dry 2- methyltetrahydrofuran (18 mL) and water (3.5 mL). The reaction mixture was heated to 80 °C for 2.5 h. After cooling to room temperature, the solution was concentrated and the crude mixture was purified by column chromatography on silica gel, eluting with 0–100% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield 4-(7-(5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepan-6-ol (1.63 g, 1.68 mmol, 79% yield). m / z (ESI): 967.8 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.23 – 9.07 (m, 1 H), 8.01 – 7.91 (m, 1 H), 7.65 – 7.46 (m, 6 H), 7.46 – 7.22 (m, 8 H), 5.89 – 5.77 (m, 1 H), 4.59 – 4.43 (m, 1 H), 4.43 – 4.21 (m, 4 H), 4.05 – 3.76 (m, 3 H), 3.76 – 3.54 (m, 3 H), 3.27 – 3.19 (m, 2 H), 3.08 – 2.84 (m, 6 H), 2.84 – 2.61 (m, 2 H), 2.54 – 2.40 (m, 2 H), 2.35 – 2.09 (m, 5 H), 1.92 – 1.78 (m, 5 H), 1.70 (br s, 2 H), 1.39 – 1.22 (m, 13 H), 0.92 (br t, J = 6.5 Hz, 7 H), 0.88 – 0.79 (m, 10 H).19F NMR (376 MHz, METHANOL-d4) δ ppm -136.6 – -140.4 (m, 1 F), -171.54 – -175.8 (m, 1 F).

[0314] Step 4. N-(Tetrahydro-2H-pyran-2-yl)-18-chloro-32-fluoro-4-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25-dioxa-28-thia-1,3,5,9,14,15 hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one. A 100-mL round-bottom flask was charged with 4-(7-(5- (3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-1,4-thiazepan-6-ol (1.63 g, 1.68 mmol), and 1,1'-carbonyldiimidazole (0.82 g, 5.1 mmol). The solids were suspended in tetrahydrofuran (17 mL) and the reaction mixture was stirred at 40 °C for 1 h to yield 4-(7-(5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1,4-thiazepan-6-yl 1H-imidazole-1-carboxylate. m / z (ESI): 1062.0 (M+H)+.

[0315] The above reaction mixture was transferred to a 500-mL round-bottom flask and the solution was diluted with tetrahydrofuran (250 mL). To the stirred reaction mixture was added tetrabutylammonium fluoride (1 M in THF, 4.2 mL, 4.2 mmol) and the reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel, eluting with 0–80% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield N-(tetrahydro-2H-pyran-2-yl)-18-chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25-dioxa-28-thia-1,3,5,9,14,15 hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (1.60 g, 2.12 mmol). m / z (ESI): 755.8 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.45 – 9.37 (m, 1 H), 8.18 – 8.09 (m, 1 H), 7.84 – 7.75 (m, 1 H), 5.98 – 5.87 (m, 1 H), 5.48 – 5.16 (m, 2 H), 4.91 – 4.78 (m, 2 H), 4.24 – 4.21 (m, 1 H), 4.27 – 4.06 (m, 2 H), 3.94 – 3.63 (m, 5 H), 3.20 – 2.80 (m, 8 H), 2.42 – 1.95 (m, 8 H), 1.94 – 1.71 (m, 7 H), 1.64 – 1.49 (m, 2 H).19F NMR (376 MHz, DMSO-d6) δ ppm -139.93 – -142.38 (m, 1 F), -170.72 – -173.67 (m, 1 F).

[0316] Step 5.18-Chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol- 7a(5H)-yl)methoxy)-23,25-dioxa-28-thia-1,3,5,9,14,15 hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one. A 100-mL round bottom flask was charged with N- (tetrahydro-2H-pyran-2-yl)-18-chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-23,25-dioxa-28-thia-1,3,5,9,14,15 hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (1.60 g, 2.12 mmol), dichloromethane (21 mL), and trifluoroacetic acid (4.8 mL, 24 mmol) dropwise. The reaction mixture was stirred at room temperature for 4 h, then was concentrated. The crude material was purified by reversed phase chromatography using a C18 column, eluting with a gradient of 0–100% of MeCN in water (0.1% TFA as an additive) to give 18-chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-23,25-dioxa-28-thia-1,3,5,9,14,15 hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (0.49 g, 0.73 mmol, 34% yield) as a mixture of diasteroisomers after lyophilization. m / z (ESI): 672.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.28 – 9.13 (m, 1 H), 8.03 – 7.94 (m, 1 H), 7.64 – 7.49 (m, 1 H), 5.89 – 5.78 (m, 1 H), 4.43 – 4.33 (m, 2 H), 4.20 – 3.92 (m, 4 H), 3.91 – 3.77 (m, 1 H), 3.35– 3.26 (m, 5 H), 2.93 – 2.62 (m, 3H), 2.39 – 2.21 (m, 2 H), 2.16 – 1.90 (m, 10 H), 1.84 (s, 11 H), 1.72 – 1.56 (m, 4 H), 1.49 – 1.38 (m, 12 H), 1.29 – 1.22 (m, 3 H).19F NMR (376 MHz, METHANOL-d4) δ ppm -138.13 – -141.40 (m, 1 F), - 171.86 – -174.65 (m, 1 F).

[0317] Step 6. (26R)-18-Chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-23,25-dioxa-28-thia-1,3,5,9,14,15hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (Example 2-048) and (26S)-18-chloro-32-fluoro-4- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25-dioxa-28-thia- 1,3,5,9,14,15-hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (Example 2-019). The mixture of diastereomers from Step 5 was purified via SFC using an (S,S) Whelk-0, 2 x 25 cm, 5 µm column with a mobile phase of 50% MeOH with 0.2% DEA using a flow rate of 80 mL / min. The first peak was assigned as (26R)- 18-chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)- 23,25-dioxa-28-thia-1,3,5,9,14,15 hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (Example 2-048, 0.20 g, 0.29 mmol, 42% yield). m / z (ESI): 672.6 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 13.28 (br s, 1 H), 9.47 – 9.29 (m, 1 H), 7.90 – 7.81 (m, 1 H), 7.78 – 7.66 (m, 1 H), 5.51 – 5.28 (m, 2 H), 5.22 (br s, 1 H), 4.93 – 4.79 (m, 2 H), 4.26 – 4.08 (m, 3 H), 3.80 – 3.65 (m, 2 H), 3.52 – 3.42 (m, 1 H), 3.42 – 3.41 (m, 1 H), 3.25 – 3.01 (m, 4 H), 2.95 – 2.94 (m, 1 H), 2.94 – 2.81 (m, 2 H), 2.29 (dd, J = 14.6, 10.0 Hz, 1 H), 2.22 – 1.99 (m, 3 H), 1.91 – 1.72 (m, 5 H).19F NMR (376 MHz, DMSO-d6) δ ppm -139.12 – -142.21 (m, 1 F), -170.78 – -173.38 (m, 1 F).

[0318] The second peak was assigned as (26S)-18-chloro-32-fluoro-4-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25-dioxa-28-thia-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (Example 2-019, 0.17 g, 0.26 mmol, 36% yield). m / z (ESI): 672.8 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 13.4 – 13.2 (m, 1 H), 9.47 – 9.35 (m, 1 H), 7.89 – 7.81 (m, 1 H), 7.82 – 7.66 (m, 1 H), 5.51 – 5.18 (m, 2 H), 4.91 – 4.79 (m, 2 H), 4.30 – 4.05 (m, 3 H), 3.82 – 3.63 (m, 2 H), 3.54 – 3.31 (m, 3 H), 3.15 – 2.99 (m, 4 H), 3.03 – 2.72 (m, 4 H), 2.41 – 1.70 (m, 9 H).19F NMR (376 MHz, DMSO-d6) δ ppm -139.12 – -142.86 (m, 1 F), -170.94 – -173.38 (m, 1 F).

[0319] (12E,17R,19S)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-15-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,12,22,24,26,28-decaen-19-ol (Example 2-009)

[0320] Step 1.2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)acetaldehyde. A round-bottom flask was charged with 2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)ethan-1-ol (Intermediate D, 2.00 g, 5.56 mmol), Dess-Martin periodinane (2.83 g, 6.67 mmol) and dichloromethane (18 mL). The reaction mixture was stirred at room temperature for 2 h, was then diluted with saturated aqueous sodium bicarbonate and washed with saturated aqueous sodium thiosulfate. The aqueous phase was extracted with DCM and the combined organic phases were washed with saturated aqueous thiosulfate, aqueous sodium bicarbonate, brine, dried over anhydrous Na2SO4, filtered, and concentrated to provide 2-(4-bromo-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)acetaldehyde (2.10 g, 5.87 mmol, quantitative yield) which was used directly in the next step. m / z (ESI): 357.0 / 359.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.79 (s, 1 H) 8.01 (s, 1 H) 7.54 - 7.82 (m, 1 H) 5.63 - 5.76 (m, 1 H) 4.23 - 4.31 (m, 2 H) 3.96 - 4.06 (m, 1 H) 3.72 - 3.82 (m, 1 H) 2.44 - 2.56 (m, 1 H) 2.09 - 2.20 (m, 2 H) 1.69 - 1.82 (m, 3 H).

[0321] Step 2. Methyl (E)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)but-2-enoate. A vial was charged with (2-methoxy-2-oxoethylidene)triphenylphosphorane (1.87 g, 5.59 mmol, Combi-Blocks Inc.), 2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)acetaldehyde (2.00 g, 5.59 mmol) and toluene (28 mL). The reaction mixture was heated to 100 °C for 30 min. After cooling the crude mixture was concentrated and the residue was purified by column chromatography on silica gel, eluting with 0–30% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield methyl (E)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but- 2-enoate (1.37 g, 3.31 mmol, 59% yield). m / z (ESI): 413.0 / 415.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J=12.96 Hz, 2 H) 6.98 (dt, J=15.68, 5.85 Hz, 1 H) 5.90 (dd, J=9.41, 2.30 Hz, 1 H) 5.63 (dt, J=15.62, 1.70 Hz, 1 H) 3.94 (dd, J=5.85, 1.67 Hz, 2 H) 3.84 - 3.90 (m, 1 H) 3.72 -3.82 (m, 1 H) 3.62 (s, 3 H) 2.24 - 2.44 (m, 1 H) 1.86 - 2.12 (m, 2 H) 1.63 - 1.81 (m, 1 H) 1.49 - 1.63 (m, 2 H).

[0322] Step 3. (E)-4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-2- en-1-ol. A round-bottom flask was charged with methyl (E)-4-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)but-2-enoate (1.35 g, 3.26 mmol) in dichloromethane (10 mL). The contents were cooled to -78 °C and DIBAL-H (1 M in THF, 7.2 mL, 7.2 mmol) was added dropwise, then the reaction was stirred at -78 °C for 5 min. The reaction was carefully quenched with the addition of methanol (0.036 mL / mmol DIBAL-H), then was allowed to warm to room temperature. Saturated aqueous Rochelle's salt and EtOAc were added to the reaction mixture, then the mixture was stirred vigorously for 1 h. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with Rochelle's salt, water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide (E)-4-(4- bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-2-en-1-ol (1.20 g, 3.11 mmol, 95% yield). m / z (ESI): 384.8 / 386.8 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.93 - 8.04 (m, 1 H) 7.72 - 7.87 (m, 1 H) 7.11 - 7.29 (m, 1 H) 5.75 - 5.88 (m, 2 H) 5.56 - 5.70 (m, 1 H) 4.01 (br d, J=5.64 Hz, 2 H) 3.84 (br d, J=5.02 Hz, 2 H) 2.40 - 2.51 (m, 1 H) 2.34 (s, 1 H) 2.10 - 2.18 (m, 1 H) 2.03 (s, 2 H) 1.80 - 1.90 (m, 1 H) 1.67 - 1.72 (m, 1 H).

[0323] Step 4. tert-Butyl (3R,5S)-3-((((E)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)but-2-en-1-yl)oxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate. A vial was charged with (E)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-2-en-1- ol (1.20 g, 3.11 mmol), sodium hydride (60% in mineral oil, 0.13 g, 3.30 mmol) and THF (5 mL). The reaction mixture was stirred at room temperature for 20 min. A solution of tert-butyl (3S,5R)-3- (methoxymethoxy)-5-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (Intermediate H, 0.73 g, 2.10 mmol) in THF (5 mL) was added, and the reaction mixture was heated to 45 °C for 18 h. After cooling to room temperature, the reaction was carefully quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography on silica gel, eluting with 0–10% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield tert-butyl (3R,5S)-3-((((E)-4-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-2-en-1-yl)oxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate (0.56 g, 0.87 mmol, 42% yield). m / z (ESI): 664.0 / 666.0 (M+Na)+.

[0324] Step 5. tert-Butyl (3R,5S)-3-((((E)-4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)but-2-en-1-yl)oxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate. A vial was charged with tris(4- methoxyphenyl)phosphine (36 mg, 0.10 mmol), palladium acetate (19 mg, 0.086 mmol,),4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.26 g, 1.00 mmol), cesium carbonate (0.42 g, 1.30 mmol), tert-butyl (3R,5S)-3-((((E)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)but-2-en-1-yl)oxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (0.55 g, 0.86 mmol) and ethyl acetate (1.7 mL), then sparged with nitrogen. The reaction mixture was heated to 80 °C for 1 h. After cooling to room temperature, the crude material was filtered through a plug of celite, and the filtrate was concentrated. The crude residue purified by column chromatography on silica gel, eluting with 0–10% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield tert-butyl (3R,5S)- 3-((((E)-4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indazol-5-yl)but-2-en-1-yl)oxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (0.32 g, 0.46 mmol, 54% yield). m / z (ESI): 711.9 (M+Na)+.

[0325] Step 6. tert-Butyl (3R,5S)-3-((((E)-4-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-2-en-1-yl)oxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate. A vial was charged with potassium phosphate tribasic (0.26 g, 1.20 mmol), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'- biphenyl)]palladium(II) (35 mg, 0.048 mmol), 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate B, 0.20 g, 0.48 mmol), water (0.2 mL) and 2-methyltetrahydrofuran (2.2 mL). The reaction mixture was then heated to 80 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel, eluting with 0–80% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to yield tert-butyl (3R,5S)-3-((((E)-4-(4-(4-(tert-butoxy)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-2-en-1-yl)oxy)methyl)-5- (methoxymethoxy)piperidine-1-carboxylate (60 mg, 0.064 mmol, 13% yield). m / z (ESI): 939.7 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.20 (s, 1 H) 7.74 - 7.93 (m, 1 H) 7.42 - 7.63 (m, 1 H) 5.56 - 5.82 (m, 2 H) 5.17 - 5.47 (m, 2 H) 4.65 - 4.71 (m, 2 H) 3.96 - 4.47 (m, 5 H) 3.72 - 3.87 (m, 3 H) 3.44 - 3.65 (m, 3 H) 2.98 - 3.32 (m, 6 H) 1.71 - 2.59 (m, 29 H) 1.45 (s, 9 H).

[0326] Step 7.7-(6-Chloro-5-((E)-4-(((3R,5S)-5-hydroxypiperidin-3-yl)methoxy)but-2-en-1- yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. A round-bottom flask was charged with tert-butyl (3R,5S)- 3-((((E)-4-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but- 2-en-1-yl)oxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (55 mg, 0.058 mmol) and dichloromethane (1.2 mL). Hydrogen chloride (4 N in 1,4-dioxane, 0.4 mL, 1.6 mmol) was added andthe reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness to provide 7-(6-chloro-5-((E)-4-(((3R,5S)-5-hydroxypiperidin-3-yl)methoxy)but-2-en-1-yl)- 1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. m / z (ESI): 656.2 (M+H)+.

[0327] Step 8. (12E,17R,19S)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-15-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,12,22,24,26,28-decaen-19-ol. A round-bottom flask was charged with 7-(6-chloro-5- ((E)-4-(((3R,5S)-5-hydroxypiperidin-3-yl)methoxy)but-2-en-1-yl)-1H-indazol-4-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (38 mg, 0.058 mmol), N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.58 mmol) and tetrahydrofuran (12 mL). PyBOP (60 mg, 0.12 mmol) was added, and the reaction mixture was stirred at room temperature for 20 h. The crude reaction mixture was purified by column chromatography on silica gel, eluting with 0–80% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, followed by purification by HPLC using an XBridge C18, 19 x 100 mm, 5 um column, eluting with a gradient from 30–60% acetonitrile with 0.1% NH4OH in water with 0.1% NH4OH, to provide (12E,17R,19S)-9-chloro-30-fluoro-24- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-15-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,12,22,24,26,28-decaen-19-ol (2.6 mg, 0.0041 mmol, 7% yield). m / z (ESI): 638.2 (M+H)+.1H NMR (600 MHz, DMSO-d6) δ ppm 9.09 - 9.26 (m, 1 H) 7.68 - 7.95 (m, 2 H) 4.93 - 5.37 (m, 4 H) 4.48 - 4.79 (m, 2 H) 3.89 - 4.21 (m, 5 H) 3.71 (br d, J=13.79 Hz, 2 H) 2.96 - 3.33 (m, 7 H) 2.78 - 2.86 (m, 1 H) 1.69 - 2.14 (m, 9 H) 1.43 - 1.55 (m, 1 H).

[0328] (28S,32R)-18-Chloro-33-fluoro-4-(((7aS)-2-methylidenetetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-1,3,5,9,14,15,25- heptaazaheptacyclo[23.5.2.1~6,10~.0~2,7~.0~11,19~.0~12,16~.0~28,32~]tritriaconta- 2,4,6,8,10(33),11,13,16,18-nonaen-24-one (Example 1-005).

[0329] Step 1. (S)-4-(tert-Butoxy)-7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a 40-mL vial was charged with 4-(tert-butoxy)- 2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (0.60 g, 2.1 mmol, Step 1 in Intermediate B), acetonitrile (7 mL), and N,N-diisopropylethylamine (1.1 mL, 6.2 mmol). (S)-(2-Methylenetetrahydro- 1H-pyrrolizin-7a(5H)-yl)methanol (0.48 g, 3.10 mmol, Chemscene) was then added and the reaction mixture was heated to 60 °C for 18 h. After cooling to room temperature the mixture was concentrated and the residue was purified by column chromatography on silica gel, eluting with a gradient of 0–85% 3:1 EtOAc / EtOH (with 2% TEA) in heptane, to give (S)-4-(tert-butoxy)-7-chloro- 8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.54 g, 1.30 mmol, 64% yield). m / z (ESI): 407.0 (M+H)+.

[0330] Step 2. Methyl 5-(4-(4-(tert-butoxy)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)pentanoate. A vial was charged with potassium phosphate tribasic (0.85 g, 4.00 mmol), (S)-4-(tert-butoxy)-7-chloro-8-fluoro-2-((2-methylenetetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidine (0.54 g, 1.30 mmol), methyl 5-(6-chloro-1-(tetrahydro-2H- pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)pentanoate (Intermediate I, 0.82 g, 1.70 mmol), water (0.8 mL) and 2-methyltetrahydrofuran (8 mL). The solution was degassed by sparging with nitrogen and then (S)-(-)-2-(diphenylphosphino)-2-methoxy- 1-,1-binaphthyl(S)-MOP (0.25 g, 0.53 mmol) was added. The reaction was then heat at 80 °C for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by column chromatography on silica gel, eluting with a gradient of 0–60% 3:1 EtOAc / EtOH(with 2% TEA) in heptane, to give methyl 5-(4-(4-(tert-butoxy)-8-fluoro-2-(((S)-2- methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (0.45 g, 0.63 mmol, 47% yield). m / z (ESI): 710.8 (M+H)+.

[0331] Step 3.5-(4-(4-(tert-Butoxy)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)pentanoic acid. To a 40-mL vial was charged with methyl 5-(4-(4-(tert-butoxy)-8- fluoro-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoate (0.45 g, 0.63 mmol), tetrahydrofuran (1.6 mL), and water (1.6 mL). Lithium hydroxide, monohydrate (53 mg, 1.3 mmol) was added, and the reaction mixture was stirred at 45 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with ethanol and stirred at room temperature for 4.5 h. The solution was then concentrated and lyophilized to give 5-(4-(4-(tert-butoxy)-8-fluoro-2-(((S)-2- methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoic acid (0.42 g, 0.59 mmol, 95% yield). m / z (ESI): 707.2 (M+H)+.

[0332] Step 4. tert-Butyl (3aR,7aR)-1-(5-(4-(4-(tert-butoxy)-8-fluoro-2-(((S)-2- methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoyl)octahydro-6H-pyrrolo[2,3-c]pyridine- 6-carboxylate. To a 40-mL vial was charged with 5-(4-(4-(tert-butoxy)-8-fluoro-2-(((S)-2- methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoic acid (0.42 g, 0.59 mmol), N,N- dimethylformamide (6 mL), and N,N’-diisopropylethylamine (0.3 mL, 1.8 mmol). The solution was cooled to 0 °C and HATU (0.27 g, 0.71 mmol) was added. The reaction mixture was stirred for 5 min and then tert-butyl(3aR,7aR)-1,2,3,3a, 4,5,7,7a-octahydropyrrolo[2,3-c] pyridine-6-carboxylate (0.18 g, 0.80 mmol, AA Blocks) was added. The reaction mixture was stirred at 0 °C for 45 min and then purified by reversed phase column chromatography, eluting with a gradient of 5–100% 0.1% formic acid in CH3CN / H2O to give tert-butyl (3aR,7aR)-1-(5-(4-(4-(tert-butoxy)-8-fluoro-2-(((S)-2- methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoyl)octahydro-6H-pyrrolo[2,3-c]pyridine-6- carboxylate (0.35 g, 0.38 mmol, 64% yield). m / z (ESI): 914.8 (M+H)+.

[0333] Step 5.5-(6-Chloro-4-(8-fluoro-4-hydroxy-2-(((S)-2-methylenetetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)-1-((3aS,7aR)- octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)pentan-1-one. To a 20-mL vial was charged with tert- butyl (tert-butyl (3aR,7aR)-1-(5-(4-(4-(tert-butoxy)-8-fluoro-2-(((S)-2-methylenetetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pentanoyl)octahydro-6H-pyrrolo[2,3-c]pyridine-6-carboxylate (0.35 g, 0.38 mmol), dichloromethane (2.5 mL), and HCl (4 M in 1,4-dioxane, 3.3 mL, 13.2 mmol) dropwise. The reaction mixture was stirred at room temperature for 15 min and then 3 mL of isopropanol was added and stirred for an additional 10 min. The reaction was concentrated, loaded onto a SCX column with methanol, and eluted with 2 M ammonia in methanol to give 5-(6-chloro-4-(8-fluoro-4-hydroxy-2- (((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H- indazol-5-yl)-1-((3aS,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)pentan-1-one (0.22 g, 0.33 mmol, 86% yield). m / z (ESI): 675.0 (M+H)+.

[0334] Step 6. (28S,32R)-18-Chloro-33-fluoro-4-(((7aS)-2-methylidenetetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-1,3,5,9,14,15,25- heptaazaheptacyclo[23.5.2.1~6,10~.0~2,7~.0~11,19~.0~12,16~.0~28,32~]tritriaconta- 2,4,6,8,10(33),11,13,16,18-nonaen-24-one diformate. To a 40-mL vial was charged with 5-(6- chloro-4-(8-fluoro-4-hydroxy-2-(((S)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)-1-((3aS,7aR)-octahydro-1H-pyrrolo[2,3- c]pyridin-1-yl)pentan-1-one (0.22 g, 0.32 mmol), dimethylsulfoxide (5.3 mL), acetonitrile (27 mL), and N,N’-diisopropylethylamine (0.21 mL, 1.30 mmol). To this was added with vigorous stirring bromotris(dimethylamino)phosphonium hexafluorophosphate (0.20 g, 0.51 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated. The crude material was purified by reversed phase column chromatography, eluting with a gradient of 5–100% 0.1% formic acid in CH3CN / H2O, to give (28S,32R)-18-chloro-33-fluoro-4-(((7aS)-2-methylidenetetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-1,3,5,9,14,15,25- heptaazaheptacyclo[23.5.2.1~6,10~.0~2,7~.0~11,19~.0~12,16~.0~28,32~]tritriaconta- 2,4,6,8,10(33),11,13,16,18-nonaen-24-one (35 mg, 0.047 mmol, 14% yield). m / z (ESI): 657.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.21 (s, 1H), 8.55 - 8.57 (m, 1H), 8.21 - 8.18 (m, 1H), 7.75 - 7.81 (m, 2H), 5.50 - 5.58 (m, 1H), 5.10 (br s, 2H), 4.88 – 4.95 (m, 1H), 4.46 (br d, 2H, J=14.8 Hz), 3.51 – 3.94 (m, 3H), 3.50 - 3.57 (m, 2H), 3.26 - 3.39 (m, 2H), 2.76 – 2.95 (m, 4H), 2.54 - 2.65 (m, 2H), 2.38 - 2.45 (m, 1H), 2.20 - 2.31 (m, 2H), 1.89 - 2.07 (m, 7H), 1.54 - 1.66 (m, 2H), 1.39 - 1.51 (m, 2H), 1.28 - 1.39 (m, 2H).19F NMR (376 MHz, METHANOL-d4) δ ppm -142.28 (s, 1F).

[0335] (16R,17R)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-16-hydroxy-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-15-one (Example 2-003).

[0336] Step 1. tert-Butyl (R)-3-(((((Z)-4-(2-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-4- (methoxymethoxy)phenyl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate. A suspension of 4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidine (Intermediate J, 0.41 g, 0.61 mmol), tert- butyl (3R)-3-(6-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1- (methoxymethoxy)-2-oxohexyl)piperidine-1-carboxylate (Intermediate K, 0.20 g, 0.30 mmol), Catacxium A Pd G3 (44 mg, 0.061 mmol), copper(I) iodide (2 mg, 0.15 mmol) and lithium chloride (26 mg, 0.61 mmol) in DMF (2 mL) was sparged with nitrogen and then heated at 100 °C for 4 h. After cooling to room temperature, the crude material purified by column chromatography on silica gel, eluting with a gradient of 0–90% 3:1 EtOAc / EtOH (with 1% TEA) in heptane, followed by purification on a reversed phase C18 column, eluting with a gradient of 5–100% (0.1% formic acid MeCN) / (0.1% formic acid water), to give 96 mg of desired product. m / z (ESI): 953.8 (M+H)+.

[0337] Step 2.6-(6-Chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)-1-hydroxy-1-((R)- piperidin-3-yl)hexan-2-one. To a 100-mL round-bottom flask was added tert-butyl (R)-3-(((((Z)-4- (2-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-4-(methoxymethoxy)phenyl)but-3-en-1- yl)oxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (80 mg, 0.084 mmol) and HCl (4.0 M in 1,4-dioxane, 0.6 mL, 2.4 mmol) in acetonitrile (1.7 mL). The reaction mixture was stirred at room temperature for 2 h, was then fully concentrated. The crude material was purified by reversed phase chromatography on a C18 column, eluting with a gradient of 5–100% (0.1% formic acid MeCN) / (0.1% formic acid water), followed by a SCX column to removed the formic acid, to give 6- (6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)-1-hydroxy-1-((R)-piperidin-3-yl)hexan-2-one (32 mg, 0.048 mmol, 57% yield). m / z (ESI): 669.9 (M+H)+.

[0338] Step 3. (16R,17R)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-hydroxy-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-15-one. A 50-mL round-bottom flask was charged with 6-(6- chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)-1-hydroxy-1-((R)-piperidin-3-yl)hexan-2-one (18 mg, 0.027 mmol), N-ethyl-N-isopropylpropan-2-amine (47 µL, 0.27 mmol) in acetonitrile (4.5 mL). Bromotris(dimethylamino)phosphonium hexafluorophosphate (16 mg, 0.04 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 h. The crude material was concentrated and the residue was purified by reversed phase chromatography on a C18 column, eluting with a gradient of 5–90% (0.1% formic acid MeCN) / (0.1% formic acid water), followed by column chromatography on silica gel, eluting with a gradient of 0–20% methanol (with 2 M ammonia) in DCM to give (16R,17R)-9-chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-hydroxy-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaen-15-one. m / z (ESI): 651.9 (M+H)+.

[0339] (17S,18R)-9-Chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-33-oxa-5,6,14,15,22,24,26,30- octaazaheptacyclo[25.3.1.1~13,16~.1~18,22~.0~2,10~.0~3,7~.0~23,28~]tritriaconta- 1(31),2,4,7,9,13,15,23,25,27,29-undecaen-17-ol (Example 2-020).

[0340] Step 1.3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanoic acid. To a solution of 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1- ol (Intermediate A, 4.30 g, 11.5 mmol) at 0 °C in acetone (115 mL) was added dropwise chromium trioxide solution in sulfuric acid (1.15 g, 5 mL, 11.5 mmol). The reaction mixture was stirred at room temperature for 16 h. More chromium trioxide solution in sulfuric acid (2 mL) was added and the reaction was stirred for another 2.5 h. Solid sodium thiosulfate was added and the solution was stirred for 10 min. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to provide 3- (4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanoic acid (4.41 g, 11.4 mmol, 99% yield). m / z (ESI): 387.0 / 389.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 12.1-12.5 (m, 1H), 8.0-8.1 (m, 1H), 8.02 (s, 1H), 5.88 (dd, 1H, J=2.4, 9.4 Hz), 3.8-3.9 (m, 1H), 3.7-3.8 (m, 1H), 3.2- 3.3 (m, 2H), 2.4-2.5 (m, 2H), 2.3-2.4 (m, 1H), 1.9-2.1 (m, 2H), 1.6-1.8 (m, 1H), 1.5-1.6 (m, 2H).

[0341] Step 2.3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)propanehydrazide. To solution of 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)propanoic acid (1.02 g, 2.63 mmol) in acetonitrile (8 mL) and N,N-dimethylacetamide (2 mL) was added DIPEA (0.5 mL) and HATU (1.26 g, 3.32 mmol). The mixture was stirred at room temperature for 20 min. Then the contents were added dropwise to a solution of hydrazine (0.19 mL, 6.1 mmol) and DIPEA (0.5 mL) in MeCN (10 mL) in an ice bath. The mixture was diluted with EtOAc and saturated NH4Cl. The organic phase was washed with water and brine, dried over Na2SO4,and concentrated in vacuo. The crude was purified by column chromatography on silica gel, elutingwith a gradient of 0–100% 3:1 EtOAc / EtOH in heptane, to provide 3-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanehydrazide (0.62 g, 1.50 mmol, 58% yield). m / z (ESI): 401.0 / 403.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (br s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 5.9-5.9 (m, 1H), 4.19 (br s, 2H), 3.8-3.9 (m, 1H), 3.7-3.8 (m, 1H), 3.1-3.3 (m, 2H), 2.2- 2.4 (m, 3H), 2.0-2.1 (m, 2H), 1.7-1.8 (m, 1H), 1.5-1.6 (m, 2H).

[0342] Step 3. tert-Butyl (S)-3-(2-(benzyloxy)-2-oxoethyl)piperidine-1-carboxylate. A mixture of (S)-(1-Boc-piperidino)acetic acid (10.5 g, 43.2 mmol) in N,N-dimethylformamide (86 mL) was cooled to 0 °C. Cesium carbonate (14.76 g, 45.3 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h. Benzyl bromide (5.4 mL, 45 mmol) was added and the reaction mixture was allowed to warm to room temperature with stirring for 16 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4,filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in heptane, to afford tert-butyl (S)-3-(2- (benzyloxy)-2-oxoethyl)piperidine-1-carboxylate (10.1 g, 30.2 mmol, 70% yield). m / z (ESI): 356.2 (M+Na)+.

[0343] Step 4. tert-Butyl (3R)-3-(2-(benzyloxy)-1-hydroxy-2-oxoethyl)piperidine-1- carboxylate. To a 250-mL round-bottom flask was added tetrahydrofuran (20 mL) under nitrogen atmosphere. The flask was cooled to -78 °C and potassium bis(trimethylsilyl)amide solution (0.5 M in toluene, 38 mL, 19 mmol) was added. A solution of tert-butyl (S)-3-(2-(benzyloxy)-2- oxoethyl)piperidine-1-carboxylate (4.90 g, 14.7 mmol) in tetrahydrofuran (20 mL) was added dropwise at -78 °C and the reaction mixture was stirred for 10 min.3-Phenyl-2-(phenylsulfonyl)-1,2- oxaziridine (4.99 g, 19.1 mmol, Synthonix Inc.) in tetrahydrofuran (20 mL) was then added and the mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched by the addition of saturated NH4Cl solution and was allowed to warm to room temperature. The mixture was partitioned between EtOAc and saturated NaCl solution. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in heptane, to afford tert-butyl (3R)-3-(2-(benzyloxy)-1-hydroxy-2- oxoethyl)piperidine-1-carboxylate (4.40 g, 12.6 mmol, 86% yield). m / z (ESI): 372.1 (M+H)+.

[0344] Step 5. tert-Butyl (3R)-3-(2-(benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2- oxoethyl)piperidine-1-carboxylate. To a 150-mL round-bottom flask was added tert-butyl (3R)-3- (2-(benzyloxy)-1-hydroxy-2-oxoethyl)piperidine-1-carboxylate (4.12 g, 11.8 mmol), imidazole (1.93 g, 28.3 mmol) and dichloromethane (40 mL). Then a solution of tert-butylchlorodimethylsilane (2.04 g, 13.6 mmol) in DCM (3 mL) was added. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in heptane, to afford tert-butyl (3R)-3-(2-(benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2-oxoethyl)piperidine-1-carboxylate (4.12 g, 8.85 mmol, 75% yield). m / z (ESI): 464.2 (M+H)+.

[0345] Step 6.2-((R)-1-(tert-Butoxycarbonyl)piperidin-3-yl)-2-((tert- butyldimethylsilyl)oxy)acetic acid. In a 100-mL round-bottom flask was added 10% palladium on activated carbon (0.66 g, 0.62 mmol). The flask was back-filled with nitrogen and tert-butyl (R)-3- ((S)-2-(benzyloxy)-1-((tert-butyldimethylsilyl)oxy)-2-oxoethyl)piperidine-1-carboxylate (4.12 g, 8.89 mmol) in ethanol (50 mL) was added. A solution of triethylsilane (4.3 mL, 26.7 mmol) in EtOH (1 mL) was then added. The reaction mixture was stirred at room temperature for 20 min, filtered through celite, washed with EtOAc and the filtrate was concentrated. The residue was azeotroped with DCM to provide 2-((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)-2-((tert-butyldimethylsilyl)oxy)acetic acid. m / z (ESI): 396.3 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 4.15 (d, 1H, J=4.2 Hz), 3.9-4.1 (m, 2H), 2.5-2.8 (m, 2H), 1.8-2.0 (m, 2H), 1.6-1.8 (m, 2H), 1.4-1.5 (m, 9H), 0.9-1.0 (m, 11H), 0.13 (d, 6H, J=5.6 Hz).

[0346] Step 7. tert-Butyl (3R)-3-(2-(2-(3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)propanoyl)hydrazinyl)-1-((tert-butyldimethylsilyl)oxy)-2-oxoethyl)piperidine-1- carboxylate. To a mixture of 2-((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)-2-((tert- butyldimethylsilyl)oxy)acetic acid (2.10 g, 5.63 mmol), HATU (2.40 g, 6.31 mmol), and 3-(4-bromo- 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanehydrazide (1.95 g, 4.85 mmol) in DMAc (20 mL) was added diisopropylethylamine (2.1 mL, 12 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc, water and aqueous Na2CO3. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% EtOAc in heptane, to afford tert-butyl (3R)-3-(2-(2-(3-(4-bromo-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanoyl)hydrazinyl)-1-((tert- butyldimethylsilyl)oxy)-2-oxoethyl)piperidine-1-carboxylate (1.55 g, 42% yield). m / z (ESI): 756.2 / 758.2 (M+H)+.

[0347] Step 8. tert-Butyl (3R)-3-((5-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)((tert-butyldimethylsilyl)oxy)methyl)piperidine-1- carboxylate. To a mixture of polymer bound triphenylphosphine, 3 mmol / g loading (2.64 g, 7.92 mmol PPh3) in dichloromethane (20 mL) was added iodine (2.01 g, 7.92 mmol). After stirring for 5 min, triethylamine (2.2 mL, 16 mmol) was added dropwise, followed by a solution of tert-butyl (3R)- 3-(2-(2-(3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanoyl)hydrazinyl)- 1-((tert-butyldimethylsilyl)oxy)-2-oxoethyl)piperidine-1-carboxylate (1.50 g, 1.98 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 16 h. The precipitate formed was filtered and the filtrate was concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–80% EtOAc in heptane, to affordtert-butyl (3R)-3-((5-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)- 1,3,4-oxadiazol-2-yl)((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate (1.46 g, 1.98 mmol, 100% yield). m / z (ESI): 738.2 / 740.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.97 (s, 1H), 7.68 (s, 1H), 5.65 (dd, 1H, J=2.6, 8.9 Hz), 4.82 (d, 1H, J=6.1 Hz), 3.99 (br d, 2H, J=13.6 Hz), 3.7-3.8 (m, 1H), 3.5-3.6 (m, 2H), 3.1-3.2 (m, 2H), 2.6-2.8 (m, 2H), 2.46 (br s, 1H), 2.4-2.5 (m, 1H), 1.9-2.2 (m, 4H), 1.90 (br d, 1H, J=10.9 Hz), 1.6-1.8 (m, 5H), 1.43 (s, 9H), 0.9-0.9 (m, 9H), 0.1-0.1 (m, 3H), - 0.05 (s, 3H).

[0348] Step 9. tert-Butyl (3R)-3-(((tert-butyldimethylsilyl)oxy)(5-(2-(6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)ethyl)-1,3,4- oxadiazol-2-yl)methyl)piperidine-1-carboxylate. A suspension of tert-butyl (3R)-3-((5-(2-(4- bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)((tert- butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate (1.28 g, 1.73 mmol), bis(pinacolato)diborane (1.14 g, 4.6 mmol), tris(4-methoxyphenyl)phosphane (0.24 g, 0.70 mmol), palladium(II) acetate (78 mg, 0.34 mmol) and cesium carbonate (1.70 g, 5.20 mmol) in ethyl acetate (15 mL) was purged with N2then heated at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered through celite, washed with EtOAc, then concentrated in vacuo. The crude material was used in next step without purification. m / z (ESI): 786.4 (M+H)+.

[0349] Step 10. tert-Butyl (3R)-3-((5-(2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)((tert- butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate. A 150-mL round-bottom flask was charged with 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate B, 0.80 g, 1.93 mmol), tert-butyl (3R)-3- (((tert-butyldimethylsilyl)oxy)(5-(2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)ethyl)-1,3,4-oxadiazol-2-yl)methyl)piperidine-1- carboxylate (1.52 g, 1.93 mmol), potassium phosphate (1.23 g, 5.80 mmol), cataCXium A Pd G3 (0.21 g, 0.9 mmol), 2-methyltetrahydrofuran (15 mL) and water (1.5 mL). The reaction mixture was purged with N2, and then heated at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% EtOAc in heptane, to afford the mixture of products (O-t-Bu and OH) (0.62 g, 0.60 mmol, 31% yield). m / z (ESI): 1980.4 (M+H)+.

[0350] Step 11.7-(5-(2-(5-(((tert-Butyldimethylsilyl)oxy)((R)-piperidin-3-yl)methyl)-1,3,4- oxadiazol-2-yl)ethyl)-6-chloro-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. To a solution of tert-butyl (3R)-3-((5- (2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)ethyl)-1,3,4-oxadiazol-2-yl)((tert-butyldimethylsilyl)oxy)methyl)piperidine-1-carboxylate (0.60 g, 0.58 mmol) in DCM (15 mL) was added hydrogen chloride (3 M in cyclopentyl methyl ether, 3 mL, 9 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 h, was then concentrated in vacuo. DCM was added and evaporated. The HCl salt of 7-(5-(2-(5-(((tert- butyldimethylsilyl)oxy)((R)-piperidin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)ethyl)-6-chloro-1H-indazol- 4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-ol was obtained. m / z (ESI): 796.3 (M+H)+.

[0351] Step 12. (33R)-4-((tert-Butyldimethylsilyl)oxy)-16-chloro-28-fluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11H-5(2,5)-oxadiazola-2(7,4)-pyrido[4,3- d]pyrimidina-1(4,5)-indazola-3(1,3)-piperidinacycloheptaphane. To a solution of bromotris(dimethylamino)phosphonium hexafluorophosphate(V) (0.94 g, 2.40 mmol) and DIPEA (1.3 mL, 7.3 mmol) in MeCN (50 mL) was added a solution of 7-(5-(2-(5-(((tert- butyldimethylsilyl)oxy)((R)-piperidin-3-yl)methyl)-1,3,4-oxadiazol-2-yl)ethyl)-6-chloro-1H-indazol- 4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-ol (0.38 g, 0.48 mmol) in DMSO (5 mL) dropwise. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to remove MeCN. The residue was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc, and the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH (with 2% ammonia hydroxide) in heptane, to provide the product as a mixture of OTBS and OH (0.29 g, 0.37 mmol, 77% yield). m / z (ESI): 778.3 / 644.3 (M+H)+.

[0352] Step 13. (17S,18R)-9-Chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-33-oxa-5,6,14,15,22,24,26,30- octaazaheptacyclo[25.3.1.1~13,16~.1~18,22~.0~2,10~.0~3,7~.0~23,28~]tritriaconta- 1(31),2,4,7,9,13,15,23,25,27,29-undecaen-17-ol. To a 150-mL round-bottom flask was added (33R)- 4-((tert-butyldimethylsilyl)oxy)-16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-11H-5(2,5)-oxadiazola-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,3)- piperidinacycloheptaphane (0.29 g, 0.37 mmol) and tetrahydrofuran (8 mL). The solution was cooled to 0oC, then tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.6 mL, 0.6 mmol) was added dropwise. The mixture was stirred for 45 min. Isopropanol (1 mL) was added and the mixture was concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH (with 2% ammonia hydroxide) in heptane. The solid product was dissolved in DMF and further purified by Gilson reversed phase prep. HPLC using a C18 column, eluting with 10-90% CH3CN (with 0.1% TFA) in water (with 0.1% TFA) to provide (17S,18R)-9-chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-33-oxa-5,6,14,15,22,24,26,30- octaazaheptacyclo[25.3.1.1~13,16~.1~18,22~.0~2,10~.0~3,7~.0~23,28~]tritriaconta- 1(31),2,4,7,9,13,15,23,25,27,29-undecaen-17-ol (93 mg, 0.12 mmol, 32% yield). m / z (ESI): 664.2 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.0-9.2 (m, 1H), 7.8-8.0 (m, 2H), 5.4-5.8 (m, 1H), 4.9-5.0 (m, 2H), 4.6-4.8 (m, 3H), 4.2-4.4 (m, 2H), 3.7-4.1 (m, 4H), 3.4-3.6 (m, 2H), 3.3-3.4 (m, 2H), 3.2-3.3 (m, 1H), 2.5-2.8 (m, 3H), 2.3-2.5 (m, 3H), 1.9-2.3 (m, 3H), 1.7-1.9 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -77.43 (s, 3F), -142.88--142.65 (m, 1F), -174.12 (s, 1F).

[0353] (11RS,13RS,20R)-9-Chloro-33-fluoro-27-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-5,6,16,17,24,26,28,32,35- nonaazaoctacyclo[27.3.1.1~16,19~.1~20,24~.0~2,10~.0~3,7~.0~11,13~.0~25,30~]pentatriaconta- 1(33),2,4,7,9,17,19(35),25,27,29,31-undecaene (Compound 2-055).

[0354] Step 1. (R)-7-(6-Chloro-5-((1RS,2RS)-2-(2-(4-((R)-piperidin-3-yl)-2H-1,2,3-triazol-2- yl)ethyl)cyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. In a 250-mL round-bottom flask, to a stirred mixture of tert-butyl (3R)-3-(2-(2-((1RS,2RS)-2-(4-((R)-4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethyl)-2H-1,2,3-triazol-4-yl)piperidine-1- carboxylate (Intermediate N, 1.30 g, 1.40 mmol) in dichloromethane (14 mL) at room temperature, was added hydrogen chloride (4 M in 1,4-dioxane, 7.0 mL, 27.9 mmol). The resulting mixture was stirred at room temperature for 30 minutes, and isopropanol (7 mL) was added. The resulting mixture was concentrated, and DCM (50 mL) was added. The solvent was decanted, the residue was re- dissolved in a mixture of MeOH-MeCN (1:1, 30 mL) and concentrated to provide (R)-7-(6-chloro-5- ((1RS,2RS)-2-(2-(4-((R)-piperidin-3-yl)-2H-1,2,3-triazol-2-yl)ethyl)cyclopropyl)-1H-indazol-4-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.71 g, 1.02 mmol, 73% yield). m / z (ESI): 690.8 (M+H)+.

[0355] Step 2. (11RS,13RS,20R)-9-Chloro-33-fluoro-27-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-5,6,16,17,24,26,28,32,35- nonaazaoctacyclo[27.3.1.1~16,19~.1~20,24~.0~2,10~.0~3,7~.0~11,13~.0~25,30~]pentatriaconta- 1(33),2,4,7,9,17,19(35),25,27,29,31-undecaene. To a stirred mixture of (R)-7-(6-chloro-5- ((1RS,2RS)-2-(2-(4-((R)-piperidin-3-yl)-2H-1,2,3-triazol-2-yl)ethyl)cyclopropyl)-1H-indazol-4-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol(0.71 g, 1.02 mmol) in tetrahydrofuran (200 mL) at room temperature, was added N,N’- diisopropylethylamine (1.32 g, 1.8 mL, 10.2 mmol) and PyBOP hexafluorophosphate (0.80 g, 1.54 mmol). The resulting mixture was stirred at room temperature for 16 h in the dark. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) + 2% Et3N in heptane, followed by prep-HPLC on a Phenomenex Gemini column, 5 micron, C18, 100 Å, 150 x 30 mm eluting at 20 mL / min with a gradient of 0-60% acetonitrile (0.1% TFA) in water (0.1% TFA). The combined fractions containing the product were washed with a 10 wt% aqueous solution of sodium carbonate (50 mL). The mixture was extracted with ethyl acetate (3 x 50 mL), and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The product was further purified by HPLC using an XBridge C18, 19 x 100 mm, 5 um, with a gradient from 20-60% acetonitrile w / 0.1% NH4OH in water with 0.1% NH4OH to provide (11RS,13RS,20R)-9-chloro-33-fluoro-27-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol- 7a(5H)-yl)methoxy)-5,6,16,17,24,26,28,32,35- nonaazaoctacyclo[27.3.1.1~16,19~.1~20,24~.0~2,10~.0~3,7~.0~11,13~.0~25,30~]pentatriaconta- 1(33),2,4,7,9,17,19(35),25,27,29,31-undecaene (42 mg, 0.06 mmol, 6% yield). m / z (ESI): 673.1 (M+H)+.1H NMR (500 MHz, METHANOL-d4) δ ppm 9.16 (s, 1H), 7.92 (br d, J = 3.1 Hz, 1H), 7.82 (s, 1H), 7.33 (s, 1H), 5.40 – 5.25 (m, 1H), 5.25 – 5.06 (m, 2H), 4.36 (d, J = 10.5 Hz, 1H), 4.30 – 4.24 (m, 2H), 4.22 (d, J = 10.4 Hz, 1H), 4.13 (br d, J = 10.3 Hz, 1H), 3.35 (br d, J = 1.7 Hz, 1H), 3.29 – 3.17 (m, 4H), 3.07 – 3.00 (m, 1H), 2.38 – 2.12 (m, 8H), 2.06 – 1.99 (m, 2H), 1.98 – 1.90 (m, 1H), 1.87 (br d, J = 11.9 Hz, 1H), 1.62 – 1.45 (m, 1H), 1.26 (br d, J = 4.8 Hz, 1H), 1.15 – 1.05 (m, 1H), 0.80 – 0.69 (m, 1H), 0.18 – 0.04 (m, 1H).19F NMR (471 MHz, METHANOL-d4) δ ppm -138.11 (s, 1F), -173.69 (s, 1F).

[0356] (26S)-18-Chloro-32-fluoro-4-(((2R,6R,7aS)-2-fluoro-6-hydroxytetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (Compound 1-039).

[0357] Step 1. (16S)-36-Chloro-28-fluoro-22-(methylthio)-31-(tetrahydro-2H-pyran-2-yl)- 31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan- 8-one. To a solution of (6S)-4-(7-(5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan- 6-ol (Intermediate Q, 3.00 g, 4.18 mmol) in tetrahydrofuran (15 mL) was added CDI (3.39 g, 20.91 mmol) and purged with nitrogen. The mixture was stirred at 45 °C for 5 h. The solution was cooled to room temperature, and then to the solution was added TBAF (1.0 M in THF, 6.27 mL, 6.27 mmol) at room temperature and the mixture was diluted with THF (180 mL) and stirred at 45 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethyl acetate in petroleum ether to provide (16S)-36-chloro-28-fluoro-22-(methylthio)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa- 1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (1.11g, 4.77 mmol, 37% yield). m / z (ESI): 629.0 (M+H)+.

[0358] Step 2. (16S)-36-Chloro-28-fluoro-22-(methylsulfinyl)-31-(tetrahydro-2H-pyran-2-yl)- 31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan- 8-one. To a solution of (16S)-36-chloro-28-fluoro-22-(methylthio)-31-(tetrahydro-2H-pyran-2-yl)- 31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8- one (1.00 g, 1.59 mmol) in dichloromethane (15 mL) was purged with nitrogen, and added m-CPBA (77 wt%, 0.35 g, 1.74 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated and the crude residue was purified by column chromatography on silica gel eluting with a gradient of 2 / 1 / 0 to 0 / 10 / 1 ethyl acetate / ethyl alcohol in petroleum ether to provide (16S)-36- chloro-28-fluoro-22-(methylsulfinyl)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)- oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.45 g, 0.69 mmol, 44% yield). m / z (ESI): 645.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.43 (br s, 1H), 7.87 (d,1H, J=10.0 Hz), 7.72 (br t, 1H, J=4.8 Hz), 5.74 (ddd, 1H, J=2.4, 8.8, 14.4 Hz), 5.4-5.6 (m, 1H), 4.9- 5.1 (m, 2H), 4.1-4.3 (m, 3H), 3.9-4.1 (m, 2H), 3.7-3.9 (m, 3H), 3.4-3.6 (m, 1H), 3.17 (ddd, 1H, J=5.2, 8.4, 13.2 Hz), 3.0-3.1 (m, 2H), 3.01 (s, 1H), 2.5-2.7 (m, 2H), 2.1-2.2 (m, 2H), 1.7-2.0 (m, 6H) 30 H's / 30 H's (spectrum / structure).19F NMR (377 MHz, CDCl3) δ ppm -135.12 (s, 1 F).

[0359] Step 3. (16S)-36-Chloro-28-fluoro-22-(((2R,6R,7aS)-2-fluoro-6-hydroxytetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana- 2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one. To a stirred mixture of (2R,6R,7aS)-6-fluoro-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-2-ol (81 mg, 0.47 mmol) in tetrahydrofuran (2.6 mL) at -78 °C under nitrogen, was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.50 mL, 0.50 mmol). The resulting mixture was stirred at 0 °C for 10 minutes. To this was added (16S)-36-chloro-28-fluoro-22-(methylsulfinyl)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa- 1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.25 g, 0.38 mmol) as a solution in THF (0.60 mL). The reaction was allowed to stir at 0 °C for 30 minutes. To this was added 5 drops of methanol and the reaction was concentrated. The crude material was purified by chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) + 2% TEA in heptane to provide (16S)-36-chloro-28-fluoro-22-(((2R,6R,7aS)-2-fluoro-6- hydroxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa- 1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.16 g, 0.21 mmol, 54% yield). m / z (ESI): 756.0 (M+H)+.

[0360] Step 4. (26S)-18-Chloro-32-fluoro-4-(((2R,6R,7aS)-2-fluoro-6-hydroxytetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one bis(trifluoroacetate). To a stirred mixture of (16S)-36- chloro-28-fluoro-22-(((2R,6R,7aS)-2-fluoro-6-hydroxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina- 3(4,5)-indazolacyclononaphan-8-one (0.14 g, 0.19 mmol) in dichloromethane (1.2 mL) at room temperature under ambient atmosphere, was added trifluoroacetic acid (0.50 mL, 6.48 mmol). The resulting mixture was stirred at room temperature for 1 h. Upon completion the reaction was diluted with DMSO (2 mL) and concentrated. The mixture was purified by prep-HPLC on a Phenomenex Gemini column, 5 micron, C18, 100 Å, 150 x 30 mm eluting at 40 mL / min with a gradient of 5-95% acetonitrile (0.1% TFA) in water (0.1% TFA). The combined fractions were lyophilized to provide (26S)-18-chloro-32-fluoro-4-(((2R,6R,7aS)-2-fluoro-6-hydroxytetrahydro-1H-pyrrolo[1,2-a]pyrrol- 7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one bis(trifluoroacetate) (Compound 1-039, 58 mg, 35% yield). m / z (ESI): 672.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 - 13.58 (m, 1 H), 11.02- 11.23 (m, 1 H), 9.48 - 9.56 (m, 1 H), 7.80 - 7.91 (m, 1 H), 7.71 - 7.81 (m, 1 H), 5.49 - 5.91 (m, 2 H), 5.35 - 5.49 (m, 1 H), 4.94 - 5.04 (m, 1 H), 4.84 - 4.89 (m, 1 H), 4.55 - 4.66 (m, 3 H), 3.37 - 4.24 (m, 15 H), 2.65 - 2.96 (m, 1 H), 2.32 - 2.38 (m, 2 H), 1.63 - 1.86 (m, 2 H), 1.18 - 1.36 (m, 1 H) .19F NMR (376 MHz, DMSO-d6) δ ppm -74.15 (s, 6 F), -141.20 (s, 1 F), -173.76 (s, 1 F).

[0361] (17S)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol- 7a(5H)-yl)methoxy)-13-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaene (Compound 2-056 & 2-057).

[0362] Step 1: 7-(6-Chloro-5-(2-(3-(piperidin-3-yl)propoxy)ethyl)-1H-indazol-4-yl)-8-fluoro-2- (((2S,3aR)-2-fluorohexahydropentalen-3a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. To a 6- mL vial was added tert-butyl 3-(3-(2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)ethoxy)propyl)piperidine-1-carboxylate (Intermediate R, 0.21 g, 0.24 mmol) in dichloromethane (4.8 mL). Then HCl (4 M in 1,4-dioxane, 1.78 mL, 7.11 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction was concentrated to provide 7-(6- chloro-5-(2-(3-(piperidin-3-yl)propoxy)ethyl)-1H-indazol-4-yl)-8-fluoro-2-(((2S,3aR)-2- fluorohexahydropentalen-3a(1H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.15 g, 0.24 mmol). m / z (ESI): 641.8 (M+H)+.

[0363] Step 2: (17R)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-13-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaene. A 150-mL round-bottom flask was charged with 7-(6-chloro-5- (2-(3-(piperidin-3-yl)propoxy)ethyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.15 g, 0.24 mmol) and 1,1'- dimethyltriethylamine (0.41 mL, 2.37 mmol, Sigma-Aldrich Corporation) in tetrahydrofuran (47.3mL). PyBOP (benzotriazol-1-yl-oxytrispyrrolidinophosphonium hexafluorophosphate) (0.25 g, 0.47 mmol, Combi-Blocks Inc.) was added in one portion, then the reaction was stirred at room temperature for 21 h in the dark. After 21 h, additional PyBOP (benzotriazol-1-yl- oxytrispyrrolidinophosphonium hexafluorophosphate) (0.25 g, 0.47 mmol, Combi-Blocks Inc.) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) with 2% triethylamine in heptane to provide (17R)-9-chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)- yl)methoxy)-13-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaene (50 mg, 0.080 mmol, 35% yield). m / z (ESI): 632.95 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.37 – 9.27 (m, 1H), 8.00 – 7.87 (m, 1H), 7.87 – 7.76 (m, 1H), 5.43 – 5.20 (m, 1H), 5.13 – 5.06 (m, 1H), 4.44 – 4.16 (m, 2H), 4.01 – 3.86 (m, 1H), 3.54 – 3.46 (m, 1H), 3.19 – 3.12 (m, 1H), 3.06 – 2.94 (m, 2H), 2.77 – 2.62 (m, 2H), 2.51 – 2.13 (m, 4H), 2.04 – 1.80 (m, 5H), 1.76 – 1.58 (m, 3H), 1.44 – 1.20 (m, 3H), 1.23 – 1.10 (m, 5H), 1.01 – 0.85 (m, 2H), 0.57 – 0.44 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -141.21 – -141.70 (m, 1F), -173.36 – -174.08 (m, 1F).

[0364] Step 3. (17R)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-13-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaene (Compound 2-057) and (17S)-9-chloro-30-fluoro-24- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-13-oxa- 5,6,21,23,25,29-hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaene (Compound 2-056). The mixture of diastereomers from Step 4 was purified via SFC using a Chiralcel OD, 2 x 25 cm, 5 µm column with a mobile phase of 40% MeOH with 0.2% DEA using a flowrate of 80 mL / min. The first eluting peak was assigned as (17R)- 9-chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)- 13-oxa-5,6,21,23,25,29-hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaene (Compound 2-057, 11 mg, 0.017 mmol, 24% yield). The second eluting peak was assigned as (17S)-9-chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-13-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaene (Compound 2-056, 15 mg, 0.02 mmol, 33% yield).

[0365] Peak 1: (17R)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-13-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta-1(30),2,4,7,9,22,24,26,28-nonaene (Compound 2-057): m / z (ESI): 623.9 (M+H)+.1H NMR (600 MHz, DMSO-d6) δ ppm 7.93 – 7.87 (m, 1H), 7.84 – 7.80 (m, 1H), 5.35 – 5.23 (m, 1H), 4.87 – 4.82 (m, 1H), 4.73 – 4.66 (m, 1H), 4.21 – 4.13 (m, 1H), 4.09 – 4.02 (m, 1H), 3.86 – 3.81 (m, 1H), 3.26 – 3.16 (m, 1H), 3.16 – 3.09 (m, 2H), 3.03 – 2.98 (m, 1H), 2.94 – 2.82 (m, 3H), 2.31 – 2.22 (m, 1H), 2.18 – 1.98 (m, 4H), 1.97 – 1.89 (m, 1H), 1.89 – 1.75 (m, 4H), 1.68 (br s, 3H), 1.58 – 1.49 (m, 3H), 1.35 – 1.25 (m, 1H), 1.11 – 1.01 (m, 2H), 0.90 – 0.86 (m, 1H), 0.40 – 0.29 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -140.37 – -142.38 (m, 1F), -173.41 – -173.84 (m, 1F).

[0366] Peak 2: (17S)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-13-oxa-5,6,21,23,25,29- hexaazahexacyclo[24.3.1.1~17,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,22,24,26,28-nonaene (Compound 2-056): m / z (ESI): 623.9 (M+H)+.1H NMR (600 MHz, DMSO-d6) δ ppm 9.42 – 9.34 (m, 1H), 7.92 – 7.88 (m, 1H), 7.84 – 7.80 (m, 1H), 5.35 – 5.22 (m, 1H), 4.89 – 4.84 (m, 1H), 4.73 – 4.67 (m, 1H), 4.19 – 4.13 (m, 1H), 4.10 – 4.03 (m, 1H), 3.85 – 3.81 (m, 1H), 3.39 – 3.34 (m, 1H), 3.23 – 3.17 (m, 1H), 3.16 (br s, 1H), 3.13 – 3.06 (m, 2H), 3.05 – 3.01 (m, 1H), 3.00 – 2.96 (m, 1H), 2.94 – 2.88 (m, 1H), 2.86 – 2.81 (m, 1H), 2.80 – 2.75 (m, 1H), 2.30 – 2.24 (m, 1H), 2.15 – 2.07 (m, 2H), 2.03 – 1.96 (m, 1H), 1.94 – 1.85 (m, 1H), 1.88 – 1.74 (m, 3H), 1.71 – 1.61 (m, 2H), 1.57 – 1.49 (m, 2H), 1.35 – 1.14 (m, 1H), 1.13 – 0.98 (m, 2H), 0.89 – 0.84 (m, 1H), 0.38 – 0.31 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -141.18 – -141.77 (m, 1F), -173.50 – -173.98 (m, 1F). (16S)-36-Chloro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-25- methyl-31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)- indazolacyclononaphan-8-one (Compound 2-054).

[0367] Step 1. (16S)-36-Chloro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-25-methyl-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)- pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one. To a stirred mixture of (6S)-4-(7- (5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin- 4-yl)-1,4-oxazepan-6-ol (Intermediate P, 1.30 g, 1.37 mmol) in tetrahydrofuran (10 mL) at room temperature under nitrogen, was added carbodiimidazole (0.31 g, 1.92 mmol). The resulting mixture was stirred at 60 °C for 1 h. The reaction was diluted with tetrahydrofuran (100 mL) and treated withtetrabutylammonium fluoride (1.0 M in THF, 4.11 mL, 4.11 mmol). The resulting mixture was stirred at 60 °C for 5 h. The reaction mixture was concentrated, diluted with sat. aq. solution of ammonium chloride folowed by water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) with 2% TEA in heptane to provide (16S)-36-chloro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-25-methyl-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)- oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.54 g, 0.73 mmol, 54% yield). m / z (ESI): 736.3 (M+H)+.19F NMR (376 MHz, CDCl3) δ ppm -173.08 (s, 1F).

[0368] Step 2. (16S)-36-Chloro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-25-methyl-31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)- indazolacyclononaphan-8-one. To a stirred mixture of (16S)-36-chloro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-25-methyl-31-(tetrahydro-2H-pyran-2-yl)-31H- 7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.54 g, 0.73 mmol) in dichloromethane (10 mL) at room temperature under nitrogen, was added hydrogen chloride (4.0 M in 1,4-dioxane, 9.17 mL, 36.7 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and the crude material was purified by reversed phase chromatography on a C18 column, eluting with a gradient of 0-80% water (0.1% formic acid) in acetonitrile (0.1% formic acid) to provide (16S)-36-chloro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-25-methyl-31H-7,9-dioxa-1(4,6)-oxazepana- 2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (16 mg, 0.022 mmol, 3% yield). m / z (ESI): 652.3 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 7.88 (s, 1H), 7.77 (s, 1H), 7.35 – 7.19 (m, 1H), 5.52 – 5.24 (m, 1H), 4.83 – 4.57 (m, 4H), 4.49 – 4.24 (m, 4H), 4.13 – 4.02 (m, 2H), 4.01 – 3.93 (m, 1H), 3.93 – 3.81 (m, 1H), 3.79 – 3.68 (m, 1H), 3.68 – 3.53 (m, 1H), 3.45 – 3.37 (m, 2H), 3.23 – 3.09 (m, 2H), 2.85 (s, 3H), 2.40 – 2.15 (m, 3H), 2.14 – 1.90 (m, 4H), 1.83 – 1.70 (m, 2H).19F NMR (376 MHz, METHANOL-d4) δ ppm -173.78 (s, 1F). (26S)-18-Chloro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)- 23,25,28-trioxa-1,3,5,14,15 pentaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (Compound 2-053)

[0369] Step 1. N-(Tetrahydro-2H-pyran-2-yl)-(26S)-18-chloro-4-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,14,15 pentaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one. A 250 mL round bottom flask was charged with (6S)-4- (7-(5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepan- 6-ol (Intermediate O, 1.31 g, 1.40 mmol), and 1,1'-carbonyldiimidazole (0.57 g, 3.51 mmol). The solids were suspended in dry tetrahydrofuran (19 mL). The reaction mixture was stirred at 50 °C for 1 h to provide (6S)-4-(7-(5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4- yl)-1,4-oxazepan-6-yl 1H-imidazole-1-carboxylate. m / z (ESI): 1027.2 (M+H)+.

[0370] The above mixture was transferred to a 500 mL round bottom flask, and the solution was diluted with dry tetrahydrofuran (152 mL). To the stirred mixture was added tetrabutylammonium fluoride (1 M in THF, 4.21 mL, 4.21 mmol) and the reaction was stirred at 50 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to provide N-(tetrahydro-2H-pyran-2-yl)-(26S)-18-chloro-4-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,14,15 pentaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (1.00 g, 1.39 mmol, 99% yield, 70% purity) which was used directly in the next step. m / z (ESI): 721.2 (M+H)+.

[0371] Step 2. (26S)-18-Chloro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol- 7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,14,15 pentaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one. A 100-mL round bottom flask was charged with N- (tetrahydro-2H-pyran-2-yl)-(26S)-18-chloro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol- 7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,14,15 pentaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (1.00 g, 1.39 mmol), dichloromethane (9.50 mL), and trifluoroacetic acid (3.16 mL, 27.7 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reversed phase chromatography on a C18 column, eluting with a gradient of 10-100% of water (0.1 % formic acid) in acetonitrile (0.1% formic acid) to afford the product (26S)-18-chloro-4-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,14,15 pentaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one (0.26 g, 0.41 mmol, 29% yield, 90% purity). m / z (ESI):637.2 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.26 – 8.20 (m, 1H), 7.76 – 7.70 (m, 2H), 7.59 – 7.55 (m, 1H), 7.38 – 7.32 (m, 1H), 5.61 (t, J = 3.3 Hz, 1H), 5.52 – 5.45 (m, 2H), 4.69 – 4.64 (m, 1H), 4.62 – 4.51 (m, 2H), 4.43 – 4.33 (m, 1H), 4.11 – 4.03 (m, 2H), 4.00 – 3.83 (m, 4H), 3.81 – 3.65 (m, 6H), 3.59 – 3.51 (m, 1H), 2.93 – 2.93 (m, 1H), 2.65 – 2.52 (m, 1H), 2.41 – 2.25 (m, 4H), 2.15 (br s, 1H), 1.86 – 1.76 (m, 1H), 1.74 – 1.65 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -173.87 – -174.03 (m, 1F).

[0372] (26S)-18-Chloro-32-fluoro-4-(((2R,5R,7aR)-2-fluoro-5-propanoyltetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one 2,2,2-trifluoroacetate and (26S)-18-chloro-32-fluoro-4- (((2R,5R,7aS)-2-fluoro-5-propanoyltetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)- 23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one 2,2,2-trifluoroacetate (Compound 1-036 & 1-037).

[0373] Step 1. (16S)-36-Chloro-28-fluoro-22-(((2R)-2-fluoro-5-(1-hydroxypropyl)tetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)- oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one. To a stirred solution of 1-((6R)-6-fluoro-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)propan-1-ol (Intermediate S, 97 mg, 0.45 mmol) in tetrahydrofuran (1.8 mL) at -78 °C under nitrogen, was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.54 mL, 0.54 mmol). The resulting mixture was stirred at 0 °C for 10 minutes. To this was added (16S)-36-chloro-28-fluoro-22-(methylsulfinyl)-31- (tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.35 g, 0.54 mmol) as a solution in tetrahydrofuran (1 mL). The reaction was allowed to stir at 0 °C for 30 minutes. To this was added 10 drops of methanol and the reaction was concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) + 2% TEA in heptane to provide (16S)- 36-chloro-28-fluoro-22-(((2R)-2-fluoro-5-(1-hydroxypropyl)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3- d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.22 g, 0.28 mmol, 62% yield). m / z (ESI): 798.4 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.25 (d, J = 4.2 Hz, 1H), 7.95 – 7.80 (m, 1H), 7.77 – 7.65 (m, 1H), 5.95 – 5.68 (m, 1H), 5.54 – 5.28 (m, 2H), 5.07 – 4.76 (m, 2H), 4.46 – 4.33 (m, 1H), 4.28 – 4.23 (m, 1H), 4.09 – 3.96 (m, 1H), 3.93 – 3.68 (m, 4H), 3.59 – 3.35 (m, 4H), 3.30 – 3.13 (m, 2H), 3.01 (s, 3H), 2.70 (s, 4H), 2.55 – 2.31 (m, 2H), 2.20 – 2.08 (m, 3H), 1.94 – 1.72 (m, 8H), 1.55 – 1.35 (m, 4H), 1.02 (s, 4H).19F NMR (376 MHz, CDCl3) δ ppm -138.32- -138.45 (m, 1F), -171.81 - - 173.06 (m, 1F).

[0374] 1-((6R)-6-fluoro-7a-(hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)propan-1-ol (fraction 2) was converted to the desired product in a similar fashion. m / z (ESI): 798.4 (M+H)+.19F NMR (376 MHz, CDCl3) δ ppm -138.40 - -138.52 (m, 1F), -175.64 (s, 1F)).

[0375] Step 2. (16S)-36-Chloro-28-fluoro-22-(((2R)-2-fluoro-5-propionyltetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana- 2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one. To a stirred mixture of (16S)-36-chloro-28-fluoro-22-(((2R)-2-fluoro-5-(1-hydroxypropyl)tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3- d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.10 g, 0.13 mmol) in DCM (1.2 mL) at 0 °C under ambient atmosphere, was added Dess-Martin periodinane (96 mg, 0.23 mmol, Combi-Blocks Inc.). The resulting mixture was stirred at 0 °C for 10 minutes then stirred at 42 °C for 2 h. The reaction mixture was diluted with 10 wt% aq. solution of sodium thiosulfate and extracted with ethyl acetate. The combined organic extracts were washed with sat. NaHCO3solution, brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-16% dichloromethane in methanol to provide (16S)-36-chloro-28-fluoro-22-(((2R)-2-fluoro-5-propionyltetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-31-(tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3- d]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (80 mg, 0.10 mmol, 80% yield). m / z (ESI): 796.2 (M+H)+.19F NMR (376 MHz, CDCl3) δ ppm -138.44 - -138.57 (s, 1F), -171.21 (s, 1F).

[0376] The other isomer from above step was converted to the desired product in a similar fasion. m / z (ESI): 796.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.27 – 9.22 (m, 1H), 7.89 – 7.82 (m, 1H), 7.73 (d, J = 5.5 Hz, 1H), 5.74 (ddd, J = 18.6, 8.8, 2.7 Hz, 1H), 5.58 – 5.31 (m, 2H), 4.96 (br t, J = 7.1 Hz, 1H), 4.82 (br d, J = 13.0 Hz, 1H), 4.45 – 4.30 (m, 2H), 4.23 – 4.15 (m, 3H), 4.12 – 3.98 (m,1H), 3.94 – 3.74 (m, 4H), 3.62 – 3.29 (m, 2H), 3.25 – 3.09 (m, 2H), 3.08 – 2.84 (m, 2H), 2.76 – 2.49 (m, 5H), 2.42 – 2.28 (m, 1H), 2.24 – 2.03 (m, 4H), 1.97 – 1.85 (m, 3H), 1.85 – 1.67 (m, 6H), 1.06 (dt, J = 13.2, 7.2 Hz, 3H), 0.95 – 0.77 (m, 1H).19F NMR (376 MHz, CDCl3) δ ppm -138.44 - -138.57 (m, 1F), -171.20 (s, 1F).

[0377] Step 3. (26S)-18-Chloro-32-fluoro-4-(((2R,5R,7aR)-2-fluoro-5-propanoyltetrahydro- 1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one 2,2,2-trifluoroacetate and (26S)-18-chloro-32-fluoro-4- (((2R,5R,7aS)-2-fluoro-5-propanoyltetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)- 23,25,28-trioxa-1,3,5,9,14,15- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaen-24-one 2,2,2-trifluoroacetate. To a stirred mixture of (16S)-36- chloro-28-fluoro-22-(((2R)-2-fluoro-5-propionyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-31- (tetrahydro-2H-pyran-2-yl)-31H-7,9-dioxa-1(4,6)-oxazepana-2(4,7)-pyrido[4,3-d]pyrimidina-3(4,5)- indazolacyclononaphan-8-one (80 mg, 0.10 mmol) in DCE (1.0 mL) at 0 °C under ambient atmosphere was added TFA (0.57 g, 0...

Claims

What is claimed is:

1. A compound of Formula (or a pharmaceutically acceptable salt thereof, wherein; Z is C-H, C-halogen, C-CN, C-C1-4alkyl, C-C1-4haloalkyl, C-C1-4alkoxy, C-C1-4haloalkoxy, C-C3-7cycloalkyl or N; Q is CH, C-halogen, C-C1-4alkyl, C-C1-4haloalkyl or N; B is a 4-15 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S and N; p is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4alkyl, C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkylene, 5-7 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2N(Rz)2, -C(O)Rz, -C(O)ORz, -C(O)N(Rz)2, -C1-4alkylene-C(O)-C1-4zR4is hydrogen, hydroxyl, halogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl or cyano; each R6a,R6band R6cindependently is hydrogen, halogen, hydroxyl, cyano, -N(Rz)2, - C(O)Rz, -C(O)ORz, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4alkynyl or C3-6cycloalkyl or R6aand R6b, together with the atom to which they are attached form a fused C3-7cycloalkyl; and each Rzindependently is hydrogen or C1-4alkyl.

2. A compound of Formula (or a pharmaceutically acceptable salt of said compound, wherein X is O or S; and, Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

3. A compound of Formula (III):or a pharmaceutically acceptable salt of said compound, wherein X is O or S; and, Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

4. A compound of Formula ((or a pharmaceutically acceptable salt of said compound, wherein Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

5. A compound of Formula (or a pharmaceutically acceptable salt of said compound, wherein Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

6. A compound of Formula (VI):or a pharmaceutically acceptable salt of said compound, wherein Q, Z, p, Rx, L2, L1, R1, R4, R6a, R6b, R6cand Rzare as defined above for Formula (I).

7. The compound or salt of any of claims 1-6, wherein Z is C-H, C-F, C-CN, C-CH3, C-CF3, C- OMe, C-Cl or N.

8. The compound or salt of claim 7, wherein Z is N.

9. The compound or salt of any of claims 1-8, wherein Q is CH or N.

10. The compound or salt of claim 9, wherein Q is CH.

11. The compound or salt of any of claims 1-6, wherein Z is N and Q is CH.

12. The compound of any of claims 1-11, wherein p is 0.

13. The compound or salt of claim 12, wherein B is14. The compound or salt of claim 13, wherein15. The compound or salt of claim 12, wherein, wherein X is -O- or -S-.

16. The compound or salt of claim 15, wherein B is.

17. The compound or salt of claim 12, wherein B is.

18. The compound or salt of claim 17, wherein B is.

19. The compound or salt of claim 12, wherein B is.

20. The compound or salt of claim 19, wherein B is.

21. The compound or salt of claim 12, wherein.

22. The compound or salt of claim 21, wherein23. The compound of any of claims 1-11, wherein p is 1.

24. The compound of claim 23, wherein each Rxindependently is hydroxyl, halogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy.

25. The compound of claim 24, wherein each Rxindependently is hydroxyl, fluorine, methyl or monofluoromethyl.2 The compound or salt of claim 23, wherein, wherein X is -O- or -S-.

27. The compound or salt of claim 26, wherein.

28. The compound or salt of claim 23, wherein29. The compound or salt of claim 28, wherein30. The compound or salt of claim 23, wherein31. The compound or salt of claim 30, whereinor .

32. The compound or salt of claim 23, wherein B is.=3 The compound of salt of any of claims 1-33, wherein -35.

36. The compound or salt of any of claims 1-33, wherein -37. The compound or salt of claim 36, wherein -.

38. The compound or salt of any of claims 1-33, wherein -40. The compound or salt of any of claims 1-39, wherein L1is,The compound or salt of any of claims 1-39, wherein L1is,.

42. The compound or salt of any of claims 1-41, wherein R4is hydrogen, hydroxyl, halogen, C1-4alkyl or C1-4alkoxy.

43. The compound or salt of claim 42, wherein R4is hydrogen, halogen or C1-4alkyl.

44. The compound or salt of claim 43, wherein R4is fluorine.

45. The compound or salt of claim 43, wherein R4is hydrogen.

46. The compound or salt of any of claims 1-45, wherein R6a,R6band R6care each independently hydrogen, halogen, C1-4alkyl, C1-4alkoxy or C1-4haloalkyl.

47. The compound or salt of claim 46, wherein R6band R6care each hydrogen and R6ais chlorine.

48. The compound or salt of claim 46, wherein R6band R6care each hydrogen and R6ais methyl.

49. The compound or salt of claim 1, wherein the compound is:

50. A compound selected from one of the following:Ċ51. A pharmaceutical composition comprising the compound or salt according to any one of claims 1-50 and a pharmaceutically acceptable excipient.

52. A compound or salt according to any one of claims 1-50 or the pharmaceutical composition according to claim 51 for use as a medicament.

53. A compound or salt according to any one of claims 1-50 or the pharmaceutical composition according to claim 51 for use in treating cancer.

54. A compound or salt according to any one of claims 1-50 or the pharmaceutical composition according to claim 51 for use in treating cancer, wherein one or more cells of the cancer express a KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutant protein.

55. The compound, salt or pharmaceutical composition for use of claim 53 or 54, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferativeneoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

56. A use of the compound or salt according to any one of claims 1-50 or the pharmaceutical composition according to claim 51 in the preparation of a medicament for treating cancer.

57. A use of the compound or salt according to any one of claims 1-50 or the pharmaceutical composition according to claim 51 in the preparation of a medicament for treating cancer, wherein one or more cells of the cancer express a KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutant protein.

58. The use according to claim 56 or 57, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

59. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or salt according to any one of claims 1-50 or a pharmaceutical composition according to claim 51.

60. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or salt according to any one of to any one of claims 1-50 or a pharmaceutical composition according to claim 51, wherein one or more cells of the cancer express a KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutant protein.

61. The method according to claim 59 or 60, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

62. The method according to claim 59 or 60, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophagealcancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.

63. The method according to claim 62, wherein the cancer is non-small cell lung cancer.

64. The method according to claim 62, wherein the cancer is colorectal cancer.

65. The method according to claim 62, wherein the cancer is pancreatic cancer.

66. The method according to anyone of claims 59-65, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutant protein prior to administration of the compound, salt or composition.

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