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 THEREOFCROSS REFERENCE TO PRIOR APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 647,543, filed May 14, 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 (Malumbrcs et al., 2003). Despite progress in die development of inhibitors of upstream and downstream nodes in the MAPK padrway (e.g., EGFR (Sridhar et al., 2003), BRAF (Holderfield et al., 2014) and MEK (Carmt 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 sen es 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 GTPasc-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 discover}' 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-C1.4 alkyl, C-C1.4 haloalkyl, C-C1.4 alkoxy, C-C1.4 haloalkoxy. C-C3.7 cycloalkyl or N;Q is CH, C-halogen, C-CM 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; q is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(RZ)2, CM alkyl, CM deuteroalkyl, CM alkoxy, CM haloalkyl, CM haloalkoxy, CM hydroxy alkylene, C2-4 alkenyl, C2-4 haloalkenyl, 5-7 membered heteroaryl, -S(O)2-Ci-4alkyl. -S(O)2N(RZ)2, -C(O)RZ, -C(O)ORZ, -C(O)N(RZ)2, -CM alkylene-C(O)-CMalkyl, -CM alkylene-C(O)N(Rz)2, CM alkylene-S(O)2-Ci-4alkyl, or -S-CMalkyl;L2is a bond. CM alkylene, -O-CM alkylene. -S-CM alkylene, NRZ, O or S, wherein each CM alkylene, -O-CM alkylene and -S-CM alkylene chain is substituted with 0-2 occurrences of R2:R1is hydrogen, hydroxyl, Cs-in aryl. 5-10 membered heteroaryl,cycloalkyl or 4-15 membered heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R3; each R2is independently halogen, deuterium, hydroxyl or C1.4 alkyl, wherein two geminal groups, together with the atom to which they are attached, form a spiro-C, - cycloalkyl groupsubstituted with 0-2 occurrences of Rw; or wherein two adjacent R2groups, together with the atoms to which they are attached form a fused-Cs-? cycloalkyl group substituted with 0-2 occurrences of Rw;A is Ce-io aryl substituted with q occurrences of R6;R4is hydrogen, hydroxyl, halogen, Ci-4 alkyl, Ci-4 alkoxy. Ci-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl. C3-7 cycloalkyl or cyano: each R5independently is halogen, cyano, oxo, -T-Ry, hydroxyl. -N(RZ)2, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, =C(RW)2 or -O-C2-4 alkynyl; each R6independently is halogen, hydroxyl, cyano, -N(RZ)2, -C(O)RZ. -C(O)ORZ, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl. C haloalkoxy, C2-4 alkynyl or C3-6 cycloalkyl or two R6taken together on adjacent carbon atoms form a C3-7 cycloalkyl; each Rwindependently is C alkyl. CM alkoxy, halogen, hydroxyl or CM haloalkyl; T is CM alkylene, -S(O)2-, -C(O)-, -CM alkylene-C(O)-. CM alkylene-S(O)2- or -S-; Ryis Ci -4 alkyl, CM haloalkyl, hydroxyl, cyano or -N(RZ)2; and each Rzis independently hydrogen or CM alkyl.

[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 (1).

[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 same meaning 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, C;, alk l means an alkyl group that has 3 carbon atoms (e.g.. n-propyl or isopropyl). For example, a Ci-ealkyl 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 Ci -ealkyl 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 “C1.4 alkyl” 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, CTalkcnyl means the alkenyl group has 3 carbon atoms (e.g., 1-propenyl or 2-propenyl). For example, a C2-salkenyl 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 CL.ealkcny 1includes 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, Cjalkynyl means the alkynyl group has 3 carbon atoms. For example, a C2-ealkynyl 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. Cscycloalkyl 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. vcycloalkyl includes cycloalkyl groups having 3, 4, 5, 6, or 7 carbon atoms in the ring (or any combination of the foregoing), as w ell 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. norbomyl, 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, Cioaryl 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 indie ring system is aromatic, and no ring in the ring system contains a heteroatom. Where a range is indicated, ad members of that range and all subgroups within that range are envisioned. For example, a Ce-i iary I 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 w ithin that range are envisioned. For example, a hctcrocycloalkyl group having 5-7 total ring atoms and 1-3 hctcroatoms 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, hexahydro- IH-pyrrolizinyL azepanyl. 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 systemhaving 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 hctcroaryl 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), py ridaziny 1, py rimidinyl, pyrazinyl, and triazinyl. Nonlimiting examples of bicyclic heteroaiyl 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), indoliziny 1, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl (e.g., oxazolo[5,4-b]pyridinyl), phthalazinyl, ptcridinyl, purinyl, pyrrolopyridyl (e.g., pyrrolo[2,3-b]pyridyl), quinolinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, cimiolinyl, 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 “alky lene” 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 arc envisioned. For example, Ci- ealky lenc means an alky lene 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 die number of carbon atoms in analkylene group is indicated as “Co,’’ then the alkylene group is not present and the recited substituent is directly attached to the rest of the compound. For example, the term Co-ealkylene-OH indicates that die OH group can be directly attached to the compound or through a Ci-ealkylene linker. Examples of alkydene 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 ( — CH2CH2CH(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) dihaloalky 4 (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 “Ci- ihaloalkyl" refers to a Ci-ialkyl, wherein one or more hydrogen atoms is substituted with a halogen. For illustration, Ci-Jraloalkyl includes, for example, CH2F, CHF2, CF3, CHFC1, CH3CF3, CFHCF3, CF2CF3, CH(CF3)3, CF(CHF2)2, CH(CH2F)(CF3), CH2C1, CHC12. CC13, CHFC1, CH2CC13, CCIHCCI3, CC12CC13, CH(CC13)2, CC1(CHC12)2, CH(CH2C1)CC13, and CH2CF(CH3)2.

[0026] The term “hydroxyalky dene” or “hydroxylalkydene” refers to a saturated straight chain alky lene 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 hydroxy alkydene include but are not limited to, hydroxymethylene, 2 -hydroxy 'ethylene, 2- hydroxy propylene. 3-hydroxypropylene, l-(hydroxymethyl)-2- methylpropylene, 2-hydroxybutydene. 3-hydroxy butylene, 4-hydroxybutylene, 2,3-dihydroxypropylene, l-(hydroxymethyl)-2- hydroxycthylcnc, 2,3-dihydroxybutyIcnc, 3,4-dihy droxybutylcnc and the like

[0027] The term “oxo” refers to a substituent oxy gen atom connected to another atom by a double O bond (e.g., =0). For example, an oxo substituent on a cyclopentyl ring can be depicted as:.O

[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 “alkoxy!" are interchangeable and refer to an — O-alkyl group, where the alkyl group is as defined elsewhere herein. For example, a C , alkoxy 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 Ci-ealkoxy 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 tertbutoxy.

[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 “CiJialoalkoxy” refers to a Ci-4alkoxy as defined herein, wherein one or more hydrogen atoms is substituted with a halogen. Representative examples include OCH2F, OCHF2, OCF3, OCHFC1, OCH2CF3, OCFHCF3, OCF2CF3. F(CHF2)2, OCH(CH2F)(CF3). OCH2CI, OCHCI2, OCF3, OCHFC1, OCH2CCICCI2CCI3, OCH(CC13)2, OCC1(CHC12)2, OCH(CH2C1)CC13, 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 "Ci. ideiiteroalkyl" refers to a Ci-ialkyl as defined herein, wherein one or more hydrogen atoms are substituted with D. Representative examples of Ci- 4dcutcroalkyl include, but arc 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 — NFF.

[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 the, ,

[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 arc 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 or Rwithin a ring. Vicinal R groups along a chain and within a ring can be depicted as R 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-butyloxy carbonyl). Examples of protecting groups aredetailed 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) or associates 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, dogs, 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 heterocycloalkyl and the right hand side is attached to the aryl ring. For example, if L1is. .COMPOUNDS OF FORMULA (I)

[0051] Provided herein as Embodiment 1 is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein;Z is C-H, C-halogen. C-CN, C-C1-4 alkyl, C-C1.4 haloalkyl, C-C1-4 alkoxy. C-C1-4 haloalkoxy, C-C3- cycloalkyl or N;Q is CH, C-halogen, C-CM alkyl, C-CM lialoalkyl 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; q is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(RZ)2, C1-4 alkyl, CM deuteroalkyl, CM alkoxy, CM haloalkyl, CM haloalkoxy, CM hydroxyalkylene, C2-4 alkenyl, C2-4 haloalkenyl, 5-7 membered heteroaryl, -S(O)2-Ci.4alkyl, -S(O)2N(RZ)2, -C(O)RZ, -C(O)ORZ, -C(O)N(RZ)2. -CM alkvlcnc-C(O)-Ci ialkvl. -CM alkylene-C(O)N(Rz)2. CM alkylene-S(O)2-Ci-4alkyl, or -S-CMalkyl;L2is a bond. CM alkylene, -O-CM alkylene. -S-CM alkylene, NRZ, O or S, wherein each CM alkylene, -O-CM alkylene and -S-CM alkylene chain is substituted with 0-2 occurrences of R2;R1is hydrogen, hydroxyl, Ce-io aryl, 5-10 membered heteroaryl, C3-8 cycloalkyl or 4-15 membered heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R5; each R2is independently halogen, deuterium, hydroxyl or Ci -4 alkyl, wherein two geminal groups, together with the atom to which they are attached, form a spiro-Ck- cycloalkyl group substituted with 0-2 occurrences of Rw; or wherein two adjacent R2groups, together with the atoms to which they are attached form a fused-Cj-? cycloalkyl group substituted with 0-2 occurrences of Rw;A is Ce-io aryl substituted with q occurrences of R6;R4is hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy. C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl or cyano; each R5independently is halogen, cyano, oxo, -T-Ry. hydroxyl, -N(RZ)2. C1-4 alkyl. C1-4 haloalkyl, C1-4 alkoxy, =C(RW)2 or -O-C2-4 alkynyl; each R6independently is halogen, hydroxyl, cyano, -N(RZ)2, -C(O)RZ, -C(O)ORZ, C1-4 alky l, C1-4 alkoxy, C1-4 haloalky l, C1-4 haloalkoxy, C2-4 alkynyl or C3-6 cycloalky l or two R6taken together on adjacent carbon atoms form a C3-7 cycloalkyl; each Rwindependently is C1-4 alky l, C1-4 alkoxy, halogen, hydroxy l or C1-4 haloalkyl;T is C1-4 alky lene, -S(O)2-, -C(O)-, -C1-4 alkylene-C(O)-, C1-4 alky lene-S(O)2- or -S-;Ryis C1-4 alkyl, C1-4 haloalkyl, hydroxyl, cyano or -N(RZ)2; and each Rzis independently hydrogen or C1-4 alkyl.

[0052] Provided herein as Embodiment 2 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (II):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ. p, Rx. L2, L1, R1. R2, R4, R3, R6. Rw. T, Ryand Rzare as defined above for Formula (I).

[0053] Provided herein as Embodiment 3 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (III):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2. L1, R1, R2. R4. R5, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

[0054] Provided herein as Embodiment 4 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (IV):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2, L1, R1, R2. R4, R5, R6, Rw, T, Ryand Rzare as defined above for Fonnula (I).

[0055] Provided herein as Embodiment 5 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (V):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx. L2, L1, R1, R2, R4, R3, R6, Rw, T, Ryand Rzare as defined above for Formula (I)

[0056] Provided herein as Embodiment 6 is the compound or salt of Embodiment 1, wherein the compound is a compound of Fonnula (VI):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx. L2, L1, R1, R2, R4, R\ R6, Rw, T, Ryand Rzare as defined above for Formula (I).

[0057] Provided herein as Embodiment 7 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (VII):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx. L2, L1, R1, R2, R4, R3, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

[0058] Provided herein as Embodiment 8 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (VIII):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx. L2, L1, R1, R2, R4, R3, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

[0059] Provided herein as Embodiment 9 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (IX):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ. p, Rx. L2, L1, R1, R2, R4, R3, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

[0060] Provided herein as Embodiment 10 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (X):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ. p, Rx. L2, L1, R1, R2, R4, R3, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

[0061] Provided herein as Embodiment 11 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (XI):or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ. p, Rx. L2, L1, R1, R2, R4, R3, R6, Rw. T, Ryand Rzare as defined above for Formula (I).

[0062] Provided herein as Embodiment 12 is the compound or salt of any of Embodiments 1-11, wherein Z is C-H, C-F. C-CN, C-CH3, C-CF,. C-OMe. C-Cl or N. Provided herein as Embodiment 13 is the compound or salt of Embodiment 12, wherein Z is N. Provided herein as Embodiment 14 is tire compound or salt of Embodiment 12, wherein Z is CH. Provided herein as Embodiment 15 is the compound or salt of Embodiment 12, wherein Z is CF.

[0063] Provided herein as Embodiment 16 is the compound or salt of any of Embodiments 1-15, wherein Q is CH or N. Provided herein as Embodiment 17 is the compound or salt of Embodiment16, wherein Q is CH. Provided herein as Embodiment 18 is the compound or salt of Embodiment 16, wherein Q is N.

[0064] Provided herein as Embodiment 19 is the compound or salt of any of Embodiments 1-11, wherein Z is N and Q is CH. Provided herein as Embodiment 20 is the compound or salt of any of Embodiments 1-11, wherein Z is N and Q is N.

[0065] Provided herein as Embodiment 21 is the compound or salt of any of Embodiments 1-20, wherein L2is -O-methylene, -O-ethylene or -O-w-propy lenc substituted with 0-2 occurrences of R2. Provided herein as Embodiment 22 is the compound or salt of Embodiment 21, wherein L2is -O- methylene substituted with 0 occurrences of R2.

[0066] Provided herein as Embodiment 23 is the compound or salt of any of Embodiments 1-22, wherein R1is heterocycloalkyl substituted with 0-3 occurrences of R~. Provided herein as Embodiment 24 is the compound or salt of Embodiment 23, wherein R1is 7a-(hexahydro-lH- pyrrolizinyl) substituted with 0-3 occurrences of FC. Provided herein as Embodiment 25 is the compound or salt of Embodiment 24, wherein R1is unsubstituted 7a-(hexahydro-lH-pyrrolizinyl). Provided herein as Embodiment 26 is the compound or salt of Embodiment 24, wherein R1is 7a- (hexahydro-lH-pyrrolizinyl) substituted with one occurrence of R5.

[0067] Provided herein as Embodiment 27 is the compound or salt of Embodiment 26, wherein FC is halogen. -O-C24 alkynyl. =C(RW)T or C1-4 alkyl. Provided herein as Embodiment 28 is the compound or salt of Embodiment l, wherein FC is halogen. Provided herein as Embodiment 29 is the compound or salt of Embodiment 28, R5is fluorine.

[0068] Provided herein as Embodiment 30 is the compound or salt of any of Embodiments 23-29, wherein -Provided herein as Embodiment 31 is the compound or salt ofEmbodiment 30. wherein -

[0069] Provided herein as Embodiment 32 is the compound or salt of Embodiment 23, wherein R1is 5-(l-azabicyclo[3.2.0]heptanyl) substituted with 0-3 occurrences of R5. Provided herein as Embodiment 33 is the compound or salt of Embodiment 32, wherein R1is 5-(l- azabicyclo[3.2.0]heptanyl) substituted with two occurrences of R5. Provided herein as Embodiment 34 is the compound or salt of Embodiment 33, wherein both R’ are halogen (e.g., fluorine).

[0070] Provided herein as Embodiment 35 is the compound or salt of any of Embodiments 32-34, wherein -Provided herein as Embodiment 36 is the compound or salt ofEmbodiment 35. wherein -Provided herein as Embodiment 37 is the compound or salt of Embodiment 35. wherein -

[0071] Provided herein as Embodiment 38 is the compound or salt of any of Embodiments 1-37, wherein p is 0. Provided herein as Embodiment 39 is the compound or salt of Embodiment 38,wherein X is -O- or -S-. 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

[0072] Provided herein as Embodiment 42 is the compound or salt of Embodiment 38, wherein B. wherein X is -O- or -S-. Provided herein as Embodiment 43 is the compound or salt ofEmbodiment 42, wherein B isProvided herein as Embodiment 44 is the compound or salt of Embodiment 43, wherein B is

[0073] Provided herein as Embodiment 45 is the compound or salt of Embodiment 38, wherein B. Provided herein as Embodiment 46 is the compound or salt of Embodiment 45. wherein

[0074] Provided herein as Embodiment 47 is the compound or salt of Embodiment 38, wherein B rein as Embodiment 48 is the compound or salt of Embodiment 47,. Provided herein as Embodiment 49 is the compound or saltof Embodiment 48, wherein B is ""t* . Provided herein as Embodiment 50 is the compound or salt of Embodiment 48, wherein B is

[0075] Provided herein as Embodiment 51 is the compound or salt of Embodiment 38, wherein Bis '"T* . Provided herein as Embodiment 52 is the compound or salt of Embodiment 51 , wherein B rovided herein as Embodiment 53 is the compound or salt of Embodiment Provided herein as Embodiment 54 is the compound or salt of Embodiment,

[0076] Provided herein as Embodiment 55 is the compound or salt of Embodiment 38, wherein BProvided herein as Embodiment 56 is the compound or salt of Embodiment 55, whereinProvided herein as Embodiment 57 is the compound or salt of Embodiment 56, whereinProvided herein as Embodiment 58 is the compound or salt of Embodiment 56, wherein

[0077] Provided herein as Embodiment 59 is the compound or salt of any of Embodiments 1-37. wherein p is 1. Provided herein as Embodiment 60 is the compound or salt of Embodiment 59. wherein each Rxindependently is hydroxyl, halogen. Ci-4 alkyl. Ci^i alkoxy. Ci-4 haloalkyl. C1.4 haloalkoxy. Provided herein as Embodiment 61 is the compound or salt of Embodiment 60, wherein each Rxindependently is hydroxy l, halogen, Ci-4 alkyl, or Ci-4 haloalkyl. Provided herein as Embodiment 62 is the compound or salt of Embodiment 61, wherein each Rxindependently is hydroxyl or methyl. Provided herein as Embodiment 63 is the compound or salt of Embodiment 62, wherein Rxis hydroxy l. Provided herein as Embodiment 64 is the compound or salt of Embodiment 62, wherein Rxis methyl. Provided herein as Embodiment 65 is the compound or salt of Embodiment 61, wherein Rxis halogen. Provided herein as Embodiment 66 is the compound or salt of Embodiment 65, wherein Rxis fluorine.

[0078] Provided herein as Embodiment 67 is the compound or salt of any of Embodiments 59-66, wherein. Provided herein as Embodiment 68 is the compound or salt of Embodiment67, wherein B is. Provided herein as Embodiment 69 is the compound orsalt of Embodiment 68, wherein B isProvided herein as Embodiment 70 is thecompound or salt of Embodiment 68, wherein B is '"t*

[0079] Provided herein as Embodiment 71 is the compound or salt of any of Embodiments 59-66, wherein B isProvided herein as Embodiment 72 is tire compound or salt ofEmbodiment 71. wherein B isProvided herein as Embodiment73 is the compound or salt of Embodiment 72. wherein B is,"4'vProvided herein asEmbodiment 74 is the compound or salt of Embodiment 72, wherein B isherein as Embodiment 75 is the compound or salt of Embodiment 71, wherein B isor s Embodiment 76 is the compound or salt of any of Embodiments 59-66,Provided herein as Embodiment 77 is the compound or salt ofEmbodiment 76. whereinProvided herein as Embodiment 78is the compound or salt of Embodiment 77, whereinProvided herein asEmbodiment 79 is the compound or salt of Embodiment 77, whereinProvided herein as Embodiment 80 is the compound or salt of Embodiment 76, whereinrein as Embodiment 81 is the compound or salt of Embodiment 80,Provided herein as Embodiment 82 is the compound or salt ofEmbodiment 80. wherein

[0081] Provided herein as Embodiment 83 is the compound or salt of any of Embodiments 59-66, whereinProvided herein as Embodiment 84 is the compound or salt of Embodiment83, wherein. Provided herein as Embodiment 85 is the compound or saltof Embodiment 84, whereinProvided herein as Embodiment 86 is the compound or salt of Embodiment 84, wherein

[0082] Provided herein as Embodiment 87 is the compound or salt of any of Embodiments 59-66, wherein. Provided herein as Embodiment 88 is the compound or salt ofEmbodiment 87, whereinProvided herein as Embodiment 89 is the compound or salt of Embodiment 87, wherein. Provided herein asEmbodiment 90 is the compound or salt of Embodiment 89, wherein

[0083] Provided herein as Embodiment 91 is the compound or salt of any of Embodiments 1-90, wherein A is phenyl or naphthyl substituted with q occurrences of R6. Provided herein as Embodiment 92 is the compound or salt of Embodiment 91, wherein q is 0.

[0084] Provided herein as Embodiment 93 is the compound or salt of Embodiment 91, wherein q is1. Provided herein as Embodiment 94 is the compound or salt of Embodiment 93, wherein R6is Ci-4 alkyl, hydroxyl, halogen or Ci-4 haloalkyl. Provided herein as Embodiment 95 is the compound or salt of Embodiment 94, wherein R6is halogen. Provided herein as Embodiment 96 is the compound or salt of Embodiment 95, wherein R6is fluoro or chloro.

[0085] Provided herein as Embodiment 97 is the compound or salt of Embodiment 91, wherein q is2. Provided herein as Embodiment 98 is the compound or salt of Embodiment 97, wherein each R6is independently Ci-4 alkyl, hydroxyl, halogen or C1.4 haloalkyl. Provided herein as Embodiment 99 is the compound or salt of Embodiment 98, wherein each R6is independently hydroxyl or halogen. Provided herein as Embodiment 100 is the compound or salt of Embodiment 99, wherein one R6is hydroxyl and the other R6is fluoro. Provided herein as Embodiment 101 is the compound or salt of Embodiment 99, wherein one R6is hydroxyl and the other R6is chloro. Provided herein asEmbodiment 102 is the compound or salt of Embodiment 98, wherein each R6is independently hydroxyl or Ci-4 alkyl. Provided herein as Embodiment 103 is the compound or salt of Embodiment 102, wherein each R6is independently hydroxyl or methyl.

[0086] Provided herein as Embodiment 104 is tire compound or salt of any of Embodiments 1-90, wherein A is phenyl substituted with q occurrences of R6. Provided herein as Embodiment 105 is the compound or salt of Embodiment 104, wherein A is phenyl substituted with 1 occurrence of R6. Provided herein as Embodiment 106 is the compound or salt of Embodiment 105, wherein R6is halogen, hydroxyl or Cu alkyl. Provided herein as Embodiment 107 is the compound or salt of Embodiment 106, wherein R6is methyl, hydroxyl or chloro. Provided herein as Embodiment 108 is the compound or salt of Embodiment 107, wherein R6is chloro.

[0087] Provided herein as Embodiment 109 is the compound or salt of Embodiment 104, wherein A is phenyl substituted with 2 occurrences of R6. Provided herein as Embodiment 110 is the compound or salt of Embodiment 109, wherein each R6is independently halogen, hydroxyl or CM alkyl. Provided herein as Embodiment 111 is the compound or salt of Embodiment 110, wherein one R6is methyl and the other R6is hydroxyl. Provided herein as Embodiment 112 is the compound or salt of Embodiment 110, w herein one R6is chloro and the other R6is hydroxy l.

[0088] Provided herein as Embodiment 113 is the compound or salt of any of Embodiment 1-90. w herein A is naphthyl. Provided herein as Embodiment 114 is the compound or salt of Embodiment 113. wherein A is naphthyl substituted with 1 occurrence of R6. Provided herein as Embodiment 115 is the compound or salt of Embodiment 114, wherein R6is halogen, hydroxyl or CM alkyl. Provided herein as Embodiment 116 is the compound or salt of Embodiment 115, wherein R6is methyl, hydroxyl or fluoro. Provided herein as Embodiment 117 is the compound or salt of Embodiment 116, wherein R6is fluoro.

[0089] Provided herein as Embodiment 118 is the compound or salt of Embodiment 113, wherein A is naphthyl substituted with 2 occurrences of R6. Provided herein as Embodiment 119 is the compound or salt of Embodiment 118, wherein each R6is independently halogen, hydroxyl or CM alkyd. Provided herein as Embodiment 120 is the compound or salt of Embodiment 119, w herein one R6is fluoro and the other R6is hydroxyl.

[0090] Provided herein as Embodiment 121 is the compound or salt of any of Embodiments 1-120, whereinProvided herein as Embodiment 122 is the compound or salt of any of Embodiments 1-120. wherein A-L2isProvided herein as Embodiment 123 is the compound or salt of any ofEmbodiments 1-120, whereinProvided herein asEmbodiment 124 is the compound or salt of any of Embodiments 1-120, wherein A-L2iscompound or salt of Embodiment 124, whereinProvided herein as Embodiment127 is the compound or salt of Embodiment 124, whereinProvided herein asEmbodiment 128 is the compound or salt of Embodiment 121, whereinProvided herein as Embodiment 129 is the compound or salt of Embodiment 121, wherein A-L2is

[0091] Provided herein as Embodiment 130 is the compound or salt of any of Embodiments 1-129,or salt of Embodiment 130, wherein L1isProvided herein as Embodiment132 is the compound or salt of Embodiment 130, wherein L1herein as Embodiment 133 is the compound or salt of Embodiment 130, wherein L1isProvided herein as Embodiment 134 is the compound or salt ofEmbodiment 130, wherein L1isProvided herein as Embodiment 135 is the compound or salt of Embodiment 130, whereinL1isProvided herein asEmbodiment 136 is the compound or salt of Embodiment 130, wherein L1isProvided herein as Embodiment 137 is the compound or salt of Embodiment 130, wherein L1isProvided herein as Embodiment 138 is the compound or salt of Embodiment130. wherein L1isProvided herein as Embodiment 139 is the compound or salt of Embodiment 130, wherein L1is

[0092] Provided herein as Embodiment 140 is the compound or salt of any of Embodiments 1-139. wherein R4is hydrogen, hydroxyl, halogen, C1- alkyl or C1.4 alkoxy. Provided herein as Embodiment 141 is the compound or salt of Embodiment 140. wherein R4is halogen or C1-4 alkyl. Provided herein as Embodiment 142 is the compound or salt of Embodiment 141, wherein R4is fluorine.

[0093] Provided herein as Embodiment 142 is the compound or salt of Embodiment 1, wherein the compound is selected from Table 1 below:Table 1

[0094] Provided herein as Embodiment 143 is the compound or salt of Embodiment 142, wherein the compound i(Compound 1.001). Provided herein asEmbodiment 144 is the compound or salt of Embodiment 142, wherein the compound is(Compound 1.002). Provided herein as Embodiment 145 is the compound or salt of Embodiment 142, wherein the compound iscompound or salt of Embodiment 142, wherein the compound(Compound 1.004). Provided herein as Embodiment 147 is the compound or salt of Embodiment142, wherein the compound i(Compound 1.005). Provided herein as Embodiment 148 is the compound or salt of Embodiment 142, wherein the compound is(Compound 1.006). Provided herein as Embodiment 149 is the compound or salt of Embodiment 142, wherein the compound i(Compound 1.008). Provided herein as Embodiment 150 is the compound or salt of Embodiment142, wherein the compound i(Compound 1.009). Provided herein as Embodiment 151 is the compound or salt of Embodiment 142, wherein the compound is(Compound 1.010). Provided herein as Embodiment 152 is the compound or salt of Embodiment 142, wherein the compound i(Compound 1.011). Provided herein as Embodiment 153 is the compound or salt of Embodiment142, wherein the compound(Compound 1.012). Provided herein as Embodiment 154 is the compound or salt of Embodiment 142, wherein the compound is(Compound 1.013). Provided herein as Embodiment 155 is the compound or salt of Embodiment 142, wherein the compound is(Compound 1.014). Provided herein as Embodiment 156 is the compound or salt of Embodiment 142, wherein the compound i(Compound 1.015). Provided herein as Embodiment 157 is the compound or salt of Embodimentherein as Embodiment 158 is the compound or salt of Embodiment 142, wherein the compound iscompound or salt of Embodiment 142, wherein the compound i(Compound 1.019). Provided herein as Embodiment 160 is the compound or salt of Embodimentherein as Embodiment 161 is the compound or salt of Embodiment 142, wherein the compound is(Compound 1.021). Provided herein as Embodiment 162 is the compound or salt of Embodiment 142, wherein the compound i(Compound 1.022). Provided herein as Embodiment 163 is the compound or salt of Embodiment142. wherein the compound(Compound 1.023). Providedherein as Embodiment 164 is the compound or salt of Embodiment 142, wherein the compound is(Compound 1.024). Provided herein as Embodiment 165 is the compound or salt of Embodiment 142, wherein the compound i(Compound 1.025). Provided herein as Embodiment 166 is the compound or salt of Embodimentherein as Embodiment 167 is the compound or salt of Embodiment 142, wherein the compound is(Compound 1.027). Provided herein as Embodiment 168 is the compound or salt of Embodiment 142, wherein the compound i(Compound 1.030). Provided herein as Embodiment 169 is the compound or salt of Embodiment142. wherein the compound i(Compound 1.031). Provided herein as Embodiment 170 is the compound or salt of Embodiment 142. wherein the compound is(Compound 1,032). Provided herein as Embodiment 171 is the compound or salt of Embodiment 142, wherein the compound i(Compound 1.037). Provided herein as Embodiment 172 is the compound or salt of Embodimentherein as Embodiment 173 is the compound or salt of Embodiment 142, wherein the compound iscompound or salt of Embodiment 142, wherein the compound i(Compound 1.040). Provided herein as Embodiment 175 is the compound or salt of Embodiment142. wherein the compound i(Compound 1.042).

[0095] In another aspect of the disclosure, Embodiment 176 provides a compound from the Table below:Table 2

[0096] Provided herein as Embodiment 177 is the compound or salt of Embodiment 176, wherein(Compound 1.007). Provided herein asEmbodiment 178 is the compound or salt of Embodiment 176, wherein the compound is(Compound 1.016). Provided herein as Embodiment 179 is the(Compound 1.028). Provided herein as Embodiment 180 is the compound or salt of Embodimentherein as Embodiment 181 is the compound or salt of Embodiment 176, wherein tire compound is(Compound 1.033). Provided herein as Embodiment 182 is the compound or salt of Embodiment 176, wherein the compound i(Compound 1.034). Provided herein as Embodiment 183 is the compound or salt of Embodimentherein as Embodiment 184 is the compound or salt of Embodiment 176, wherein the compound iscompound or salt of Embodiment 176, wherein the compound(Compound 1.041).

[0097] It is understood that selections of values of each variable are those that result in the formation of stable or chemically feasible compounds.Stereoisomers

[0098] The compounds of die 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 fonn (for example, geometrically pure, enantiomeric ally 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.

[0099] 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. For example,representsSimilarly, for example, the chemical name (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.

[0100] 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 purecompound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having tw o 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 w eight 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 the compound 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.

[0101] 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 pharmacal 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 (Wileylnterscience, 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

[0102] 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.representsSimilarly, for example, the chemical name (4R.5R)-4- methoxy-5-methyl-4.5.6,7-tetrahydro-lH-indazole represents (4R, 5R)-4-methoxy-5-methy 1-4, 5,6,7- tetrahydro-lH-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|00103] 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 inclusion in the compounds disclosed herein include isotopes of hydrogen, such as2H and3H, carbon, such asnC,13C and14C, chlorine, such as36C1, fluorine, such as18F, iodine, such as123I and12’I, nitrogen, such as13N and15N, oxygen, such as150,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labeled 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 asnC,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 -labelled reagent in place of the non-labelled reagent previously employed.BIOLOGICAL ACTIVITY

[0104] In some cases, the compounds or salts disclosed herein (such as compounds of Formula (I). Formula (IT), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X) or Formula (XI) or compounds listed in Table 1 or Table 2 or compounds of Embodiments 1-185. or a pharmaceutically acceptable salt of any of the foregoing), have an IC5o value of less than 5 pM, or less than 4 pM, or less than 3 pM, or less than 2 pM, or less than 1 pM, or less than 0.9 pM. or less than 0.7 pM, or less than 0.6 pM, or less than 0.5 pM, or less than 0.4 pM, or less than 0.3 pM, or less than 0.2 pM, or less than 0.1 pM, or less than 0.09 pM, or less than 0.08 pM, or less than 0.07 pM, or less than 0.06 pM, or less than 0.05 pM, or less than 0.04 pM, or less than 0.03 pM, or less than 0.02 pM, or less than 0.01 pM in the G12D Coupled Exchange assay, AsPC-1 p-ERK assay, AsPC-1 CTG assay or the SW620 CTG assay, described in “SECTION3: Biochemical and Cellular Assays.’’ In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50 value of between 0.001 to 0.200 pM.FORMULATION AND ROUTE OF ADMINISTRATION|00105] 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). Formula (VI). Formula (VII), Formula (VIII), Formula (IX), Formula (X) or Formula (XI) or compounds listed in Table 1 or Table 2 or compounds of Embodiments 1-185, 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.

[0106] 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.

[0107] 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.

[0108] 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 apharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, for use as a medicament.

[0109] Provided herein as Embodiment 186 is pharmaceutical composition comprising the compound or salt of any one of Embodiments 1 to 185, and a pharmaceutically acceptable excipient.METHODS OF USE

[0110] The compounds described herein (such as compounds of Formula (I), Formula (II), Fonnula (III), Fonnula (IV), Fonnula (V), Formula (VI), Formula (VII), Fonnula (VIII), Fonnula(IX), Formula (X) or Formula (XI) or compounds listed in Table 1 or Table 2 or compounds of Embodiments 1-185, 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).

[0111] 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.

[0112] 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), Formula (VI), Formula (VII), Formula (VIII), Fonnula (IX), Fonnula(X) or Formula (XI) or compounds listed in Table 1 or Table 2 or compounds of Embodiments 1-185, or a pharmaceutically acceptable salt of any of the foregoing) to a patient.

[0113] 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.

[0114] 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), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X) or Formula (XI) or compounds listed in Table 1 or Table 2 or compounds of Embodiments 1-185, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein, for use in treating cancer.

[0115] 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.

[0116] 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.

[0117] 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, genn 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.

[0118] Provided herein as Embodiment 187 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 185. or the composition of Embodiment 186.

[0119] Provided herein as Embodiment 188 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 185. or the composition of Embodiment 186, wherein one or more cells express KRAS G12D mutant protein.

[0120] Provided herein as Embodiment 189 is a method of treating cancer in a subject in need diereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 185, or the composition of Embodiment 186, wherein one or more cells express KRAS G12V mutant protein.

[0121] Provided herein as Embodiment 190 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 185, or the composition of Embodiment 186, wherein one or more cells express KRAS G12A mutant protein.

[0122] Provided herein as Embodiment 191 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 185, or the composition of Embodiment 186. wherein one or more cells express KRAS G12S mutant protein.

[0123] Provided herein as Embodiment 192 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 185, or the composition of Embodiment 186, wherein one or more cells express KRAS G13D mutant protein.

[0124] Provided herein as Embodiment 193 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 185. or the composition of Embodiment 186, wherein one or more cells express KRAS Q61H mutant protein.

[0125] Provided herein as Embodiment 194 is a method of treating cancer in a subject in need diereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 185. or the composition of Embodiment 186, wherein one or more cells express KRAS Q61L mutant protein.

[0126] Provided herein as Embodiment 195 is a method of treating cancer in a subject in need diereof, the method comprising administering to the subject a therapeutically effective amount of the compound according of any one of Embodiments 1 to 185, or the composition of Embodiment 186, wherein one or more cells express KRAS Q61R mutant protein.

[0127] Provided herein as Embodiment 196 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 185, or the composition of Embodiment 186. wherein one or more cells express KRAS G12R mutant protein.

[0128] Provided herein as Embodiment 197 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of thecompound according of any one of Embodiments 1 to 185, or the composition of Embodiment 186, wherein one or more cells express KRAS G12C mutant protein.

[0129] Provided herein as Embodiment 198 is the method according to any one of embodiments 187-197, 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, mesotiielioma, thyroid cancer, leukemia, or melanoma.

[0130] Provided herein as Embodiment 199 is the method according to Embodiment 198, 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 200 is the method according to Embodiment 199, wherein the cancer is non-small cell lung cancer. Provided herein as Embodiment 201 is the method according to Embodiment 199, wherein the cancer is colorectal cancer. Provided herein as Embodiment 202 is the method according to Embodiment 199, wherein the cancer is pancreatic cancer.

[0131] Provided herein as Embodiment 203 is the compound or salt of any one of Embodiments 1 to 185, or the pharmaceutical composition of Embodiment 186 for use as a medicament.

[0132] Provided herein as Embodiment 204 is the compound or salt of any one of Embodiments 1 to 185, or the pharmaceutical composition of Embodiment 186 for use in the treatment of cancer.

[0133] Provided herein as Embodiment 205 is the use of the compound or salt of any one of Embodiments 1 to 185, or the pharmaceutical composition of Embodiment 186, for the manufacture of a medicament for the treatment of cancer.

[0134] Provided herein as Embodiment 206 is the use of the compound or salt of any one of Embodiments 203 to 205, 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.

[0135] Provided herein as Embodiment 207 is the method according to Embodiment 206, 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 208 is the method according to Embodiment 207, wherein die cancer is non-small cell lung cancer. Provided herein as Embodiment 209 is the method according to Embodiment 207. wherein the cancer is colorectal cancer. Provided herein as Embodiment 210 is the method according to Embodiment 207, wherein the cancer is pancreatic cancer.Combination Therapy

[0136] 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). Formula (VI). Formula (VII), Formula (VIII). Formula (IX). Formula (X) or Formula (XI) or compounds listed in Table 1 or Table 2 or compounds of Embodiments 1-185, 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 arc herewith incorporated by reference.

[0137] 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, S0S1 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.

[0138] 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.

[0139] 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)-l-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-lH-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2- mcth lpipcridinc-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazin-l-yl)-N-(5-methyl-lH- pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8- dimethyl-N-(l-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-l(14),3,6.8,10,12-liexaen-13- yljmorpholine), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4- metliyltliioplien-2-yl)phthalazin-l -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-[(lR,8S)-4-[[4- (cy clobutylamino)-5 -(trifluoromethy l)pyrimidin-2-y l]amino] - 11 -azatricyclo [6.2.1.02,7]undeca- 2(7),3,5-trien-ll-yl]-2-oxoethyl]acetamide), SNS-314 (l-(3-chlorophenyl)-3-[5-[2-(thieno[3,2- d]pyrimidin-4-ylamino)ethyl]-l,3-thiazol-2-yl]urea), CYC116 (4-methyl-5-[2-(4-morpholin-4- ylanilino)pyrimidin-4-yl]-l,3-thiazol-2-amine), TAS-119, Bl 811283, and TTP607.

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

[0141] Exemplary' AKT inhibitors for use in the methods provided herein include, but are not limited to, afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(l- aminocyclobutyl)phcnyl]-3-phcnylimidazo[l,2-b]pyridazinc-6-carboxamidc), ARQ 092 (3-[3-[4-(l- aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2 -amine), MK2206 (8-[4-(l- aminocyclobutyl)phenyl]-9-phenyl-2H-[l,2,4]triazolo[3,4-f|[l,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10-diethyl ester), ONC201 (l l-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,l l-tetrazatricyclo[7.4.0.02,6]trideca-l(9),5-dien-8-one), ARQ 751 (N-(3-aminopropyl)-N-[(lR)-l-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3- chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0142] Arginase Inhibitors. In some cases, die compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compormd, wherein the second compound is an Arginase inhibitor. Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, nurnidargistat and CB 280.

[0143] 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 compormd, wherein the second compormd 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.

[0144] Exemplar}' 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-(difhioromethy l)-8-[(lR,2R)-2 -hydroxy -2 -methy ley clopentyl]-2-[[l -(methylsulfonyl)- 4-piperidinyl]amino]).

[0145] 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 family including: ErbBl (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.

[0146] 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.

[0147] 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.

[0148] In yet another embodiment the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti- HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).

[0149] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody.

[0150] 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-l-piperazinyl)-l-butyn-l-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).

[0151] 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 toerlotinib, 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-ethy lpiperazin-1 -yl)methyl)pheny 1)-N-(1 -phenylethy 1)-7H- pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[l-[(3- Huorophenyl)methyl]-lH-indazol-5-yl]amino]-5-methylpyrrolo[2,l-f|[l,2,4]triazin-6-yl]-carbamate), and GW 583340 (N-[3-chloro-4-[(3-fluoroplienyl)methoxy]phenyl]-6-[2-[(2- methylsulfonylethy lamino)methy 1] - 1.3 -thiazol-4-yl] quinazolin-4-amine).

[0152] 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 die second compound is an ERK inhibitor.

[0153] 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 (l,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7- one), ASTX029, LTT462, and JSI-1187.

[0154] 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.

[0155] Exemplar}' 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-l,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-y lanilino)-5-(trifluoromethyl)pyridin-4-yl] amino] -N- methylbenzamide). and APG-2449.

[0156] 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.

[0157] Exemplar}' 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- dimethoxypheny l)methoxy]pyrimidin-2-yl]amino]pyrazol-l-yl]ethanol), AZD4547 (N-[5-[2-(3,5- dimethoxyphenyl)ethyl]-lH-pyrazol-3-}'l]-4-[(3S,5R)-3,5-dimethylpiperazin-l-yl]benzamide), debio 1347 ([5-amino-l-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(lH-indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]py rimidin-4-yl] amino] -5 -(4-ethylpiperazin- 1 -y l)pheny l]prop-2-enamide), ICP- 105, CPL304110, HMPL-453, and HGS1036.

[0158] 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.

[0019] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat. IPN60090, and OP 330.

[0160] 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.

[0161] Exemplary' IGF-1R inhibitors for use in the methods provided herein include, but arc not limited to, eixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS-754807 ((2S)-l-[4- [(5-cyclopropyl-lH-pyrazol-3-yl)amino]pyrrolo[2,l-f|[l,2,4]triazin-2-yl]-N-(6-fhioropyridin-3-yl)-2- methylpyrrolidine-2 -carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-l-yl]methyl]-2- [(E)-2-(lH-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.

[0162] 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.

[0163] Exemplar}' 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.|00164| 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.

[0165] Exemplar}' MEK inhibitors for use in the methods provided herein include, but are not limited to. murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,l l,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 ((aR)-a-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-l-piperazinyl)ethoxy]phenyl]-6-(4- fluoropheny l)thieno| 2.3 -d |py rimidin-4-y 11 oxy | -2- 1 |2-(2-methoxyphenyl)-4- pyrimidinyl]methoxy]benzenepropanoic acid), and ABBV-467.

[0166] MEK Inhibitors. In some cases, the compounds of tire disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein tire second compound is an MEK inhibitor.

[0167] 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)-l,5-dimethyl-6-oxopyridine-3-carboxamide), GDC-0623 (5-(2- fluoro-4-iodoanilino)-N-(2 -hydroxy ethoxy)imidazo[l,5-a]pyridine-6-carboxamide), RO4987655 (3,4- difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxycthoxy)-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- (cyclopropylmetiioxy)-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-difhioro-2-[(2-fhioro-4-iodophenyl)amino]phenyl]-l,3,4- oxadiazol-2-yl]-4-morpholineethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554.

[0168] 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 die second compound is an mTOR inhibitor.

[0169] 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 (l-(4-(4-propionylpiperazin-l-yl)-3- (trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][l,6]naphthyridin-2(lH)-one), GDC-0349 ((S)-l-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-morpholin-4-yl-9-propan-2-ylpurin-6- yl)pyrimidin-2 -amine).

[0170] 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 compoimd is a PD-1 inhibitor.

[0171] 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.

[0172] 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 die second compound is a PD-L1 inhibitor.

[0173] 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.

[0174] 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.

[0175] 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-l-[2-(l-methylpiperidin-4- y l)phenyl]propan-2-yl] -4-(2-methy Isulfonylbenzimidazol- 1 -yl)-6-morpholin-4-yl- 1 ,3 ,5 -triazin-2- amine), IPI-549 (2-amino-N-[(lS)-l-[8-[2-(l-methylpyrazol-4-yl)ethynyl]-l-oxo-2- phenylisoquinolin-3-yl]ethyl]pyrazolo[l,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 -hydro xypropanoate), XL147 (N- [3 -(2, 1.3 -benzothiadiazol-5 -y lamino)quinoxalin-2-y l]-4- methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-l,3- thiazolidine-2, 4-dione), and AMG 319 (N-[(lS)-l-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H- purin-6-amine).

[0176] 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.

[0177] 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-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-l- 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 -hydroxy ethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (l-(3,3- dimethylbutyl)-3-(2-nuoro-4-methyl-5-(7-metliyl-2-(metliylamino)pyrido[2,3-d]pyrimidin-6- yl)plienyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3- (trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP- 32496 ( l-(3-((6, 7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(l,l,l-trifluoro-2 -methy lpropan-2- y l)isoxazol-3-yl)urea), CCT 196969 ( 1 -(3 -(tert-butyl)- 1 -phenyl- 1 H-pyrazol-5 -y l)-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-l-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl- sulfamide).

[0178] 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.

[0179] Exemplar SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2 -amine dihydrochloridc), RMC-4550 ([3-[(3S,4S)-4-amino-3-mcthyl-2-oxa-8-azaspiro[4.5]dccan-8-yl]-6- (2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TNO155, (3S,4S)-8-[6-amino-5-(2-amino-3- chloropyridin-4-y 1) sulfany Ipy razin-2-y 1] -3 -methy l-2-oxa-8-azaspiro [4.5] decan-4 -amine) , and vociprotafib (RMC-4630 - Revolution Medicines).

[0180] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(lR,3R)-l-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3- dichlorophenyl)-5 -methy 1-2 -pyrazinemethanol (CAS 21726 1-08-8), 3-[(3S,4S)-4-amino-3-methyl-2- oxa-8-azaspiro [4. ] dec-8-yl] -6-[(2,3 -dichlorophenyl)thio] -5 -methy 1-2 -pyrazinemethanol (CAS 2172652-13-8), 3-[(3S.4>S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3- hydroxy-l-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).

[0181] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, l-[5-(2,3-dichlorophenyl)-6-methylimidazo[l,5-a]pyrazin-8-yl]-4- methyl-4-piperidinamine (CAS 2240981-75-1), (lR)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[l,5- a]pyrazin-8-yl]-8-azaspiro[4.5]decan-l-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3- dichlorophenyl)-6-methylpyrazolo[l,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[l,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[l,5-a]pyrazine-2 -methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)tliio]-4-[(3S,4S)-4-amino-3-niethyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[l,5-a]pyrazine-2-methanol (CAS 2240982-73-2), and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)tliio]-6-methylpyrazolo[l,5-a]pyrazin-4-yl]-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0182] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 3-[(lR)-l-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5- hydroxy-2-pyridincmcthanol (CAS 2238840-54-3), 3-[(lR)-l-amino-8-azaspiro[4.5]dcc-8-yl]-6-[(2,3- dichloropheny l)thio]-5-hy droxy-2-py ridinemethanol (CAS 2238840-56-5), 5 -[(1 R)- 1 -amino-8- azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(lR)-l-amino-8- azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methy 1-2 -pyridinemethanol (CAS 2238840-60-1), (lR)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decan-l-amine (CAS 2238840- 62-3). 3-[(lR)-l-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2- pyridinemethanol (CAS 2238840-63-4), (lR)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]- 8-azaspiro[4.5]decan-l-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-l-piperidinyl)-2-[(2,3- dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(lR)-l-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-l-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-methy 1-2 -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-l-piperidinyl)-6-(2.3-dichlorophenyl)-5 -methyl-2-pyridinem ethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4- amino-4-methyl-l-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-(hydroxymetliyl)pyridin-3-ol.

[0183] In one embodiment, the SHP inhibitor for use in the methods provided herein is 3-[(lR)-l- 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 aninhibitor disclosed in US 10,590,090 B2, US 2020 / 017517 Al, US 2020 / 017 11 Al, or WO 2019 / 075265 Al.

[0184] S0S1 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 S0S1 inhibitor.

[0185] Exemplary S0S1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(lR)-l-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6- [(3S)-oxolan-3-yl]oxyquinazolin-4-amine), and BI 1701963.

[0186] 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); Lek. 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.

[0187] Exemplar,' 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-lH-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (l-(tert-butyl)-3-(p-tolyl)-lH- pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylphenyl(2.4-dimethoxyphenyl)(2-((4-(4- methylpiperazin-l-yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide).

[0188] 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.

[0189] Exemplar}' 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

[0190] 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 alternativesynthetic 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 maimer.

[0191] 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 as solvent, reaction temperature, and reagents, for the Schemes discussed in this section, may be found in die examples provided herein.

[0192] In general, the compounds of Formula (I) can be synthesized according to Schemes I-II as shown below:Scheme I

[0193] Compounds of Formula (I- ) can be prepared according to Scheme I. In step A, compound (1-1) imdergoes S- Ar reaction with with R'-L2H in the presence of a base such as NaH, DBU, DIE A or TEA in a solvent such as 1,4-dioxane, THF or 2-MeTHF to give compound (1-2). In step B, compound (1-2) is coupled with an organometallic reagent or a boronic acid (ester) attached to an arylor heteroary l ring and an optionally substituted cy clic amine (1-3) to give compound (1-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-MeTHF, THF, 1,4-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 (1-4) is treated with ZnBr2 in a solvent such as DCM to give compound (1-5). In step D, compound (1-5) 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 compound (1-6). In step E, compound (1-6) is treated with acid such as HC1 in solvent such as 1,4-dioxane to give compounds of Formula (I-A).Scheme II

[0194] Compounds of Formula (II- A) can be prepared according to Scheme II. In step A, compound (II-l) undergoes SNAT reaction with with R' -L: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 (II-2). In step B, compound (II-2) is coupled with an organometallic reagent or a boronic acid (ester) attached to an ary l or hctcroaryl ring and an optionally substituted cyclic amine (II-3) to give compound (H-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-MeTHF, THF, 1,4- 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 (H-4) is treated with acid such as HC1 in solvent such as 1,4-dioxane to give compound (II-5). In step D, compound (II-5) 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- A).

[0195] 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 tire desired compounds.

[0196] 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.

[0197] 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

[0198] This section provides specific examples of compounds of Formula (I) and methods of making the same.List of Abbreviations

[0199] Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific examples provided herein.

[0200] 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 Cl 8 Gold column or (d) Biotage Isolute SCX-2 column; and eluting the product off the column with a solvent gradient as indicated.

[0201] 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 lO minutes. Conditions can be varied to achieve improved separations.

[0202] Proton NMR Spectra: Unless otherw ise indicated, all 'H 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. Some H signals may be missing due to exchange with D from MeOD, or due to signal suppression.

[0203] Fluorine NMR Spectra: Unless otherwise indicated, all19F NMR spectra were collected on a Bruker NMR instrument at 300. 400 or 500 MHz under ’H-decoupled conditions. All observed fluorines are reported as parts-per-million (ppm).

[0204] Mass Spectra (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or exemplary7compounds 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.

[0205] 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.SECTION 1 : Synthesis of IntermediatesIntermediate A: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrroIizin-7a(5H)yl)methoxy)pyrido[4,3-J]pyrimidine.

[0206] 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-< / |pyrimidine (50.0 g, 198 mmol) in tetrahydrofuran (1.5 L) was added t-BuOK (1 M in THF, 190 m , 190 mmol) dropwise at -60 °C and the reaction mixture was stirred at -60 °C for 2 h. The mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and 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-(re / 't-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-<f|pyrimidine (30 g, 103 mmol, 54% yield). ’H NMR (400 MHz, CDCh) 5 ppm 9.08 (s, 1 H), 1.74 (s, 9 H).

[0207] Step 2: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aA)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)yl)methoxy)pyrido[4,3-J]pyrimidine. To a solution of 4-(tert-butoxy)-2.7- dichloro-8-fluoropyrido[4,3-<7|pyrimidine (50.0 g, 172 mmol) and 4A MS (10 g) in 1,4-dioxane (1 L) was added ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5 / 7)-yl)methanol (30.2 g, 190 mmol) and DIPEA (60.0 g, 431 mmol) in sequence. The reaction mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic lay ers were washed with brine, dried over Na^SOi. filtered, and 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-(Zert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-l / 7-pyrrolizin- 7a(577)yl)metho.xy)pyrido[4,3-<7|pyrimidine (Intermediate A, 40 g, 97 mmol, 56% yield), m'z (ESI): 413.2 / 415.2 (M+H)1.Intermediate A-l: 4-(tert-butoxy)-7-chloro-2-((3,3-difluoro-l-azabicyclo[3.2.0]heptan-5- yl)methoxy)-8-fluoro])yrido[4,3-d]pyrimidine.Intermediate A-1

[0208] Step 1: 4-(tert-Butoxy)-2,7-dichloro-8-fluoropyrido[4,3-rf]pyrimidine. To a stirred mixture of 2,4,7-trichloro-8-fluoropyrido[4.3-t / |pyrimidine (1.5 g, 6.0 mmol, LabNetwork Inc.) in THF (12 mL) at -78 °C under N2 was added sodium / ert-butoxide (2 M in THF, 3.55 g, 3.9 mL, 7.8 mmol. Oakwood Products, Inc.), and the resulting mixture was stirred at -78 °C for 10 min. The reaction mixture was diluted with sat. aq. NH4C1 (15 mL) at -78 °C and allowed to warm to room temperature. The biphasic mixture was extracted with EtOAc (3 x 20 mL), and the combined organic extracts were washed with brine, dried over Na2SO / i, filtered, and concentrated to provide 4-(tert- butoxy)-2.7-dichloro-8-fluoropyrido[4,3-r / |pyrimidine (1.5 g. 5.2 mmol, 87 % yield), m'z (ESI): 234.0 (M-tBu+H)+. ’H NMR (400 MHz CDC / j) 5 ppm 9.07 - 8.99 (m, 1H), 1.84 - 1.79 (m, 9H);19FNMR (376 MHz, CDCh) 5 ppm -132.21 - -132.60 (m. IF).

[0209] Step 2: 4-(terZ-Butoxy)-7-chloro-2-((3,3-difhioro-l-azabicyclo[3.2.0]heptan-5- yl)methoxy)-8-fluoropyrido[4,3-< / |pyrimidine (Intermediate A-l). To a stirred mixture of (3,3-difluoro-l-azabicyclo[3.2.0]heptan-5-yl)methanol (0.15 g, 0.93 mmol) in THF (2.4 mL) at 0 °C under nitrogen, was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.83 mL, 0.83 mmol). The resulting mixture was stirred at 0 °C for 10 minutes. To this mixture was added 4-(Zert-butoxy)-2,7- dichloro-8-fluoropyrido[4,3-< / ]pyrimidine (0.20 g, 0.69 mmol) as a solution in THF (1.2 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with sat. aq. solution of ammonium chloride (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, fdtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-50% ethanol / EtOAc (1:3) (2% EtjN) in heptane, to provide 4-(Zert-butoxy)-7-chloro2-((3,3-difluoro-l- azabicyclo[3.2.0]heptan-5-yl)methoxy)-8-fluoropyrido[4,3-J|pyrimidine (Intermediate A-l, 0.22 g, 0.52 mmol, 75% yield), m z (ESI): 417.0 (M+H)+.Intermediate B: tert- Butyl (3.S,5R)-l-oxa-7-azadispiro[2.1 ,55.l3]undecane-7-carboxylate.

[0210] To a solution of Zert-butyl (2S',4R)-2-hydroxy-2-(hydroxymethyl)-6-azaspiro[3.5]nonane-6- carboxylate (10 g, 36.9 mmol, LabNetwork) in dichloromethane (180 mL) at 0 °C was added pyridine (8.9 mL, 111 mmol) and methanesulfonyl chloride (3.3 mL, 42.4 mmol). The resulting mixture was stirred at room temperature for 21 h. l,5-Diazabicyclo(5,4.0)undec-5-ene (13.8 mL. 92 mmol) was added and the mixture was stirred at room temperature for 40 h. The reaction mixture was washed with water and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel. eluting using a gradient of 0-100% EtOAc in heptane, to give Zert-butyl (3.S',5R)-l-oxa-7- azadispiro[2.1.55.l3]undecane-7-carboxylate (Intermediate B, 5.81 g, 22.9 mmol. 62% yield), m / z (ESI): 372.1 (M+Na)+.!H NMR (400 MHz, CDC / j) 5 ppm 3.44 - 3.41 (m, 2H), 3.40 - 3.33 (m, 2H), 2.82 - 2.69 (m, 2H), 2.27 - 2.09 (m, 4H), 1.73 - 1.66 (m, 2H), 1.58 - 1.50 (m. 2H), 1.50 - 1.46 (m. 9H).Intermediate C, C-l, and C-2: rac-((1R,25)-2-(2-Bromo-6-chloro-4- (methoxymethoxy)phenyl)cyclopropyl) methanol (Intermediate C); ((LS',2R)-2-(2-Bromo-6- chloro-4-(methoxymethoxy)phenyl)cyclopropyl) methanol (Intermediate C-2) and ((!R, 2.S’)-2-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl) methanol (Intermediate C-l).

[0211] Step 1. l-Bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene. To a stirred mixture of 3-bromo-5-chloro-4-iodophenol (1.00 g, 3.00 mmol. AOBChem) and A',A / -diisopropylcthylaininc (1.6 mL, 9.00 mmol) in dichloromethane (10 mL) at room temperature under nitrogen, was added bromomethyl methyl ether (0.5 mL, 6.0 mmol). The resulting mixture was stirred at 40 °C for 1 h.The reaction mixture was diluted with sat. aq. solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with sat. aq. solution of sodium bicarbonate, water, brine, dried over sodium sulfate, filtered, and concentrated to give l-bromo-3-chloro-2-iodo-5- (methoxymethoxy)benzene (1.10 g, 2.91 mmol. 97% yield), mz (ESI): 377.8 (M+H)+. ' H NMR (400 MHz, DMSO-dfi) 5 ppm 7.53 - 7.35 (m, 1H), 7.34 - 7.22 (m, 1H), 5.35 - 5.16 (m, 2H), 3.38 (s. 3H).

[0212] Step 2. rac-Ethyl ( 1 R,25)-2-(2-broino-6-chloro-4- (methoxymethoxy)phenyl)cyclopropane-l-carboxylate. To a mixture of l-bromo-3-chloro-2-iodo- 5-(methoxymethoxy)benzene (1.80 g. 4.77 mmol), rac-c / .s-cthyl (LR,2S)-2-(tetramethyl-l,3,2- dioxaborolan-2-yl)cyclopropane-l-carboxylate (1.48 g, 6.20 mmol. Aurum Pharmatech LLC), potassium phosphate tribasic (3.04 g, 14.31 mmol) and Pd(dppf)C12 (0.35 g, 0.48 mmol) rmder nitrogen was added toluene (10 mL) and water (2 mL) at room temperature. The resulting mixture was sparged with nitrogen for 15 min and stirred at 100 °C for 6 h. After cooling to room temperature, the reaction mixture was filtered through celite. and concentrated. The residue was purified by column chromatography on silica gel. eluting using a gradient of 0-50% EtOAc in heptane, affording rac- ethyl ( lA,2S)-2-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl) cyclopropane- 1 -carboxylate (0.98 g. 2.69 mmol, 56% yield), m / z (ESI): 362.9 (M+H)+. 'H NMR (400 MHz, DMS0-d6) 5 ppm 7.38 - 7.20 (m, 1H). 7.20 - 7.05 (m, 1H). 5.33 - 5.11 (m, 2H). 3.97 - 3.86 (m, 2H), 3.44 - 3.35 (m, 3H), 2.37 - 2.21 (m. 2H), 1.75 - 1.67 (m, 1H), 1.53 - 1.41, (m, 1H), 1.11 - 1.02 (m. 3H).

[0213] Step 3. rac-((1R,2S)-2-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl) methanol. To a stirred mixture of rac-ethyl (lR,2S)-2-(2-bromo-6-chloro-4-(methoxymethoxy) phenyl)cyclopropane-l-carboxylate (0.98 g. 2.69 mmol) in THF (7 mL) at -78 °C under nitrogen, wasadded diisobutylaluminum hydride (1.0 M in toluene, 6.7 mL, 6.7 mmol). The resulting mixture was stirred at -78 °C and gradually allowed to warm to room temperature with stirring for 1 h. The reaction mixture was cooled to 0 °C and carefully diluted with sat. aq. solution of Rochelle’s salt (10 mL) and vigorously stirred for 15 min. The mixture was extracted with EtOAc, and the combined organic extracts were washed w itli brine, dried over sodium sulfate, fdtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting using a gradient of 0-80% EtOAc in heptane, to give rac-((lR,2S)-2-(2-bromo-6-chloro-4-(methoxymethoxy) phenyl)cyclopropyl)methanol (Intermediate C. 0.70 g, 2.17 mmol, 81% yield), m / z' (ESI): 342.9 (M+Na)+. 'H NMR (400 MHz, DMSO-dd) 5 ppm 7.33 - 7.24 (m. 1H), 7.18 - 7.09 (m, 1H), 5.27 - 5.19 (m, 2H), 4.62 - 4.15 (m, 1H), 3.90 - 3.79 (m. 1H), 3.39 - 3.37 (m. 3H), 2.45 - 2.32 (m. 1H), 1.96 - 1.85. (m, 1H), 1.62 - 1.48 (m, 1H). 1.35 - 1.28 (m, 1H). 1.06 - 0.95 (m, 1H).

[0214] Step 4: Intermediates C-l and C-2: ((LS,2R)-2-(2-Bromo-6-chloro-4- (methoxymethoxy)phenyl)cyclopropyl) methanol (Intermediate C-2) and ((1R,2A')-2-(2-Bromo- 6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl) methanol (Intermediate C-l) rao(( 1 A’.2.S)-2- (2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl) methanol (1.00 g. Intermediate C) was purified via SFC using a ChiralPak AD. 3 x 15 cm, 5 pm column with a mobile phase of 20% MeOH using a flowrate of 150 mL / min. Peak assignment determined by SFC with ChiralPak AD column with 15% MeOH.

[0215] First eluting isomer (Intermediate C-2): ((lS,2R)-2-(2-bromo-6-chloro-4- (methoxymethoxy)phenyl)cyclopropyl)methanol (0.49 g, 1.51 mmol, 49% yield), m'z (ESI): 343.0 (M+Na)+.]H NMR (400 MHz, CDCI3) 5 ppm 7.25 - 7.17 (m, 1H), 7.10 - 7.00 (m, 1H), 5.17 - 5.08 (m, 2H), 3.88 - 3.77 (m, 1H), 3.52 - 3.43 (m, 3H), 3.03 - 2.79 (m, 1H), 2.09 - 1.79 (m, 2H). 1.78 - 1.66 (m, 1H), 1.45 - 1.33 (m, 1H), 1.14 - 1.02 (m. 1H).

[0216] Second eluting isomer (Intermediate C-l): ((lR,2S)-2-(2-bromo-6-chloro-4- (methoxymethoxy)phenyl)cyclopropyl)methanol (0.46 g, 1.42 mmol, 46% yield), m / z (ESI): 343.0 (M+Na)+. ’H NMR (400 MHz, CDCI3) 5 ppm 7.26 - 7.16 (m, 1H), 7.10 - 7.01 (m, 1H), 5.18 - 5.07 (m, 2H), 3.90 - 3.76 (m, 1H), 3.52 - 3.41 (m, 3H), 3.03 - 2.78 (m, 1H), 2.10 - 1.94 (m, 1H), 1.80 - 1.66 (m, 1H), 1.45 - 1.33 (m, 1H), 1.15 - 1.04 (m, 1H).Intermediate C-3: rac-2-((ll?,21?)-2-(2-Bromo-6-chlorophenyl)cyclopropyl)ethan-l-ol.

[0217] A mixture of l-bromo-3-chloro-2 -iodobenzene (1.0 g, 3.2 mmol), potassium trifluoro((15,2.S)-2-(2-hydroxyethyl)cyclopropyl)borate (1.2 g. 6.3 mmol), K3PO4 (2.0 g, 9.5 mmol) and Pd(dppf)C12-CH2C12 (0.52 g. 0.63 mmol) in DMF (10 mL) and water (2 mb) was degassed and purged with N2(3x), and then the mixture was stirred at 80 °C for 5 h under N2atmosphere. The reaction mixture was quenched with H2O (250 mL) and then extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL). dried over Na2SC>4, filtered and concentrated to give a residue which was purified by column chromatography on silica gel. eluting with a gradient of 100:0 to 90: 10 pet. ether in EtOAc, to provide rac-2-((1R.2R)-2-(2-bromo-6- chlorophenyl)cyclopropyl)ethan-l-ol (Intermediate C-3, 1.5 g, 5.4 mmol, 34% yield).Intermediate D: rac-((1R,25)-2-(2-Bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)methanol.

[0218] Step 1. 2-(3-Bromo-4-iodo-5-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane.To a mixture of 1 -bromo-2-iodo-3 -methylbenzene (1.50 g, 5.05 mmol, Enamine), bis(pinacalato)diboron (1.30 g, 5.12 mmol, Combi-Blocks Inc.) and 4,4'-di-tert-butyl-2,2'-bipyridine (56 mg, 0.21 mmol, Combi-Blocks Inc.) in degassed methyl tert-butyl ether (15 mL) at room temperature under nitrogen, was added di-mu-methoxobis(l,5-cyclooctadiene)diiridium(I) (36 mg,0.050 mmol, Strem Chemicals, Inc.) under nitrogen. The resulting mixture was stirred at 60 °C for 2.5 h then fdtered through celite and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in heptane to give 2-(3-bromo-4-iodo-5-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.65 g, 3.90 mmol, 77% yield). ’HNMR (400 MHz. CDCI3) 5 ppm 8.01 - 7.75 (m, 1H), 7.69 - 7.46 (m, 1H). 2.70 - 2.46 (tn. 3H), 1.41 - 1.33 (tn. 12H).

[0219] Step 2. 3-Bromo-4-iodo-5-methylphenol. To a stirred mixture of 2-(3-bromo-4-iodo-5- methylphenyl)-4,4,5.5-tetramethyl-l,3,2-dioxaborolane (0.49 g, 1.15 mmol) in tetrahydrofuran (3 inL) and water (3 mL) at room temperature was added sodium perborate tetrahydrate (0.55 g, 3.54 mmol). The resulting mixture was stirred at room temperature for 1 h then the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give 3-bromo-4- iodo-5-methylphenol (0.42 g, 1.36 mmol, quantititive yield). ’H NMR (400 MHz, CDCI3) 5 ppm 7.13 - 6.98 (m. 1H), 6.87 - 6.63 (m. 1H), 5.43 - 5.22 (m, 1H), 2.60 - 2.47 (m, 3H).

[0220] Step 3. l-Bromo-2-iodo-5-(methoxymethoxy)-3-methylbenzene. To a stirred mixture of 3-bromo-4-iodo-5-methylphenol (0.36 g, 1.15 mmol) and ACV-diisopropylethvlamiiie (0.60 mL, 3.44 mmol) in dichloromethane (4 mL) at room temperature under nitrogen, was added bromomethyl methyl ether (0.20 mL, 2.45 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at 40 °C for 30 minutes then diluted with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel. eluting with a gradient of 0-50% ethyl acetate in heptane to give l-bromo-2-iodo-5-(methoxymethoxy)-3-methylbenzene (0.33 g. 0.93 mmol, 81% yield). ' H NMR (400 MHz, CDCI3) 5 ppm 7.26 - 7.18 (in. 1H), 6.96 - 6.87 (m, 1H), 5.20 - 5.11 (m, 2H), 3.56 - 3.44 (m, 3H), 2.57 - 2.51 (m, 3H).

[0221] Step 4. rac-Ethyl (lR,2.S’)-2-(2-bromo-4-(mcthoxyrncthoxy)-6- methylphenyl)cyclopropane-l-carboxylate. To a mixture of l-bromo-2-iodo-5-(methoxymethoxy)- 3 -methylbenzene (0.90 g, 2.51 mmol), rac-ethyl (lR,2S)-2-(tetramethyl-l,3,2-dioxaborolan-2- yl)cyclopropane-l -carboxylate (0.79 g, 3.29 mmol, Enamine), potassium phosphate tribasic (1.60 g, 7.54 mmol) and l,r-bis(diphenylphosphino)ferrocene-palladium dichloride (0.19 g, 0.25 mmol, Sigma- Aldrich Corporation) under nitrogen, toluene (7 mL) and water (1.4 mL) was added at room temperature. The resulting mixture was sparged with nitrogen and stirred at 100 °C for 21 h then the reaction mixture was filtered through celite, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in heptane to give rac-ethyl (lR,2S)-2-(2-bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropane-l -carboxylate (0.49 g, 1.42 mmol. 57% yield). w / z (ESI): 343.0 (M+H)+.’HNMR (400 MHz, CDCli) 5 ppm 7.20 - 7.03 (m, 1H), 6.84 - 6.76 (m, 1H), 5.15 - 5.11 (m, 2H), 4.05 - 3.95 (m, 2H), 3.48 - 3.46 (m, 3H), 2.50 - 2.35 (m, 3H), 2.29 - 2.20 (m, 2H), 1.70 - 1.57 (m, 2H), 1.16 - 1.07 (m, 3H).

[0222] Step 5. rac-((l R,2>S)-2-(2-Bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)methanol. To a stirred mixture of rac-ethyl ( lR.2,S)-2-(2-bromo-4- (methoxymethoxy)-6-methylphenyl)cyclopropane-l -carboxylate (0.49 g, 1.42 mmol) in tetrahydrofuran (6 mL) at -78 °C under nitrogen, was added diisobutylaluminum hydride (1.0 M in toluene, 3.60 mL, 3.60 mmol). The resulting mixture was stirred at -78 °C and gradually allowed to warm to room temperature over 1 h. The reaction mixture was cooled to 0 °C and carefully diluted with sat. aq. solution of Rochelle’s salt (10 mL) and vigorusly stirred for 1 h at room temperature. The mixture was extracted with ethyl acetate (3 x 15 mL) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give rac-((lR,2S)-2-(2-bromo-4- (methoxymethoxy)-6-methylphenyl)cyclopropyl)methanol (Intermediate D, 0.40 g, 1.33 mmol, 93% yield).]H NMR (400 MHz, CDC / 3) 6 ppm 7.17 - 7.13 (m, 1H), 6.85 - 6.79 (m, 1H), 5.16 - 5.11 (m, 2H), 3.84 - 3.72 (m, 1H), 3.51 - 3.48 (m, 3H), 3.05 - 2.93 (m, 1H), 2.45 - 2.42 (m, 3H), 2.05 - 1.96 (m, 1H), 1.72 - 1.60 (m, 1H), 1.40 - 1.32 (m, 1H), 0.96 - 0.82 (m, 1H).Intermediate D-l : ruc-2-((1R,2R)-2-(2-Bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)ethan-l-olIntermediate D-1

[0223] Step 1: rac-(1R,25)-2-(2-Bromo-4-(methoxymethoxy)-6-methylphenyl)cyclopropane-l- carbaldehyde. To a stirred mixture of rac-((lR,2S)-2-(2-bromo-4-(methoxymethoxy)-6-methylphenyl)cyclopropyl)methanol (Intermediate D, 1.02 g, 3.39 mmol) in DCM (22.6 mL) at 0 °C under ambient atmosphere, was added Dess-Martin periodinane (2.16 g, 5.08 mmol, Combi-Blocks Inc.). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was concentrated and purified by column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc in heptane, to provide rac-(1R,2S)-2-(2-bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropane-l-carbaldehyde (0.92 g. 3.1 mmol, 91% yield, m / z (ESI): 397.0 (M+Na)+.!H NMR (400 MHz. CDCI3) 5 ppm 10.01 (s, 1 H), 8.01 - 8.12 (m, 1 H), 7.63 - 7.76 (m. 1 H), 7.43 - 7.50 (m, 1 H). 7.29 - 7.35 (m, 1 H), 5.23 - 5.32 (m, 2 H), 4.73 - 4.91 (m. 2 H), 3.49 - 3.58 (m, 3 H).

[0224] Step 2: rac-l-Bromo-5-(methoxymethoxy)-3-methyl-2-((1R,2R)-2- vinylcyclopropyl)benzene. To a stirred mixture of methyltriphenylphosphonium bromide (1.37 g, 3.84 mmol, Combi-Blocks Inc.) in THF (17.1 mL) at -78 °C under nitrogen, was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 3.4 mL, 3.4 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at -78 °C for 30 minutes and then wanned to 0 °C for 30 minutes. The solution was cooled back to -78 °C and then rac-(lR,2S)-2-(2-bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropane-l-carbaldehyde (0.92 g, 3.1 mmol) was added as a solution in THF (3.4 mL). The reaction was stirred at 0 °C for 1.5 h. The reaction mixture was diluted with sat. aq. solution of sodium bicarbonate (10 mL) and extracted with EtOAc (3 x 20 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 0-40% EtOAc in heptane, to provide rac-l-bromo-5-(methoxymethoxy)-3-methyl-2-((1R,2 )-2- vinylcyclopropyl)benzene (0.73 g, 2.44 mmol, 79% yield), m / z (ESI): 337.0 (M+MeCN+H)+.1H NMR (400 MHz. CDCl3) 5 ppm 7.08 - 7.17 (m, 1 H), 6.76 - 6.84 (m. 1 H), 4.97 - 5.18 (m. 4 H). 4.85 (dd, J=9.9. 2.2 Hz, 1 H), 3.49 (s, 3 H). 2.36 - 2.42 (m, 3 H), 1.96 - 2.12 (m, 2 H), 1.45 - 1.54 (m. 1 H), 1.01 - 1.14 (m. 1 H).

[0225] Step 3 : rac-2-((1R,2R)-2-(2-Bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)ethan-l-ol. To a stirred mixture of rac-l-bromo-5-(methoxymethoxy)-3- methyl-2-((lR,2R)-2-vinylcyclopropyl)benzene (0.72 g, 2.42 mmol) in THF (8.1 mL) at 0 °C under nitrogen, was added 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 9.9 mL, 5.0 mmol). The resulting mixture was warmed to room temperature and stirred for 4 h. The reaction was cooled again to 0 °C and sodium hydroxide (10 M, 1.6 mL, 15.7 mmol) and hydrogen peroxide solution, 30% w / w (1.78 g. 15.7 mmol) was added dropwise. The solution was warmed to room temperature and stirred for 1.5 h. The reaction mixture was diluted with 10 wt% aq. solution of sodium thiosulfate (40 mL) and extracted with EtOAc (3 x 40 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 0-50% EtOAc in heptane, to yield rac-2-(( lR,2R)-2-(2-bromo-4-(methoxymethoxy)-6-methylphenyl)cyclopropyl)ethan-l -ol (Intermediate D- 1, 0.72 g, 2.29 mmol, 95% yield). m / z (ESI): 315.0 (M+H)+. ’H NMR (400 MHz, CDCli) 5 ppm 7.09 - 7.18 (m, 1 H), 6.78 - 6.85 (m, 1 H), 5.13 (s, 2 H), 3.61 - 3.77 (m, 2 H), 3.43 - 3.52 (m, 3 H), 2.35 - 2.46 (m, 3 H), 1.99 - 2.10 (m, 1 H), 1.81 - 1.95 (m, 1 H), 1.27 - 1.36 (m, 3 H), 0.65 - 0.79 (m, 1 H), 0.48 - 0.61 (m, 1 H).Intermediate D-2: rac-2-((1R,2R)-2-(2-bromo-6-chloro-4- (methoxymethoxy)phenyl)cyclopropyl)ethan-l-ol.Intermediate D-2

[0226] Step 1: r«c-(1R,2.S)-2-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropane-l- carbaldehyde. To a stirred mixture of rac-((lR.2S)-2-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl)methanol (Intermediate C, 3.5 g, 10.9 mmol) and sodium bicarbonate (2.29 g, 27.2 mmol) in DCM (20.6 mb) at 0 °C under nitrogen, was added Dess-Martin periodinane (5.5 g. 13.1 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered, rinsed with DCM, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc in heptane, to provide rac-( I R.2.S)-2-(2-bromo-6-cliloro-4-(mcthoxy methoxy (pheny l)cy clopropanc- 1 -carbaldehy de (3.15 g, 9.9 mmol, 91% yield), m / z (ESI): 319.0 (M+H)+. *H NMR (400 MHz, CDC73) 6 ppm 9.04 - 8.99 (m, 1H), 7.24 - 7.20 (m, 1H), 7.10 - 7.04 (m, 1H), 5.18 - 5.10 (m, 2H), 3.49 - 3.46 (m, 3H), 2.52 - 2.37 (m, 2H), 1.93 - 1.77 (m, 2H).

[0227] Step 2: r«c-l-Bromo-3-chloro-5-(methoxymethoxy)-2-((17f,2R)-2- vinylcyclopropyl)benzene. To a stirred mixture of methyltriphenylphosphonium bromide (2.19 g.6.14 mmol) in THF (27.3 mL) at -78 °C under nitrogen, was added lithium bis(trimetliylsilyl)amide (1.0 M in THF, 5.4 mL, 5.4 mmol). The resulting mixture was stirred at -78 °C for 30 minutes and then wanned to 0 °C for 30 minutes. The solution was cooled back to -78 °C and then rac-(lR,2S)-2- (2-bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropane-l-carbaldehyde (1.57 g, 4.91 mmol) was added as a solution in THF (5.5 mL). The reaction was stirred at 0 °C for 1.5 h. The reaction mixture was diluted with sat. aq. solution of sodium bicarbonate (20 mL) and extracted with EtOAc (3 x 20 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 0-60% EtOAc in heptane, to provide rac-l-bromo-3-chloro-5-(methoxymethoxy)- 2-((lR,2R)-2- vinylcyclopropyl)benzene (1.12 g, 3.53 mmol. 72% yield). Product did not ionize on LCMS.!H NMR (400 MHz. CDCh) 5 ppm 7.24 - 7.18 (m, 1H). 7.08 - 7.02 (m, 1H). 5.16 - 5.13 (m, 2H), 5.12 - 5.06 (m. 2H), 4.88 - 4.85 (m. 1H), 3.51 - 3.47 (m. 3H), 2.13 - 2.07 (m. 2H), 1.59 - 1.52 (m. 1H), 1.30 - 1.28 (m. 1H).

[0228] Step 3: rac-2-((1R,2R)-2-(2-Bromo-6-chloro-4- (methoxymethoxy)phenyl)cyclopropyl)ethan-l-ol. To a stirred mixture of rac-l-bromo-3-chloro-5- (methoxymethoxy)-2-((lR.2R)-2-vinylcyclopropyl)benzene (1.12 g, 3.53 mmol) in THF (11.9 mL) at 0 °C under nitrogen was added 9- borabicyclo[3.3.1]nonane (0.5 M in THF, 14.5 mL, 7.2 mmol). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was cooled again to 0 °C and sodium hydroxide (10 N, 2.3 mL, 23 mmol) and 30 wt% hydrogen peroxide (2.6 mL, 23 mmol) were added dropwise. The solution was warmed to room temperature and stirred for 1.5 h. The reaction mixture was diluted with 10 wt% aq. solution of sodium thiosulfate (50 mL) and extracted with EtOAc (3 x 20 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% EtOAc in heptane, to provide rac-2-((1R.2R)-2-(2-bromo- 6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl)ethan-l-ol (Intermediate D-2, 1.02 g. 3.04 mmol. 86% yield). Product did not ionize on LCMS. 'H NMR (400 MHz, CDClj) 8 ppm 7.24 - 7.18 (m, 1H). 7.07 - 7.03 (m, 1H). 5.15 - 5.11 (m, 2H). 3.72 - 3.67 (m, 2H). 3.50 - 3.45 (m, 3H). 2.15 - 2.08 (m, 1H). 1.94 - 1.88 (m, 1H). 1.55 - 1.49 (m, 1H). 1.43 - 1.31 (m, 2H), 0.97 - 0.86 (m, 1H), 0.60 - 0.50 (m. 1H).Intermediate E: (Z)-4-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3-en-l-ol.

[0229] Step 1. 4-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3-yn-l-ol. To a stirred mixture of l-bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene (1.87 g, 4.95 mmol), 3-butyn-l-ol (0.49 mL, 6.44 mmol, EMD MILIPORE) and triethylamine (7.0 mL, 49.5 mmol) in DMA (10 mL) was added bis(triphenylphosphine)palladium(II) dichloride (57 mg, 0.081 mmol) and copper(I) iodide (28 mg. 0.15 mmol) at room temperature under nitrogen (degassed for 5 min). The resulting mixture was stirred at 80 °C for 90 minutes. After cooling to room temperature, the reaction mixture was diluted with sat. aq. solution of ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with sat. aqueous solution of lithium chloride, brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting using a gradient of 0-60% ethyl acetate in heptane to give 4-(2-bromo-6-chloro-4- (methoxymethoxy)phenyl)but-3-yn-l-ol (1.03 g. 3.22 mmol, 65% yield), m / z (ESI): 318.9 / 320.9 (M+H)+. 'H NMR (400 MHz, CDC ) 5 ppm 7.23 (d, J=2.3 Hz, 1 H). 7.10 (d. J=2.3 Hz, 1 H), 5.16 (s, 2 H), 3.77 - 4.03 (m, 2 H), 3.48 (s, 3 H). 2.81 (s, 2 H), 1.91 - 2.14 (m, 1 H).

[0230] Step 2. (Z)-4-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3-en-l-ol. To a stirred mixture of 4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3-yn-l-ol (1.00 g, 3.13 mmol) in THF (13 mL) was added bis(cyclopentadienyl)zirconium chloride hydride (3.23 g, 12.5 mmol) (in a glove box) under nitrogen. The resulting mixture was stirred at room temperature for 7 h then heated at 35 °C for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, fdtered. and concentrated to give (Z)-4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3-en-l-ol (Intermediate E, 0.49 g, 1.52 mmol, 49% yield), m / z (ESI): 343.0 (M+Na)+. *H NMR (400 MHz, CDC / j) 5 ppm 7.26 (d, J = 2.3 Hz, 1H), 7.12 (d, J = 2.5 Hz. 1H), 6.38 - 6.26 (m. 1H), 6.01 - 5.84 (m. 1H), 5.17 (s. 2H), 3.69 (d, J = 6.1 Hz, 2H), 3.50 (s. 3H), 2.32 - 2.18 (m. 2H) (1H not observed).Intermediate F: 3-(2-Chloro-6-iodo-4-(methoxymethoxy)phenyl)propan-l-ol.

[0231] Step 1. l-Bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene. To a stirred mixture of l-chloro-3 -iodobenzene (0.36 mL, 2.9 mmol, Combi-Blocks Inc.) and l-chloro-3 -iodopropane (0.94 mL, 8.8 mmol. Ambeed, Inc.) in tetrahydrofuran (7.5 mL) at -78 °C under nitrogen, was slowly added lithiumdiisopropylamide (1 M in THF / hexanes, 7.5 mL, 7.5 mmol). The resulting mixture was stirred at -78 °C for 1.5 h. The reaction mixture was warmed to 0 °C and carefully diluted with sat. aq. solution of ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in heptane to give l-chloro-2-(3-chloropropyl)-3-iodobenzene (0.92 g, 2.9 mmol, quantitive yield). 'H NMR (400 MHz, CDCli) 5 ppm 7.84 - 7.70 (m, 1H), 7.43 - 7.33 (m, 1H), 6.90 - 6.78 (m, 1H), 3.74 - 3.65 (m, 2H), 3.22 - 3.07 (in, 2H), 2.15 - 2.00 (m, 2H).

[0232] Step 2. 3-(2-Chloro-6-iodophenyl)propyl acetate. To a stirred mixture of l-chloro-2-(3- chloropropyl)-3 -iodobenzene (0.92 g, 2.9 mmol) and potassium acetate (1.10 g, 11.4 mmol) in N, N- dimethylformamide (10 mL) was added sodium iodide (0.11 g, 0.73 mmol) at room temperature under ambient atmosphere. The resulting mixture was stirred at 80 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with 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 0-50% ethyl acetate in heptane to give 3-(2-chloro-6-iodophenyl)propyl acetate (0.80 g, 2.3 mmol, 80% yield). 'H NMR (400 MHz, CDCI3) 3 ppm 7.81 - 7.71 (m, 1H), 7.42 - 7.33 (m, 1H), 6.89 - 6.78 (m, 1H), 4.27 - 4.17 (m, 2H), 3.14 - 3.02 (m, 2H), 2.13 - 2.07 (m, 3H), 2.00 - 1.88 (m, 2H).

[0233] Step 3. 3-(2-Ch loro-6- iodo-4-(4, 4,5, 5-tetramethy 1-1,3, 2-d ioxaborolan-2- yl)phenyl)propyl acetate. To a stirred mixture of 3-(2-chloro-6-iodophenyl)propyl acetate (0.80 g, 2.3 mmol), bis(pinacalato)diboron (0.85 g, 3.3 mmol) and 4.4'-di- / e / 7-butyl-2.2'-bipyridinc (32 mg. 0.12 mmol) in degassed methyl Zert-butyl ether (8 mL) was added di-mu-methoxobis(l,5- cyclooctadiene)diiridium(I) (20 mg, 0.030 mmol) at room temperature under a stream of nitrogen. The resulting mixture was sparged with nitrogen for 15 minutes and stirred at 60 °C for 2 h. The reaction 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 0-50% ethyl acetate in heptane to give 3-(2-chloro-6-iodo-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)propyl acetate (0.86 g, 1.9 mmol. 79% yield).1H NMR (400 MHz, CDCl}) 6 ppm 8.18 - 8.12 (m, 1H), 7.79 - 7.72 (m, 1H), 4.24 - 4.17 (m. 2H), 3.14 - 3.02 (m. 2H), 2.13 - 2.08 (m. 3H), 2.00 - 1.86 (m, 2H). 1.40 - 1.32 (m, 12H).

[0234] Step 4. 3-(2-Chloro-4-hydroxy-6-iodophenyl)propyl acetate. To a stirred mixture of 3- (2-chloro-6-iodo-4-(4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2-yl)phenyl)propyl acetate (0.86 g, 1.9 mmol) in tetrahydrofuran (4 mL) and water (4 mL) at room temperature under ambient atmosphere was added sodium perborate tetrahydrate (1.00 g, 6.50 mmol). The resulting mixture was stirred at 25 °C for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give 3-(2-chloro-4-hydroxy-6-iodophenyl)propyl acetate (0.66 g, 1.9 mmol, quantitative yield).!H NMR (400 MHz, CDCI3) 5 ppm 7.34 - 7.29 (m, 1H), 7.02 - 6.76 (m, 1H), 5.86- 5.57 (m. 1H), 4.23 - 4.17 (m. 2H), 3.08 - 2.89 (m. 2H), 2.14 - 2.09 (m. 3H), 1.99 - 1.83 (m. 2H).

[0235] Step 5. 3-(2-Chloro-6-iodo-4-(methoxymethoxy)phenyl)propyl acetate. To a stirred mixture of 3-(2-chloro-4-hydroxy-6-iodophenyl)propyl acetate (0.64 g, 1.8 mmol) and N,N- diisopropylethylamine (1.1 mL, 6.3 mmol) in dichloromethane (7 mL) was added bromomethyl methyl ether (0.45 mL, 5.5 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 40 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with sat. aq. solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with sat. aq. solution of sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated to give 3-(2-chloro-6-iodo-4-(methoxymethoxy)phenyl)propyl acetate (0.63 g, 1.6 mmol, 88% yield).!H NMR (400 MHz. CDCI3) 8 ppm 7.53 - 7.44 (m, 1H), 7.15 - 7.06 (m. 1H), 5.18- 5.09 (m, 2H). 4.25 - 4.13 (m, 2H). 3.52 - 3.45 (m, 3H). 3.07 - 2.95 (m, 2H). 2.14 - 2.07 (m, 3H). 2.01 - 1.80 (m. 2H).

[0236] Step 6. 3-(2-Chloro-6-iodo-4-(methoxymethoxy)phenyl)propan-l-ol. To a stirred mixture of 3-(2-chloro-6-iodo-4-(methoxymethoxy)phenyl)propyl acetate (0.63 g. 1.6 mmol) in methanol (6 mL) and dichloromethane (1.2 mL) was added potassium carbonate (1.20 g, 8.68 mmol) at room temperature. The resulting mixture was stirred at 45 °C for 2 h then the reaction mixture wasfiltered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-60% ethyl acetate in heptane to give 3-(2- chloro-6-iodo-4-(methoxymethoxy)phenyl)propan-l-ol (Intermediate F, 0.49 g, 1.4 mmol, 87% yield).]H NMR (400 MHz, CDCI3) 5 ppm 7.51 - 7.44 (m, 1H), 7.15 - 7.07 (m, 1H), 5.17 - 5.09 (m, 2H), 3.82 - 3.71 (m, 2H), 3.53 - 3.45 (m, 3H), 3.08 - 2.95 (m, 2H), 1.92 - 1.77 (m, 2H).Intermediate G: tert-Butyl (R,Z)-3-((((4-(2-chloro-4-(methoxymethoxy)-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)but-3-en-l-yl)oxy)carbonyl)amino)-3-methyIpiperidine-l- carboxylate.Intermediate G

[0237] Step 1. tert- Butyl (R)-3-methyl-3-(((4-nitrophcnoxy)carboriyl)arni no) pi peridi ne-1- carboxylate. To a stirred mixture of Hiinigs base (0.31 mL, 1.8 mmol) and tert-butyl (3R)-3-amino- 3-methyl-piperidine-l-carboxylate (0.38 mL, 1.8 mmol, PharmaBlock, Inc.) in acetonitrile (3.5 mL) was added 4-nitrophenyl chloroformate (0.38 g, 1.9 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 1 h. m,z (ESI): 402.0 (M+Na)1.

[0238] Step 2. tert- Butyl (l?,Z)-3-((((4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3- en-l-yl)oxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate. To the above solution was added (Z)-4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3-en-l-ol (Intermediate E, 0.45 g, 1.40 mmol) and Hiinigs base (0.61 mL, 3.50 mmol) in acetonitrile (1 mL) and the reaction was heated to 80 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated, and the crude material was purified by reversed phase chromatography on a C 18 column, eluting using a gradient of 5-100% acetonitrile (0.1% formic acid) in water (0.1% formic acid) to give tert -butyl (R,Z)-3-((((4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3-en-l-yl)oxy)carbonyl)amino)-3-methylpiperidine- 1 -carboxylate (0.30 g, 0.53 mmol, 31% yield), m'z (ESI): 583.0 / 585.0 (M+Na)+. ' H NMR (400 MHz, CDCl3) 8 ppm 7.25 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.34 - 6.21 (m, 1H), 5.95 - 5.81 (in, 1H), 5.16 (s, 2H), 4.11 - 3.77 (m, 4H), 3.50 (s, 3H), 3.00 - 2.64 (m, 2H), 2.31 - 2.16 (m, 2H), 1.74 - 1.58 (m, 1H), 1.40 -1.50 (m, 10H), 1.25 -1.35 (m, 4H).

[0239] Step 3. to-t- Butyl (R,Z)-3-((((4-(2-chloro-4-(methoxymethoxy)-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)but-3-en-l-yl)oxy)carbonyl)amino)-3-methylpiperidine-l- carboxylate. To a stirred and degassed mixture of palladium(II) acetate (17 mg, 0.077 mmol), cesium carbonate (0.37 g, 1.2 mmol), terZ-butyl (R,Z)-3-((((4-(2-bromo-6-chloro-4- (methoxymethoxy )phcny l)but-3-cn- 1 -yl)oxy)carbonyl)amino)-3-mcthylpipcridinc- 1 -carboxy late (0.43 g, 0.77 mmol) and tris(4-methoxyphenyl)phosphine (54 mg, 0.15 mmol) in ethyl acetate (1.5 mL) under nitrogen, was added bis(pinacolato)diboron (0.25 g, 1.0 mmol). The resulting mixture was stirred at 80 °C for 4 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated. The crude material was purified by column chromatography on silica gel, eluting using a gradient of 0-70% ethyl acetate in heptane to give tert -butyl (R,Z)-3-((((4-(2-chloro-4- (methoxymethoxy)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)but-3-en-l- yl)oxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate (Intermediate G, 0.34 g, 0.56 mmol. 73% yield), m / z (ESI): 631.2 (M+Na)+.Intermediate H: 2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaboroIane.Intermediate H

[0240] Step 1: 7-Fluoro-8-((triisopropyIsilyl)ethynyl)naphthalene-l,3-dioI. To a mixture of 7- fluoronaphthalene-l,3-diol (3.30 g, 18.5 mmol) and 2-bromoethynyl(triisopropyl)silane (5.81 g, 22.2 mmol) in 1,4-dioxanc (60 inL) was added KOAc (3.64 g, 37.1 mmol) and dichloro(p- cymene)rutlienium(II) dimer (1.13 g, 1.85 mmol) in one portion at 15 °C under N2. The reactionmixture was stirred at 110 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The combined organic phases were dried with anhydrous Na2SO4, fdtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting using a gradient of 15-50% EtOAc in petroleum ether to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diol (4.30 g, 11.3 mmol, 65% yield). m / z (ESI): 359.2 (M+H)+.

[0241] Step 2: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-ol.To a mixture of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-l,3-diol (4.30 g, 12.0 mmol) in DCM (60 mL) was added DIPEA (6.3 mL, 36 mmol). Then MOMC1 (1.1 mL 14 mmol) was added in portions at 0 °C under Nj. The reaction mixture was stirred at 15 °C for 12 h. The mixture was then poured into ice-water, stirred for 20 minutes, then extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 25-50% EtOAc in petroleum ether to give 7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)naphthalen-l-ol (2.00 g, 4.97 mmol, 41% yield).

[0242] Step 3: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsiIyl)ethynyI)naphthalen-l-yl trifluoromethanesulfonate. To a mixture of 7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylcthynyl)naphthalcn-l-ol (2.50 g, 6.21 mmol) in DCM (30 mL) was added DIPEA (3.3 mL, 19 mmol) in one portion at 15 °C under N2. Then to the mixture was added Tf2O (1.5 mL, 9.3 mmol) in portions at -40 °C under N2 and the mixture was stirred at -40 °C for 1 h. The reaction mixture was poured into ice water then the aqueous phase was extracted with dichloromethane. The combined organic phase was dried with anhydrous Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 2-15% EtOAc in petroleum ether to give 7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoromethanesulfonate (2.50 g, 4.68 mmol, 75% yield).

[0243] Step 4: ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl)ethynyl)triisopropylsilane. To a mixture of 7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoromethanesulfonate (2.50 g, 4.68 mmol) in toluene (25 mL) was added KOAc (1.38 g, 14.0 mmol), bis(pinacolato)diboron (2.37 g, 9.35 mmol) and Pd(dppl)C12 (0.34 g, 0.47 mmol) in sequence at 15 °C under N2. The mixture was stirred at 130 °C for 3 h, then concentrated under reduced pressure at 45 °C. The residue was poured into ice water and extracted with ethyl acetate. The combined organic phase was dried with anhydrous Na2SC>4. filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 2-10% EtOAc in petroleum ether to give ((2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (1.20 g, 2.34 mmol, 50% yield), m / z (ESI): 513.2 (M+H)+.

[0244] Step 5: 2-(8-Ethynyl-7-fIuoro-3-(methoxymethoxy)naphthalen-l-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane. To a mixture of ((2-fluoro-6-(methoxymethoxy)-8-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (1.10 g, 2.15 mmol) in DMF (20 mL) was added CsF (1.96 g, 12.9 mmol) in one portion at 15 °C under N2. The reaction mixture was stirred at 50 °C for 2 h then the mixture was poured into water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na2SC>4, filtered, and concentrated in vacuo to give the crude 2-(8-ethynyl-7-fluoro-3 -(methoxymethoxy )naphthalen-l- yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.20 g, crude).

[0245] Step 6: 2-(8-Ethyl-7-fluoro-3-(mcthoxymcthoxy)naphthalen-l-yl)-4,4,5,5-tctramcthyl- 1,3,2-dioxaborolane. To a solution of 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.20 g, 3.37 mmol) in THF (10 mL) was added Pd-C (10 wt%, 20 mg) under argon. The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred under H2 (15 psi) at 15 °C for 1 h then the reaction mixture was filtered, and the filter cake was washed with THF. The combined filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a gradient of 4-10% EtOAc in petroleum ether to give 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate H, 0.62 g. 1.69 mmol, 75% yield over two steps), m z ' (ESI): 361.1 (M+H)1.Intermediate I: 2-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yI)ethan-l-ol.Intermediate I

[0246] Step 1. ((2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)ethynyl)triisopropylsilane. To a solution of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen- 1 -yl)ethynyl)triisopropylsilane (Intermediate H (up to Step 4), 30.0 g, 58.5 mmol) in A'-dimethylformainide (600 mL) and toluene (300 mL) was added Cui (16.72 g, 88 mmol), K2CO3 (16.18 g, 117 mmol) and NIS (15.8 g, 70.2 mmol) at 20 °C insequence and the mixture was stirred at 110 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO i. filtered, and concentrated under reduced pressure to give ((2-fhioro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)ethynyl)triisopropylsilane (30 g, crude).

[0247] Step 2: l-Ethynyl-2-fluoro-8-iodo-6-(methoxymethoxy)naphthalene. To a solution of ((2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethynyl)triisopropylsilane (50 g, 98 mmol) in MA'-dimcthy 1 formamide (500 inL) was added CsF (74.1 g, 488 mmol) at 20 °C then the reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 10-100% EtOAc in petroleum ether. The crude product was triturated with petroleum ether (20 mL) at 20 °C for 10 min. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give l-ethynyl-2-fluoro-8- iodo-6-(methoxymethoxy)naphthalene (29.0 g, 81.5 mmol, 85% yield over 2 steps).

[0248] Step 3. 2-Fluoro-8-iodo-6-(methoxymethoxy)-l-vinylnaphthalene. To a solution of 1- ethynyl-2-fluoro-8-iodo-6-(methoxymethoxy)naphthalene (10.0 g, 28.1 mmol) in dichloromethane (100 mL) was added Schwartz's reagent (14.5 g, 56.2 mmol) in one portion at 0 °C with protection from light. The reaction mixture was stirred at room temperature for 2 h, then was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO i. filtered, and concentrated under reduced pressure. The crude product was purified by reversed phase MPLC (using a gradient of 40-70% over 25 min; 70% 10 min) to give 2-fluoro-8-iodo-6- (methoxymethoxy)-l-vinylnaphthalene (4.00 g, 11.24 mmol. 40% yield). ' H NMR (400 MHz, CDCls) 5 ppm 8.07 (d. J = 2.40 Hz, 1 H), 7.51-7.60 (m, 1 H), 7.40-7.51 (m, 1 H), 7.40 (d, J= 2.80 Hz, 1 H), 7.24-7.29 (m, 1 H), 5.72-5.75 (m. 1 H), 5.49-5.50 (m, 1 H), 5.25 (s. 2 H), 3.52 (s, 3 H).19F NMR (376 MHz. CDCI3) 5 ppm -113.23 (s, 1 F).

[0249] Step 4: 2-(2-Fluoro-8-iodo-6-(methoxymcthoxy)naphthalcn-l-yl)cthan-l-ol. To a solution of 2-fluoro-8-iodo-6-(methoxymethoxy)-l-vinylnaphthalene (1.00 g, 2.79 mmol) in tetrahydrofuran (10 mL) was added dropwise Bf L Mc2S (10 M in THF, 1.4 mL, 14 mmol) at 0 °C. The mixture was degassed and purged with N2, and then warmed to room temperature and stirred for 12 h under N2. The mixture was cooled again to 0 °C then aq. NaOH (4 N aqueous solution, 4.65 mL, 18.6 mmol) was added dropwise under N2at 0 °C. Then 30% aq. H2O2(2.85 mL, 27.9 mmol) was added dropwise at 0 °C under N2. The reaction mixture was allowed to warm to room temperature with stirring for 6 h then sat. Na2SO2(20 mL) was added dropwise to the mixture at 0 °C under N2. and stirred for 20 minutes. The mixture was extracted with EtOAc, and the combined organic layers were 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 10-100% EtOAc inpetroleum ether. The crude product was triturated with petroleum ether / ethyl acetate 5:1 (50 mL) at 20 °C for 30 min. The suspension was fdtered, and the filter cake was concentrated under reduced pressure to give 2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethan-l-ol (Intermediate I, 0.27 g, 0.71 mmol, 26% yield), m / z (ESI): 377.0 (M+H)+. ’HNMR (400 MHz, DMSO-d 5 ppm 8.08 (d, J = 2.40 Hz, 1 H), 7.81 (m, 1 H), 7.58 (d, J = 2.80 Hz, 1 H), 7.44 (t, J = 9.20 Hz, 1 H), 5.29 (s, 2 H), 4.77 - 4.80 (m. 1 H), 3.64 - 3.72 (m, 4 H), 3.41 (s, 3 H).19F NMR (376 MHz, OMSO-de) 5 ppm - 113.29 (s, I F).Intermediate 1-1 : 3-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propan-l-ol.

[0250] Step 1: 2-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)acetaldehyde. To a stirred mixture of 2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethan-l-ol (Intermediate I, 1.62 g, 4.31 mmol) in DCM (28.7 mL) at 0 °C under ambient atmosphere, was added Dess-Martin periodinane (2.74 g, 6.46 mmol, Combi-Blocks Inc.). The resulting mixture was warmed to room temperature and stirred for 2 h. Upon completion the reaction was concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc in heptane, to give 2-(2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-l-yl)acetaldehyde (1.28 g, 3.42 mmol. 79% yield), m / z (ESI): 397.0 (M+Na+). ’HNMR (400 MHz, CDCI3) 8 ppm 10.01 (s, 1 H), 8.01 - 8.12 (m, 1 H), 7.63 - 7.76 (m, 1 H), 7.43 - 7.50 (m, 1 H), 7.29 - 7.35 (m. 1 H), 5.23 - 5.32 (m, 2 H), 4.73 - 4.91 (m, 2 H), 3.49 - 3.58 (m, 3 H).

[0251] Step 2: l-Allyl-2-fhioro-8-iodo-6-(methoxymethoxy)naphthalene. To a stirred mixture of methyltriphenylphosphonium bromide (1.53 g, 4.28 mmol) in THF (19.0 mL) at -78 °C under nitrogen, was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 3.8 mL, 3.8 mmol). The resulting mixture was stirred at -78 °C for 30 minutes and then warmed to 0 °C for 30 minutes. The solution was cooled back to -78 °C and then 2-(2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-l-yl)acetaldehyde (1.28 g, 3.42 mmol) was added as a solution in THF (3.8 mL). The reaction was stirred at 0 °C for 1.5 h. The reaction mixture was diluted with sat. aq. solution of ammonium chloride (10 mL) and extracted with EtOAc (3 x 20 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 0-40% EtOAc in heptane, to provide l-allyl-2-fluoro-8-iodo-6-(methoxymethoxy)naphthalene (1.14 g, 3.06 mmol, 90% yield, m / z (ESI): 373.0 (M+H)+. H NMR (400 MHz, CDCI3) 5 ppm 8.07 - 8.19 (m, 1 H), 7.57 - 7.66 (m, 1 H), 7.40 - 7.45 (m, 1 H), 7.29 - 7.32 (m, 1 H), 6.14 - 6.29 (m, 1 H), 5.25 - 5.31 (m, 2 H), 5.07 - 5.15 (m, 1 H), 4.76 - 4.96 (m, 1 H), 4.32 - 4.46 (m, 2 H), 3.51 - 3.57 (m. 3 H).

[0252] Step 3: 3-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propan-l-ol. To a stirred mixture of l-allyl-2-fluoro-8-iodo-6-(methoxymethoxy)naphthalene (1.14 g, 3.06 mmol) in THF (10.21 mL) at 0 °C under nitrogen, was added 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 12.6 mL, 6.3 mmol). The resulting mixture was warmed to room temperature and stirred for 4 h. The reaction was cooled to 0 °C and sodium hydroxide (10 N, 4.24 g, 1.99 mL, 19.9 mmol) and hydrogen peroxide solution, 30% w / w (2.26 g, 2.26 mL. 19.9 mmol) was added dropwise. The solution was wanned to room temperature and stirred for 1.5 h. The reaction mixture was diluted with 10 wt% aq. solution of sodium thiosulfate (40 mL) and extracted with EtOAc (3 x 40 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 0-50% EtOAc in heptane, to provide 3-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propan-l-ol (Intermediate 1-1, 0.96 g. 2.46 mmol, 80% yield), m / z (ESI): 412.8 (M+Na)+. *H NMR (400 MHz. CDCI3) 5 ppm 8.13 (d, J=2.7 Hz, 1 H), 7.56 - 7.65 (m, 1 H), 7.40 - 7.46 (m, 1 H), 7.29 - 7.32 (m, 1 H), 5.26 (s. 2 H). 3.76 - 3.83 (m, 2 H). 3.58 - 3.67 (m, 2 H), 3.53 (s, 3 H). 1.99 - 2.08 (m, 2 H), 1.33 - 1.39 (m, 1 H).Intermediate J: (R)-3-((Allyloxy)mcthyl)piperidine hydrochlorideStep 1 Step 2 Intermediate J

[0253] Step 1: tert- Butyl (R)-3-((allyloxy)methyl)piperidine-l-carboxylate. To a stirred mixture of (R)-Zert-butyl 3-(liydroxymcthyl)pipcridinc-l-carboxylatc (1.5 g, 7.0 mmol, Arnbccd, Inc.) in THF (35 mL) at 0 °C and potassium ZerZ-butoxide solution (1.0 M in THF, 9.7 mL, 9.7 mmol) was added allyl bromide (1.69 g, 13.9 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with satd. NH4CI and extracted two times with ethyl acetate. The organic extract waswashed with sat’d NaCl and dried over MgSQi. The solution was fdtered and concentrated in vacuo to give the crude material. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0-60% ethyl acetate / ethanol (3 :1) with 1% TEA in heptane, to provide tert-butyl (R)-3-((allyloxy)methyl)piperidine- 1 -carboxylate, m / z (ESI): 278.2 (M+Na)+.

[0254] Step 2: (R)-3-((Allyloxy)methyl)piperidine hydrochloride. tert-Butyl (R)-3- ((allyloxy)methyl)piperidine-l -carboxylate from Step 1 was dissolved in 10 mL of 1,4-dioxane. To tlie solution was added HC1 (4 M in 1,4-dioxane, 17.4 mL, 69.7 mmol). The mixture was stirred for 2 hr at room temperature. The solution was fully concentrated to provide (R)-3-((allyloxy)methyl)piperidine hydrochloride (Intermediate J, 1.3 g, 6.8 mmol, 97% yield), m / z (ESI): 156.2 (M+H)+.SECTION 2: Synthesis of Example Compounds

[0255] 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), Fonnula (III), Fonnula (IV), Fonnula (V), Formula (VI), Formula (VII), Fonnula (VIII), Fonnula (IX), Formula (X) or Formula (XI) or compounds listed in Table 1 or Table 2 or compounds of Embodiments 1-185, or a pharmaceutically acceptable salt of any of the foregoing) whose preparation is not specifically described in this section could be prepared in an analogous manner.

[0256] Example 1.001 & 1.002: (lR.3R.7R.9.S)-l l-( hl()ro-30-fliioro-22-(((2R.7a.S)-2- flu()rotctrahvdro-l / / -pvrrolo|l ,2-tf|pvrrol-7a(5 / / )-yl)methoxy)-5-oxa-17,21 ,23,25- tetraazaheptacyclo[23.3.1.1~l,3~.l~16,20~.0~7,9~.0~10,15~.0~19,24~]hentriaconta- 10,12,14,16(30),17,19,21,23-octaene-3,13-diol (Example 1.001) and (15',3R,75',9R)-ll-chloro-30- fluoro-22-(((2R,7a5)-2-fluorotetrahydro-l / f-pyrrolo[l,2-a]pyrrol-7a(5 / 7)-yl)methoxy)-5-oxa- 17,21,23,25-tetraazaheptacyclo[23.3.1.1~l,3~.l~16,20~.0~7,9~.Q~10,15~.0~19,24~]hentriaconta- 10,12,14,16(30),17,19,21,23-octaene-3,13-diol (Example 1.002)

[0257] Step 1. tert- Buty l (2.S.4R)-2-(((( 1 R.S.2.SR)-2-(2-bronio-6-chloro-4- (methoxymethoxy)phenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6- carboxylate. To a stirred mixture of rac-((lA.2S)-2-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl)methanol (Intermediate C. 0.70 g, 2.2 mmol) and yttrium(III) trifluoromethanesulfonate (0.29 g. 0.54 mmol) in toluene (11 mL) was added tert-buty l (3.S’.5R)-l- oxa-7-azadispiro[2.1.5’.l3]undecane-7-carboxylate (Intermediate B, 0.83 g, 3.3 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 40 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with sat. aq. solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-80% ethyl acetate in heptane to give tert-butyl (2.S',4R)-2- (((( 1 RS,2>SR)-2-(2-bromo-6-chloro-4-(methoxy methoxy )phenyl)cyclopropyl)methoxy)methyl)-2- hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.85 g, 1.50 mmol, 68% yield). m,'z (ESI): 596.0 (M+Na)+. ’H NMR (400 MHz, CDCI3) 5 ppm 7.25 - 7.19 (m, 1H), 7.12 - 7.01 (m, 1H), 5.19 - 5.10, (m, 2H), 3.90 - 3.79 (m, 1H), 3.54 - 3.47 (m, 3H). 3.40 - 3.28 (m, 4H), 3.26 - 3.18 (m, 2H), 2.85 - 2.74 (m, 1H), 2.74 - 2.57 (m, 1H), 2.04 - 1.90 (m, 3H), 1.74 - 1.61 (m, 5H), 1.52 - 1.48 (m, 2H), 1.47 - 1.45 (m, 9H), 1.35 - 1.31 (m, 2H).

[0258] Step 2. tert-Butyl (2.S,4R)-2-((((l RS,2SR)-2-(2-clil()i (»-4-(nietho\y nietho\y )-6-(4.4.5.5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of rac-tert-butyl (2SAR)-2-((((\RS.2SR)- 2-(2-bromo-6-cliloro-4-(methoxymethoxy)phenyl)cyclopropyl)methoxy)methyl)-2 -hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (0.85 g, 1.5 mmol), bis(pinacolato)diboron (0.57 g, 2.2 mmol) and cesium carbonate (0.96 g, 2.95 mmol) in ethyl acetate (5 mL) was added palladium(II) acetate (33 mg, 0.15 mmol) and tris(4-methoxyphenyl)phosphine (62 mg, 0.18 mmol) at room temperature under nitrogen. The resulting mixture was sparged with nitrogen for 15 minutes and stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-80% ethyl acetate in heptane to give tert-butyl (2S,4R)-2- ((((lRS.25R)-2-(2-chloro-4-(methoxymethoxy)-6-(4,4.5.5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.79 g, 1.3 mmol, 86% yield), m / z (ESI): 644.2 (M+Na)+.!H NMR (400 MHz. DMSO-d6) 5 ppm 7.16 - 7.12 (m, 1H), 7.05 - 7.00 (m. 1H), 5.30 - 5.08 (m. 2H), 4.89 - 4.53 (m. 1H), 3.65 - 3.49 (m. 1H), 3.42 - 3.36 (m, 3H), 3.35 - 3.05 (m, 8H), 2.48 - 2.39 (m, 1H), 2.19 - 2.08 (m, 1H), 1.93 - 1.80 (m, 2H). 1.65 -1.53 (m. 2H), 1.53 - 1.43 (m. 3H), 1.38 - 1.29 (m, 21H), 1.29 - 1.21 (m, 2H).

[0259] Step 3. tert- Butyl (2.S',4R)-2-((((lR>S',2.SR)-2-(2-(4-(tcv / -but()xt )-8-fluoro-2-(((2R,7a.S')-2- fluorotetrahydro-1 W-pyrrolizin-7a(5 / / )-yl)inethoxy)pyrido|4,3-ti]pyrimidin-7-yl)-6-chloro-4- (methoxymethoxy)phenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6- carboxylate. To a mixture of tert-butyl (2S.4R)-2-((((lRS.25R)-2-(2-chloro-4-(methoxymethoxy)-6- (4,4,5,5-tetramethyl-L3.2-dioxaborolan-2-yl)phenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (0.79 g, 1.3 mmol), 4-(tert-butoxy)-7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(57 / )-yl)methoxy)pyrido[4,3-<7|pyrimidine (Intermediate A, 0.55 g, 1.3 mmol), potassium phosphate tribasic (0.68 g, 3.2 mmol) and cataCXium A Pd G3 (45 mg. 0.062 mmol) were added 2-Me-THF (6 mL) and water (0.6 mL) under nitrogen. The resulting mixture was sparged with nitrogen for 15 minutes and stirred at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-80% 1 :3 ethanol / ethyl acetate (with 2% EtjN) in heptane to give tertbutyl (2S,4R)-2-((((lR>S',2SR)-2-(2-(4-(tert-butoxy)-8-fluoro-2-(((2.R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5J7)-yl)methoxy)pyrido[4.3-<7|pyrimidin-7-yl)-6-chloro-4-(methoxymethoxy)pheny l)cyclopropy l)methoxy)methy l)-2-hydroxy-6-azaspiro [3.5]nonane-6- carboxylate (0.69 g, 0.79 mmol, 62% yield), m / z (ESI): 872.2 (M+H)+. *H NMR (400 MHz, DMSO- d6) 5 ppm 9.21 - 9.06 (m, 1H), 7.35 - 7.21 (m, 1H), 7.13 - 6.97 (m, 1H), 5.41 - 5.14 (m, 3H), 4.83 -4.53 (m, 1H), 4.27 - 4.12 (m, 2H), 3.45 - 3.38 (m, 3H), 3.33 - 3.24 (m, 2H), 3.22 - 2.97 (m, 9H), 2.91 - 2.77 (m, 1H), 2.44 - 2.29 (m, 1H), 2.26 - 2.02 (m, 4H), 1.94 - 1.65 (m, 15H), 1.63 - 1.49 (in,2H), 1.49 - 1.38 (m, 3H), 1.38 - 1.23 (m, 11H).19F NMR (376 MHz, DMSO-do) 8 ppm -172.16 (s, 1 F) -141.30 - -133.24 (m, I F).

[0260] Step 4. 7-(3-( hloro-2-((l R.S.2.S7?)-2-((((2.S.4.S)-2-h)(li ()\)-6-azaspiro|3.5|nonan-2- yl)methoxy)methyl)cyclopropyl)-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((21?,7aS)-2- fluorotetrahydro-177-pyrrolizin-7a(577)-yl)methoxy)pyrido[4,3-< / ]pyrimidin-4-ol. To a stirred mixture of tert-butyl (2S,4R)-2-((((lRS,2SR)-2-(2-(4-(Ie / 7-butoxy)-8-fluoro-2-(((2R,7aS)-2- Iluorotetrahydro-lF7-pyrrolizin-7a(5J7)-yl)methoxy)pyrido[4,3-<7|pyrimidin-7-yl)-6-chloro-4- (methoxymethoxy )pheny l)cyclopropy l)methoxy)methy l)-2-liydroxy-6-azaspiro [3.5]nonane-6- carboxylatc (0.20 g, 0.23 mmol) in dichloromcthanc (5.5 mL) was added zinc bromide (0.42 g, 1.86 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 21 h, was then diluted with water (5 mL) and stirred for 1 h. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 7-(3-chloro-2-((lRS,2SR)-2-((((25,45)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)methoxy)methyl)cyclopropyl)-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-r / ]pyrimidin-4-ol (0.16 g. 0.23 mmol, quantitative yield), m / z (ESI): 716.2 (M+H)+. *H NMR (400 MHz, DMSO-d / ) 3 ppm 9.19 - 8.77 (m, 1H), 7.45 - 7.17 (m, 1H), 7.17 - 6.85 (m, 1H), 5.39 - 5.03 (m, 3H), 4.91 - 4.66 (m, 1H), 4.21 - 4.07 (m, 1H), 3.48 - 3.37 (m, 4H), 3.21 - 2.92 (m, 5H), 2.92 - 2.66 (m, 4H), 2.45 - 2.29 (m, 1H). 2.21 - 1.88 (m, 8H), 1.87 - 1.60 (m, 4H), 1.60 - 1.48 (m. 4H), 1.47 - 1.28 (m. 3H), 0.81 - 0.61 (m. 1H).19F NMR (376 MHz, DMSO-dd) 3 ppm -139.54 (br d, J = 23.4 Hz. IF). -168.88 - -177.36 (m, IF).

[0261] Step 5. (13R,41lSR,42R5,83R)-33-Chloro-28-fluoro-22-(((2R,7a5)-2-fluorotetrahydro- l / 7-pyrrolizin-7a(5 / 7)-yl)methoxy)-35-(methoxymethoxy)-6-oxa-2(4,7)-pyrido[4,3-<Z|pyrimidina- 1 (1 ,3)-piperidina-3(l ,2)-benzena-8(l ,3)-cyclobutana-4(l ,2)-cyclopropanaoctaphan-83-ol. To a stirred mixture of 7-(3-chloro-2-((lR5',2SR)-2-((((2S,4>S)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)methoxy)methyl)cyclopropyl)-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7a>S)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-r / ]pyrimidin-4-ol (0.16 g. 0.23 mmol) and M / V-diisopropylcthylaminc (0.4 mL, 2.3 mmol) in tetrahydrofuran (50 mL) was added PyBOP (0.24 g. 0.47 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 46 h. 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% 1:3 ethanol / ethyl acetate (with 2% EfeN) in heptane to give (13R,41>SK,42R>S',83A)-33-chloro-28-fluoro- 22-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(527)-yl)methoxy)-35-(methoxymethoxy)-6-oxa- 2(4,7)-pyrido[4,3-G?|pyrimidina-l(L3)-piperidina-3(l,2)-benzena-8(L3)-cyclobutana-4(l,2)- cyclopropanaoctaphan-83-ol (42 mg, 0.06 mmol, 26% yield), m / z (ESI): 698.0 (M+H)+. *H NMR (400 MHz, DMSO-ds) 8 ppm 9.26 - 9.08 (m, 1H), 7.51 - 7.39 (m, 1H), 7.37 - 7.26 (m, 1H), 5.43 - 5.15 (m, 3H). 4.79 - 4.64 (m, 1H). 4.60 - 4.47 (m, 1H). 4.24 - 3.99 (m, 3H), 3.64 - 3.53 (m, 1H), 3.48 -3.40 (m, 3H), 3.25 - 3.19 (m, 1H), 3.16 - 3.00 (m, 6H), 2.89 - 2.78 (m, 1H), 2.71 - 2.63 (m, 1H), 2.45 - 2.35 (m, 1H), 1.91 - 1.83 (m, 2H), 1.82 - 1.59 (m, 9H), 1.57 - 1.48 (m, 1H), 1.42 - 1.28 (m, 3H), 0.88 - 0.74 (in, 1H), 0.38 - 0.24 (m, 1H).19FNMR (376 MHz, DMSO-d6) 5 ppm -138.92 (br d, J = 10.4 Hz, IF), -172.12 (d, J = 42.5 Hz, IF).

[0262] Step 6. ( 1 R,3R,7R,95)-l l-Chloro-30-fluoro-22-(((2R,7a5)-2-fluorotetrahydro-l H- pyrroIo[l,2-a]pyrroI-7a(5 / 7)-yl)methoxy)-5-oxa-17,21,23,25- tetraazaheptacyclo[23.3.1.1~l,3~.l~16,20~.0~7,9~.0~10,15~.0~19,24~]hentriaconta- 10,12,14,16(30),17,19,21,23-octaene-3,13-diol (Example 1.001) and (153R,7531i)-ll-chloro-30- fluoro-22-(((2R,7a£)-2-fluorotetrahydro-lZ7-pyrrolo[l,2-«]pyrrol-7a(5Z7)-yl)methoxy)-5-oxa- 17,21 ,23,25-tetraazaheptacyclo|23.3.1.1~l,3~.l~16,20~.0~7,9~.0~10,15~.0~19,24~|hentriaconta- 10,12,14,16(30),17,19,21,23-octaene-3,13-diol (Example 1.002). To a stirred mixture of(13R, 4 lSR,42RS,83R)-33-chloro-28-fluoro-22-(((2R,7a5)-2-fluorotetrahydro-lH-pyrrolizin-7a(5Fr)- yl)methoxy)-35-(methoxymethoxy)-6-oxa-2(4,7)-pyrido[4,3-J|pyrimidina-l(l,3)-piperidina-3(l,2)- benzena-8(l,3)-cyclobutana-4(l,2)-cyclopropanaoctaplran-83-ol (42 mg, 0.06 mmol) in dichloromethane (1.5 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane, 0.15 mL, 0.6 mmol) at room temperature under ambient atmosphere. The resulting mixture was stirred at room temperature for 80 minutes then the mixture was concentrated under reduced pressure. The residue was purified by reversed phase HPLC on a Phenomenex Gemini column, Cl 8, 100 A. 150 x 30 mm, 5 pm, eluting at 45 mL / min with a gradient of 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA), followed by purification using an a Chiralcel OD, 2 x 25 cm. 5 pm column with a mobile phase of 35% MeOH with 0.2% DEA using a flowrate of 80 mL / min to generate

[0263] Peak 1: (1R,32?,7R.9S)-ll-Chloro-30-fluoro-22-(((2Z?,7a(S)-2-fluorotetraliydro-17f- pyrrolo[l,2-a]pyrrol-7a(5 / 7)-yl)methoxy)-5-oxa-17,21,23,25- tetraazaheptacyclo[23.3.1.1~l,3~.l~16.20~.0~7,9~.0~10,15~.0~19,24~]hentriaconta- 10,12,14,16(30).17,19.21,23-octaene-3.13-diol (Example 1.001, 10 mg, 0.02 mmol, 5% yield), m / z (ESI): 654.2 (M+H)1.]H NMR (400 MHz, DMSO-d6) 5 ppm 10.77 - 9.29 (m, 1H), 9.25 - 9.01 (m. 1H), 7.27 - 7.13 (m. 1H), 7.08 - 6.94 (m. 1H), 5.48 - 5.12 (m, 1H), 4.98 - 4.41 (m, 3H), 4.31 - 3.99 (m. 2H), 3.71 - 3.49 (m, 1H), 3.17 - 2.99 (m, 4H), 2.90 - 2.78 (m, 1H), 2.71 - 2.60 (m, 1H). 2.44 - 2.34 (m, 1H), 2.24 - 1.96 (m, 4H), 1.93 - 1.43 (m. 11H), 1.42 - 1.24 (m, 3H). 0.84 - 0.66 (m, 1H). 0.48 - 0.11 (m, 1H).19F NMR (376 MHz, DMSO-d6) 5 ppm -139.12 (s, IF), -172.05 (s, IF).

[0264] Peak 2: (1S,3R,7S,9R)-1 l-Chloro-30-fluoro-22-(((2R,7aS)-2-fluorotetraliydro-17f- pyrrolo[l,2-a]pyrrol-7a(5 / 7)-yl)methoxy)-5-oxa-17,21,23,25- tetraazaheptacyclo[23.3.1.1~l,3~.l~16.20~.0~7,9~.0~10,15~.0~19,24~]hentriaconta- 10,12,14,16(30).17,19.21,23-octaene-3.13-diol (Example 1.002, 10.3 mg, 0.02 mmol. 5% yield), m / z (ESI): 654.2 (M+H)+. ’H NMR (400 MHz, DMSO-de) 5 ppm 10.37 - 9.73 (m, 1H), 9.24 - 9.04 (m. 1H), 7.28 - 7.12 (m. 1H), 7.10 - 6.94 (m, 1H), 5.45 - 5.09 (m, 1H), 4.96 - 4.77 (m, 1H), 4.77 - 4.42(m, 2H), 4.21 - 4.04 (m, 2H), 3.68 - 3.50 (m, 1H), 3.24 - 3.18 (m, 1H), 3.17 - 2.97 (m, 4H), 2.96 - 2.78 (m, 1H), 2.71 - 2.60 (m. 1H), 2.45 - 2.34 (m, 1H), 2.22 - 2.10 (m, 1H), 2.10 - 1.93 (m, 3H), 1.92 - 1.57 (m, 9H), 1.57 - 1.48 (m, 1H), 1.39 - 1.27 (m, 3H), 0.82 - 0.70 (m, 1H), 0.36 - 0.23 (m, 1H).19FNMR (376 MHz, DMSO-dg) 5 ppm -139.10 (s, IF), -172.16 (s, IF).Table 4: Additional Examples 1.013-1.015 and 1.037-1.039. Prepared in an Analogous Manner to Examples 1.001 and 1.002.Table 5: Additional Data for Examples 1.013-1.015 and 1.037-1.039.Table 6: Conditions for Chiral Separation.

[0265] Example 1.003: (135',15R)-22,31-Difluoro-8-(((2R,7a5)-2-fluorotetrahydro-17f- pyrrolo[l,2-a]pyrrol-7a(5 / / )-yl)methoxy)-17-oxa-3,7,9,H- tetraazahexacyclo[ 19.7.1.1 ~2,6~.l~1 1,15~-.0~5,10~.0~25,29~|hentriaconta- l(28),2(31),3,5,7,9,21,23,25(29),26-decaene-13,27-diol (Example 1.003)

[0266] Step 1. ((2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)ethynyl)triisopropylsilane. A round-bottom flask (protected from light) was charged with ((2- fluoro-6-(methoxy methoxy)-8-(4,4.5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-y l)naphthalen- 1 - yl)ethynyl)triisopropylsilane (Intermediate H, Step 4, 7.00 g, 13.7 mmol), A, A-dmic thy I formamide (34 inL) and methanol (34 mL). Copper(I) iodide (3.90 g, 20.5 mmol) and NIS (4.61 g, 20.5 mmol) were added sequentially, then the reaction mixture was stirred at room temperature for 25 min. The mixture was combined with four other 7 g batches and poured into saturated aqueous sodium thiosulfate and extracted with EtOAc. The combined organic phases were washed with aqueous sodium thiosulfate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide ((2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)ethynyl)triisopropylsilane (19.7 g, 38.4 mmol), nvz (ESI): 513.0 (M+H)+.!H NMR (400 MHz, C C73) 5 ppm 7.99 - 8.13 (m, 1 H) 7.56 - 7.67 (m. 1 H) 7.36 - 7.42 (m. 1 H) 7.26 - 7.29 (m, 1 H) 5.26 (s, 2 H) 3.30 - 3.60 (m, 3 H) 1.19 - 1.25 (m. 21 H).

[0267] Step 2. l-Ethynyl-2-fluoro-8-iodo-6-(methoxymethoxy)naphthalene. A vial was charged with ((2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethynyl)triisopropylsilane (4.00 g, 7.81 mmol), cesium fluoride (5.93 g, 39.0 mmol) and A / A'-dinicthylformamidc (26 mL). The reaction mixture was heated to 50 °C for 3 h. After cooling to room temperature, the reaction was combined with four other 4 g batches and 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 using a gradient of 0-40% EtOAc / heptane, to give l-ethynyl-2-fluoro-8-iodo-6- (methoxymethoxy)naphthalene (12.6 g, 35.4 mmol), m / z (ESI): 357.0 (M+H) . ’H NMR (400 MHz, C C / j) 5 ppm 8.01 - 8.15 (m, 1 H) 7.59 - 7.74 (m, 1 H) 7.35 - 7.46 (m, 1 H) 7.20 - 7.30 (m, 1 H) 5.26 (s. 2 H) 3.85 - 4.02 (m, 1 H) 3.53 (s. 3 H).

[0268] Step 3. 2-Fluoro-8-iodo-6-(methoxymethoxy)-l-vinylnaphthalene. A vial was charged with bis(cyclopentadienyl)zirconium chloride hydride (5.79 g, 22.5 mmol) in a dry box under nitrogen, then cooled to 0 °C in an ice-water bath (with protection from light). A solution of 1- ethynyl-2-fluoro-8-iodo-6-(methoxymethoxy)naphthalene (4.00 g, 11.2 mmol) in dichloromethane (56 mL) was added, and the reaction mixture was allowed to warm to room temperature while stirring for 25 min. The reaction was combined with two other 4 g batches and cooled in an ice bath, diluted with water, and extracted with DCM. 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 using a gradient of 0-20% EtOAc / heptane, to provide 2-fluoro-8-iodo-6-(methoxymethoxy)-l-vinylnaphthalene (8.22 g, 23.0 mmol), m'z (ESI): 358.9 (M+H)+.!H NMR (400 MHz, CDCI3) 5 ppm 8.01 - 8.13 (m, 1 H) 7.59 - 7.64(m, 1 H) 7.48 - 7.57 (m, 1 H) 7.38 - 7.44 (m, 1 H) 7.28 (s, 1 H) 5.71 - 5.78 (m, 1 H) 5.48 - 5.59 (m, 1 H) 5.27 (s, 2 H) 3.50 - 3.55 (m, 3 H).

[0269] Step 4. 2-Fluoro-8-iodo-6-(methoxymethoxy)-l -naphthaldehyde. A round -bottom flask was charged with 2-fluoro-8-iodo-6-(methoxymethoxy)-l-vinylnaphthalene (2.00 g, 5.58 mmol), water (28 mL) and 1.4-dioxane (84 mL). To the mixture was charged with 2,6-dimethylpyridine (1.3 mL. 11.2 mmol), potassium osmate (VI) dihydratepotassium osmate (VI) dihydrate (41 mg, 0.11 mmol) and sodium periodate (4.78 g, 22.3 mmol), and then the reaction was stirred at room temperature for 20 h. The reaction mixture was combined with three other 2 g batches and quenched by the addition of saturated aqueous sodium thiosulfate. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with 0.5 N HC1, 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 a gradient of 0-20% EtOAc / heptane, to provide to provide 2-fluoro-8-iodo-6-(methoxymethoxy)-l-naphthaldehyde (6.00 g, 16.7 mmol). / n z (ESI): 360.9 (M+H)+. ’H NMR (400 MHz, CDCI3) 5 ppm 11.48 (s, 1 H) 7.95 - 8.13 (m, 1 H) 7.72 - 7.90 (m, 1 H) 7.37 - 7.54 (m, 1 H) 7.27 - 7.31 (m, 1 H) 5.29 (s, 2 H) 3.54 (s, 3 H).

[0270] Step 5. Methyl (£)-3-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)acrylate. A vial was charged with 2-fluoro-8-iodo-6-(methoxymethoxy)-l-naphthaldehyde (1.50 g, 4.17 mmol), (2-mcthoxy-2-oxocthylidcnc)triphcnylphosphoranc (1.53 g, 4.58 mmol) and toluene (21 mL). The reaction mixture was heated to 100 °C for 4 h. After cooling to room temperature, the reaction combined with three other 1.5 g batches and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-30% EtOAc / heptane, to provide methyl (E)-3-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)acrylate (5.40 g, 13.0 mmol), m / z (ESI): 416.8 (M+H)+.]H NMR (400 MHz, CDCI3) 3 ppm 8.54 - 8.66 (m, 1 H) 8.05 - 8.12 (m, 1 H) 7.64 - 7.73 (m, 1 H) 7.36 - 7.46 (m, 1 H) 7.28 (s, 1 H) 6.22 - 6.31 (m, 1 H) 5.27 (s, 2 H) 3.88 (s, 3 H) 3.53 (s, 3 H).

[0271] Step 6. Methyl (£)-3-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)acrylate. A vial was charged with cesium carbonate (3.17 g, 9.73 mmol), palladium(II) acetate (0.15 g, 0.65 mmol), bis(pinacalato)diboron (1.98 g, 7.78 mmol), tris(4-methoxyphenyl)phosphine (0.27 g, 0.78 mmol), methyl (E)-3-(2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-l-yl)acrylate (2.70 g, 6.49 mmol) and ethyl acetate (22 mL). The reaction mixture was heated to 80 °C for 45 min. After cooling to room temperature, the reaction was combined with another 2.7 g batch and concentrated. The crude residue was purified by column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc / heptane. to provide methyl (E)-3-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)acrylate (4.85 g, 11.7 mmol), m / z (ESI): 417.2 (M+H)+. *H NMR (400 MHz, CDCI3) 8 ppm 7.95 -8.09 (m, 1 H) 7.68 - 7.80 (in, 1 H) 7.58 - 7.66 (m, 1 H) 7.36 - 7.47 (m, 1 H) 7.20 - 7.27 (m, 1 H) 6.43 - 6.65 (m, 1 H) 5.17 - 5.40 (in, 2 H) 3.74 - 3.89 (m, 3 H) 3.39 - 3.60 (m, 3 H) 1.38 (s, 12 H).

[0272] Step 7. Methyl 3-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)propanoate. A pressure tube was charged with methyl (£)-3-(2- fluoro-6-(methoxy methoxy)-8-(4.4,5 ,5-tetramethy 1- 1 ,3 ,2-dioxaborolan-2-y l)naphthalen- 1 -yl)acry late (4.85 g, 11.7 mmol), platinum oxide (0.26 g, 1.17 mmol) and ethanol (78 m ). The vessel was purged with nitrogen for 15 min. then pressurized with hydrogen gas to 20 psi, then vented (3x). The vessel was pressurized with hydrogen gas to 25 psi, sealed and stirred at room temperature for 17 h. The reaction mixture was filtered through a plug of silica / cclitc and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-20% EtOAc / heptane, to provide methyl 3-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)propanoate (2.59 g, 6.19 mmol), m / z (ESI): 419.1 (M+H)+. ' H NMR (400 MHz, CDCI3) 6 ppm 7.60 - 7.67 (m, 1 H) 7.42 - 7.47 (m, 2 H) 7.20 - 7.26 (m, 1 H) 5.27 - 5.33 (m, 2 H) 3.66 - 3.75 (m, 3 H) 3.49 - 3.58 (m, 3 H) 3.32 - 3.45 (m, 2 H) 2.70 - 2.79 (m, 2 H) 1.44 (s, 12 H).

[0273] Step 8. Methyl 3-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propanoate. A vial (protected from light) was charged with methyl 3-(2-fhioro-6-(methoxymethoxy)-8-(4, 4,5,5- tctramcthyl-l,3,2-dioxaborolan-2-yl)naphthalcn-l-yl)propanoatc (2.55 g, 6.10 mmol), N, N- dimethylformamide (31 mL) and methanol (31 inL). Cuprous iodide (1.74 g, 9.14 mmol) and NIS (2.06 g, 9.14 mmol) were added sequentially, then the reaction mixture was stirred at room temperature for 45 min. The reaction mixture was poured into saturated aqueous sodium thiosulfate 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 methyl 3-(2- fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propanoate (2.50 g, 5.98 mmol), m / z (ESI): 440.8 (M+Na)+. ’H NMR (400 MHz, CDCI3) 3 ppm 8.10 - 8.15 (m, 1 H) 7.57 - 7.64 (m. 1 H) 7.39 - 7.45 (m, 1 H) 7.26 - 7.29 (m, 1 H) 5.26 (s. 2 H) 3.85 - 3.91 (m, 2 H) 3.75 (s. 3 H) 3.53 (s, 3 H) 2.76 - 2.82 (m. 2 H).

[0274] Step 9. 3-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propan-l-ol. A vial was charged with methyl 3-(2-fhioro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propanoate (2.10 g, 5.02 mmol) and THF (5 mL) under nitrogen, then cooled to -78 °C. Diisobutylaluminum hydride (1.0 M in THF, 20.1 mL, 20.1 mmol) was added dropwise, then the reaction mixture was stirred at -78 °C. The reaction was allowed to warm to 0 °C for 10 minutes, then cooled back to -78 °C and stirred for 10 minutes. The reaction mixture was carefully quenched with the addition of EtOAc, then allowed to warm to room temperature. Saturated aqueous Rochelle's salt (2 mL / mmol DIBAL-H) and EtOAc (4 mL / mmol DIBAL-H) was added, and the reaction mixture was vigorously stirred for 30 minutes. The aqueous phase was extracted with EtOAc. and the combined organic phases were washed withRochelle's salt, water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 3-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propan-l-ol (2.00 g, 5.13 mmol). m / z (ESI): 412.9 (M+Na)+. ’H NMR (400 MHz, CDCli) 5 ppm 8.13 (d, .7=2.51 Hz, 1 H) 7.56 - 7.61 (m, 1 H) 7.42 (s, 1 H) 7.28 (s, 1 H) 5.26 (s, 2 H) 3.76 - 3.86 (m, 2 H) 3.59 - 3.66 (m, 2 H) 3.53 (s. 3 H) 1.99 - 2.06 (m, 2 H) (1H not observed).

[0275] Step 10. 3-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propyl methanesulfonate. A vial was charged with 3-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)propan-l-ol (2.00 g, 5.13 mmol), triethylamine (1.1 mL. 7.7 mmol) and dichloromethane (34 mL). then cooled to 0 °C with an ice-water bath. Methane sulfonyl chloride (0.48 mL, 6.2 mmol) was added dropwise, then the reaction mixture was allowed to warm to room temperature with stirring for 10 minutes. The mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel, eluting using a gradient of 0-40% EtOAc / lieptane, to provide 3-(2- fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propyl methanesulfonate (1.50 g, 3.20 mmol, 62% yield), m / z (ESI): 490.8 (M+Na)+. ’H NMR (400 MHz, CDCI3) 5 ppm 8.11 - 8.24 (m, 1 H) 7.55 - 7.65 (m, 1 H) 7.37 - 7.47 (m, 1 H) 7.28 - 7.31 (m, 1 H) 5.26 (s, 2 H) 4.38 (s, 2 H) 3.62 - 3.72 (m, 2 H) 3.53 (s, 3 H) 3.05 (s. 3 H) 2.15 - 2.29 (m, 2 H).

[0276] Step 11. tert- Butyl (3R,55)-3-((3-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)propoxy)mcthyl)-5-(mcthoxymcthoxy)pipcridinc-l-carboxylate. A vial was charged with tert- butyl (3R,5>S)-3-(hydroxymethyl)-5-(methoxymethoxy)piperidine-l-carboxylate (4.59 g, 16.7 mmol), sodium 2-methylpropan-2-olate (4.5 mL, 9.0 mmol), 3-(2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-l-yl)propyl methanesulfonate (1.20 g, 2.56 mmol) and THF (13 mL). The reaction mixture was stirred at room temperature for 10 minutes, then heated at 50 °C for 3 h. After cooling to room temperature, the reaction was carefully quenched with aqueous ammonium chloride and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting using a gradient of 0-20% EtOAc / lieptane to provide tert-butyl (3R.5 )-3-((3-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propoxy)methyl)-5- (methoxymethoxy)piperidine-l -carboxylate (1.20 g. 1.85 mmol), m / z (ESI): 669.9 (M+Na)+.

[0277] Step 12. / ert- Butyl (31?,55)-3-((3-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)propoxy)methyl)-5-(methoxymethoxy)piperidine-l- carboxylate. A vial was charged with cesium carbonate (0.45 g, 1.4 mmol), palladium(II) acetate (21 mg. 0.093 mmol), bis(pinacalato)diboron (0.28 g, 1.1 mmol), tris(4-methoxyphenyl)phosphine (39 mg. 0.11 mmol), Zert-butyl (3R,5S)-3-((3-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)propoxy)methyl)-5-(methoxymethoxy)piperidine-l-carboxylate (0.60 g, 0.93 mmol) and ethyl acetate (4.6 mL) (degassed with nitrogen). The reaction mixture was heated to 80 °C for 1.5 h. After cooling to room temperature the reaction mixture was concentrated and the residue was purified bycolumn chromatography on silica gel, eluting using a gradient of 0-40% EtOAc / heptane, to provide tert-butyl (3R,55)-3-((3-(2-fhioro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)naphthalen-l-yl)propoxy)methyl)-5-(methoxymethoxy)piperidine-l-carboxylate (0.48 g, 0.73 mmol). m / z (ESI): 670.0 (M+Na)+. *H NMR (400 MHz, CDCl3) 5 ppm 7.56 - 7.63 (m, 1 H) 7.36 - 7.47 (m, 2 H) 7.15 - 7.25 (m, 1 H) 5.25 - 5.33 (m, 2 H) 4.61 - 4.73 (m, 3 H) 4.18 - 4.35 (m, 1 H) 4.06 - 4.13 (m, 1 H) 3.92 - 4.03 (m, 1 H) 3.53 (s, 4 H) 3.39 (s, 3 H) 3.29 - 3.36 (m, 2 H) 3.20 - 3.26 (m, 3 H) 2.34 - 2.55 (m, 2 H) 2.09 - 2.15 (in. 1 H) 1.88 - 1.95 (m, 2 H) 1.75 - 1.88 (m, 1 H) 1.46 (d, J=3.14 Hz, 21 H).

[0278] Step 13. tert- Butyl (3R,55)-3-((3-(8-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aA)-2- fluorotetrahydro-l / 7-pyrrolizin-7a(5 / 7)-yl)methoxy)pyrido[4,3-< / |pyrimidin-7-yl)-2-fluoro-6- (methoxymethoxy)naphthalen-l-yl)propoxy)methyl)-5-(methoxymethoxy)piperidine-l- carboxylate. A vial was charged with 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7a>8)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-J]pyrimidine (0.39 g, 0.95 mmol), tert-butyl (3R,5S)-3-((3-(2-fluoro-6-(methoxymethoxy)-8-(4.4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)naphthalen-l-yl)propoxy)methyl)-5-(methoxymethoxy)piperidine-l-carboxylate (0.48 g, 0.73 mmol), cataCXium A Pd G3 (53 mg, 0.073 mmol), potassium phosphate tribasic (0.39 g, 1.8 mmol), water (0.3 mL) and 2-Me-THF (3.3 mL), then bubbled with nitrogen for 10 min. The reaction mixture was heated to 80 °C for 2.5 h, then concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel, eluting using a gradient of 0-50% (3:1 EtOAc / EtOH with 2% TEA) / heptane, to provide tert-butyl (3R,5S)-3-((3-(8-(4-(tert-butoxy)-8-fluoro- 2-(((2A.1aS)-2 -fluorotetrahydro-lH-pyrrolizin-7a(5 / 7)-yl)methoxy)pyrido[4,3-t / |pyrimidin-7-yl)-2- fluoro-6-(methoxy methoxy)naphthalen- 1 -y l)propoxy)methy l)-5 -(metho xymethoxy)piperidine- 1 - carboxylate (0.24 g, 0.26 mmol), m / z (ESI): 897.9 (M+H)+. *H NMR (400 MHz. CDCl3) 8 ppm 9.10 - 9.15 (m. 1 H) 7.65 - 7.76 (m, 1 H) 7.48 - 7.58 (m, 1 H) 7.23 - 7.27 (m. 1 H) 7.15 - 7.21 (m. 1 H) 5.22 - 5.43 (m. 3 H) 4.63 - 4.74 (m, 2 H) 3.92 - 4.40 (m, 4 H) 3.53 (s, 4 H) 3.37 (s. 3 H) 3.17 - 3.33 (m, 3 H) 2.99 - 3.10 (m. 3 H) 2.81 - 2.94 (m, 2 H) 2.43 - 2.63 (m, 2 H) 2.21 - 2.33 (m, 4 H) 2.12 - 2.18 (m. 1 H) 1.88 - 2.08 (m. 4 H) 1.82 (s, 9 H) 1.65 - 1.76 (m. 1 H) 1.45 (s, 11 H) 1.01 - 1.13 (m, 1 H).|00279] Step 14. 8-Fluoro-7-(7-fluoro-3-hydroxy-8-(3-(((3R,55)-5-hydroxypiperidin-3- yl)mcthoxy)propyl)naphthalen-l-yl)-2-(((2R,7aA’)-2-fluorotetrahydro-lf / -pyiTolizin-7a(5 / f)- yl)rncthoxy)pyrido[4,3-d|pyrimidin-4-ol. A vial was charged with tert-butyl (3R,5«S)-3-((3-(8-(4- (tert-butoxy)-8-fluoro-2-(((2A,7a<S)-2-fluorotetrahydro-lH-pyrrolizin-7a(5 / r)-yl)methoxy)pyrido[4,3- t7]pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-l-yl)propoxy)methyl)-5-(methoxy methoxy )pipcridinc-l -carboxylate (0.20 g, 0.22 mmol) and dichloromethane (4.5 mL). Hydrogen chloride (4.0 M in 1 ,4-dioxane, 1.7 mL, 6.8 mmol) was added dropwise, then the reaction mixture was stirred vigorously at room temperature for 15 minutes. The reaction was concentrated under reduced pressure to provide 8-fluoro-7-(7-fluoro-3-hydroxy-8-(3-(((3R,5<S)-5-hydroxypiperidin-3-yl)methoxy)propyl)naphthalen-l-yl)-2-(((2R,7a*S)-2-fluorotetrahydro-lH-pyrrolizm-7a(5H)- yl)methoxy)pyrido[4,3-(7]pyrimidin-4-ol (0.18 g), which was used directly in the next step, m / z (ESI): 654.0 (M+H)+.

[0280] Step 15. (135,15R)-22,31-Difluoro-8-(((2R,7a5)-2-fluorotetrahydro-17T-pyrrolo[l,2- a] py rrol-7a(5H)-y l)methoxy)-l 7-oxa-3,7,9,l 1 - tetraazahexacyclo[19.7.1.1~2,6~.l~ll,15~.O~5,10~.0~25,29~]hentriaconta- l(28),2(31),3,5,7,9,21,23,25(29),26-decaene-13,27-diol (Example 1.003). A vial (protected from light) was charged with 8-fhioro-7-(7-fluoro-3-hydroxy-8-(3-(((3R,5S)-5-hydroxypiperidin-3- yl)mcthoxy)propyl)naphthalcn-l-yl)-2-(((2R,7aS)-2-fluorotctrahydro-lH-pyrrolizin-7a(5J7)- yl)methoxy)pyrido[4,3-J]pyrimidin-4-ol (0.18 g, crude), DIPEA (0.39 mL, 2.2 mmol) and THF (45 mL). PyBOP (0.17 g, 0.33 mmol) was added in one portion, then the reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by chromatography on silica gel, eluting using a gradient of 0-100% (3:1 EtOAc / EtOH with 2% TEA) / heptane. The compound was further purified via two steps. Step 1 : HPLC using an XSelect C 18. 19 x 100 mm, 5 urn, with a gradient from 20-80% acetonitrile with 0.1% formic acid in water with 0.1% formic acid. Step 2: HPLC using an XBridge C18, 19 x 100 mm, 5 um, with a gradient from 20-80% acetonitrile with 0.1% NH4OH in water with 0.1% NH4OH to provide (13S, 15A)-22,3 l-difluoro-8-(((2R,7a5)-2-fluorotetrahydro-l / 7-pyrrolo[ l,2-o]pyrrol-7a(5 / 7)- yl)methoxy)- 17-oxa-3.7.9, 11- tetraazahexacyclo[19.7.1.1~2,6~.l~l l,15~.0~5.10~.0~25,29~Jhentriaconta- l(28).2(31).3.5,7,9,21.23,25(29).26-decaene-13,27-diol (Example 1.003. 25 mg, 0.039 mmol), m / z (ESI): 636.0 (M+H)+.]H NMR (400 MHz, DMSO-de) 8 ppm 9.57 - 10.15 (m, 1 H) 9.14 - 9.31 (m, 1 H) 8.07 - 8.24 (m, 1 H) 7.71 - 7.85 (m, 1 H) 7.08 - 7.46 (m. 3 H) 5.22 - 5.43 (m, 1 H) 4.70 - 5.19 (m, 2 H) 4.02 - 4.27 (m, 2 H) 3.68 - 3.88 (m, 1 H) 3.03 - 3.41 (m. 12 H) 2.82 - 2.88 (m, 1 H) 2.30 - 2.42 (m.1 H) 2.13 - 2.22 (m, 1 H) 2.02 - 2.10 (m. 2 H) 1.67 - 1.93 (m. 6 H).19F NMR (376 MHz, DMSO-d6) 8 ppm -117.39 (br s, 1 F) -142.53 - -140.22 (m, 1 F) -172.05 (s. 1 F).Table 7: Additional Example 1.032. Prepared in an Analogous Manner to Example 1.003.Table 8: Additional Data for Example 1.032.

[0281] Example 1.004: (17Z,24R)-15-Chloro-29-fluoro-4-(((2R,7aA)-2-fluorotetrahydro-l / / - pyrrolo[l,2-a]pyrrol-7a(5£0-yl)methoxy)-13-hydroxy-24-methyl-21-oxa-l,3,5,9,23- pentaazapentacyclo [22.3.1.1~6,10~.0~2,7~.0~l 1 ,16~] nonacosa-2,4,6,8,10(29),l 1 ,13,15,17-nonaen- 22-one (Example 1.004).

[0282] Step 1. tert-Buty 1 (R)-3-(((((Z)-4-(2-(4-(tert-butoxy)-8-fluoro-2-(((2R,7a5)-2- flu()rotetrahydro-l / / -pyrrolizin-7a(5 / / )-yl)methoxy)pyrido|4,3-r / |pyrirnidin-7-vl)-6-chloro-4- (methoxymethoxy)phenyl)but-3-en-l-yl)oxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate. To a degassed mixture of cataCXium A Pd G3 (81 mg, 0.11 mmol), tert-butyl (R,Z)-3-((((4-(2-chloro- 4-(methoxymethoxy)-6-(4, 4,5, 5-tetramethy 1-1,3, 2-dioxaborolan-2-yl)phenyl)but-3-en-l- yl)oxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate (Intermediate G, 0.34 g, 0.56 mmol) and 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2A,7a5)-2-fluorotetrahydro-lH-pyrrolizin-7a(5 / 7)- yl)methoxy)pyrido[4,3-J|pyrimidine (Intermediate A, 0.23 g, 0.56 mmol) in 2-Me-THF (2 mL) and water (0.2 mL) was added potassium phosphate (0.36 g, 1.7 mmol). The resulting mixture was stirred at 80 °C for 1 h. The 2-Me-THF was decanted and concentrated. The crude material was purified by chromatography on silica gel, eluting using a gradient of 0-60% 1 :3 ethanol / ethyl acetate (with 2% triethylamine) in heptane, to give tert-butyl (R)-3-(((((Z)-4-(2-(4-(Iert-butoxy)-8-fluoro-2-(((2A,7aS)- 2-fluorotetrahydro- lH-pyrrolizin-7a(5FT)-yl)methoxy)pyrido[4,3-J|pyrimidin-7-yl)-6-chloro-4- (methoxymethoxy)phenyl)but-3-en-l-yl)oxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate (0.28 g, 0.33 mmol, 58% yield), m / z (ESI): 859.2 (M+H)+.

[0283] Step 2. (Z)-4-(2-Chloro-6-(8-fluoro-2-(((2R,7a.S’)-2-fluorotetrahydro-l / / -pyrrolizin- 7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-r / |pyrimidin-7-yl)-4-hydroxyphenyl)but-3-cn-l-yl ((R)- 3-methylpiperidin-3-yl)carbamate. To a stirred mixture of tert-butyl (R)-3-(((((Z)-4-(2-(4-(tert- butoxy)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-l / f-pyrrolizin-7a(5 / / )-yl)methoxy)pyrido[4.3- J|py nmidin-7-yl)-6-chloro-4-(mcthoxy methoxy )phcnvl)but-3-cn- 1 -yl)oxy)carbonyl)amino)-3- methylpiperidine- 1 -carboxylate (0.28 g, 0.33 mmol) in dichloromethane (6 mL) was added hydrogen chloride (4.0 M in 1 ,4-dioxanc. 1.6 mL, 6.4 mmol). The resulting mixture was stirred vigorously at 25 °C for 1 h, then was diluted with methanol (0.6 mL) and concentrated in vacuo and used directly in the next step, nu'z (ESI): 659.2 (M+H)+.

[0284] Step 3. (17Z,24R)-15-Chloro-29-fluoro-4-(((2R,7a5)-2-fluorotetrahydro-lH- pyrrolo[l,2-a]pyrrol-7a(5fl)-yl)methoxy)-13-hydroxy-24-methyl-21-oxa-l,3,5,9,23- pentaazapentacyclo[22.3.1.1~6,10~.O~2,7~.O~ll,16~]nonacosa-2,4,6,8,10(29),ll,13,15,17-nonaen-22-one. To a stirred mixture of bromotris(dimetliylamino)phosphonium hexafluorophosphate (0.63 g, 1.6 mmol) and Hiinig's base (0.68 mL, 3.9 mmol) in acetonitrile (56 mL) in a round-bottom flask was added (Z)-4-(2-chloro-6-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-l / 7-pyrrolizin-7a(5 / 7)- yl)methoxy)-4-hydroxypyrido[4,3-< / ]pyrimidin-7-yl)-4-hydroxyphenyl)but-3-en-l-yl ((R)-3- methylpiperidin-3-yl)carbamate HC1 salt (0.22 g, 0.33 mmol) in dimethyl sulfoxide (9.5 mL). The reaction mixture was covered with aluminum foil, then, the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was diluted with water and EtOAc. Aqueous NaHCCL was added to adjust the pH to > 8 in the aqueous phase and the aqueous layer was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting using a gradient of 0-100% 1:3 ethanol / ethyl acetate (with 1% TEA) in heptane. The mixture was further purified by prep-HPLC on a Phenomenex Luna column. C8(2), 100 A. 150 x 21.2 mm, 5 pm eluting with a gradient of 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA) at 20 mL / min to give (17Z,24R)-15-chloro-29-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-17f-pyrrolo[l,2-<7]pyrrol-7a(577)- yl)methoxy)-13-hydroxy-24-methyl-21-oxa-1.3,5,9,23- pentaazapentacyclo[22.3.Ll~6,10~.0~2,7~.0~l l,16~]nonacosa-2,4,6,8,10(29),11.13,15.17-nonaen- 22-one (Example 1.004, 80 mg, 0.11 mmol, 33% yield), m / z (ESI): 641.2 (M+H)+.!H NMR (400 MHz, METHANOL-d^ 5 ppm 9.27 (br s, 1H), 7.18 (br s, 1H), 7.03 (d, J = 2.5 Hz, 1H), 6.51 - 6.26 (m, 1H), 5.77 - 5.50 (m, 2H), 5.45 - 5.03 (m, 2H), 4.72 (s, 2H), 4.17 - 3.81 (in, 4H), 3.74 - 3.41 (in, 3H), 3.24 - 3.09 (in, 1H), 2.85 - 2.56 (m, 2H), 2.48 - 2.29 (m, 3H), 2.25 - 2.13 (m, 1H), 2.06 - 1.60 (m, 7H), 1.39 (br s, 3H) (2H not observed).19F NMR (376 MHz, METHANOL-dA) 5 ppm -77.28 (TFA), -138.52 (s, IF), -174.03 (s, IF).Example 1.005 & 1.006: (155,17R)-23,33-Difluoro-8-(((2R,7a5)-2-fluorotetrahydro-lH- pyrrolo[l,2-tf]pyrrol-7a(5 / 7)-yl)methoxy)-19-oxa-3,7,9,ll- tetraazaheptacyclo[20.7.1.1~2,6~.l~ll,15~.l~15,17~.0~5,10~.0~26,30~]tritriaconta- 1(29), 2(33), 3, 5,’ 1; 9,22, 24, 26(30), 27 -decaene-17, 28-diol (Example 1.005) and (15R,175)-23,33- Difluoro-8-(((2R,7a5)-2-fluorotetrahydro-17 / -pyrrolo[l,2-a]pyrrol-7a(5 / 7)-yl)methoxy)-19-oxa- 3, 7, 9,11 -tetraazaheptacyclo[20.7.1 ,l~2,6~.l ~11 ,15~.1~15,17~.0~5,l 0~.0~26,30~| t ritriaconta- 1 (29),2(33),3,5,7,9,22,24,26(30),27-decaene-l 7, 28-diol (Example 1.006)

[0285] Step 1. tert- Butyl (2S,4R)-2-((2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)ethoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of 2-(2- fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethan-l-ol (Intermediate I, 1.20 g, 3.19 mmol) and yttrium(III) trifluoromethanesulfonate (0.86 g. 1.6 mmol) in toluene (40 mL) was added tert-butyl (3S,5R)-l-oxa-7-azadispiro[2.1.5’.l3]undecane-7-carboxylate (Intermediate B, 1.21 g, 4.79 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 55 °C for 16 h. The reaction was quenched by sat. aq. ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, concentrated and the crude material was purified by column chromatography on silica gel, eluting using a gradient of 0-80% ethyl acetate in heptane, to give tert-butyl (2S,4R)-2-((2-(2-fluoro-8-iodo-6-(methoxymetlioxy')naphthalen-l-yl)ethoxy)methyl)- 2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.89 g, 1.4 mmol, 44% yield), m'z (ESI): 652.0 (M+H)+. ’HNMR (400 MHz, CDCli) 6 ppm 8.13 (d, 1H, J=2.3 Hz), 7.61 (dd, 1H, J=6.1, 9.0 Hz), 7.42 (d, 1H, J=2.5 Hz), 1.3-1.3 (m, 1H), 5.26 (s, 2H), 3.8-4.0 (m, 4H), 3.53 (s, 4H), 3.32 (br s, 2H), 3.25 (s, 2H), 2.79 (s, 1H), 1.99 (br d, 2H, J=13.6 Hz), 1.8-1.8 (m, 1H), 1.6-1.7 (m, 2H), 1.5-1.5 (m. 4H), 1.46 (s, 9H).

[0286] Step 2. tert-Butyl (25',4R)-2-((2-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6- carboxylate. To a stirred mixture of / crt-butyl (2S,4R)-2-((2-(2-fluoro-8-iodo-6-(methoxymethoxy )naphthalen-l-yl)ethoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate(1.70 g, 2.70 mmol) and bis(pinacolato)diborane (0.96 g, 3.8 mmol) in ethyl acetate (25 mL) was added tris(4-methoxyphenyl)phosphine (95 mg, 0.27 mmol), palladium (II) acetate (61 mg, 0.27 mmol) and cesium carbonate (1.32 g, 4.05 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 80 °C for 4 h then was cooled to room temperature, filtered over celite and concentrated. The crude material was purified by column chromatography on silica gel, eluting using a gradient of 0-60% ethyl acetate in heptane, to give tert-butyl (2S.4R)-2-((2-(2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethoxy)methyl)-2- hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (1.22 g. 1.94 mmol, 72% yield), m / 'z (ESI): 652.3 (M+Na)+.

[0287] Step 3. tert- Butyl (2.S’,4R)-2-((2-(8-(4-(tert-butoxy)-8-flu<)ro-2-(((2R,7«.S’)-2- flu()rotetrahvdro-l / / -pvrrolizin-7a(5 / / )-yl)rnethoxv)pyrido|4,3-< / |pyrirnidin-7-vl)-2-fluoro-6- (methoxymethoxy)naphthalen-l-yl)ethoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6- carboxylate. To a mixture of tert-butyl (2S,4R)-2-((2-(2-fhioro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)naphthalen-l-yl)ethoxy)methyl)-2 -hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (1.10 g, 1.75 mmol), 4-(tert-butoxy)-7-chloro-8-fluoro-2- (((2A.7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(577)-yl)methoxy)pyrido[4,3-£ / ]pyrimidine (Intermediate A, 0.87 g, 2.1 mmol), K.3PO4 (0.93 g. 4.4 mmol) and cataCXium Pd G3 (0.25 g, 0.35 mmol) were added 2-Me-THF (12 mL) and water (2 mL) at room temperature under nitrogen. The resulting mixture was stirred at 80 °C for 4 h, then was cooled to room temperature and concentrated. The crude material was purified by column chromatography on silica gel. eluting using a gradient of 0-100% 1:3 ethanol / ethyl acetate (with 2% TEA) in heptane, to give tert-butyl (2>S’,4R)-2-((2-(8-(4- (tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(57f)-yl)methoxy)pyrido[4,3- 17] pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-l-yl)ethoxy)methyl)-2 -hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (0.91 g, 1.00 mmol. 59% yield). m / z (ESI): 880.3 (M+H)+. *H NMR (400 MHz. CDCI3) 5 ppm 9.1-9.2 (m, 1H). 7.73 (dd, 1H, J=6.0. 8.9 Hz). 7.5-7.5 (m, 1H). 7.2- 7.3 (m, 1H), 5.38 (br s, 1H), 5.2-5.3 (m, 3H), 4.2-4.4 (m, 2H), 3.5-3.6 (m, 3H), 3.2-3.4 (m, 8H), 3.1- 3.2 (m, 3H), 2.9-3.1 (m, 2H), 2.7-2.8 (m, 1H), 2.5-2.7 (m, 1H), 2.2-2.3 (m, 1H), 2.21 (br s, 1H), 2.13 (br d, 1H, .7=8.4 Hz), 1.9-2.0 (m, 4H), 1.81 (s, 9H), 1.7-1.8 (in, 2H), 1.5-1.6 (in, 5H), 1.4-1.4 (in, 9H).Step 4. (15.S',17R)-23,33-Ditluoro-8-(((2R,7aA’)-2-tluorotetrahydro-l / / -pyrrolo[l,2-«|pyiTol- 7a(577)-yl)methoxy)-l 9-oxa-3, 7,9,11- tetraazaheptacyclo [20.7.1.1-2, 6-.1-11 ,15~.1 ~15,17~.0-5,10~.0~26,30~]tritriaconta- l(29),2(33),3,5,7,9,22,24,26(30),27-decaene-17,28-diol and (15R.17.S)-23.33-difluoro-8-(((2R.7a.S)- 2-fluorotetrahydro-177-pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-19-oxa-3, 7,9,11- tetraazaheptacyclo [20.7.1.1 ~2,6~.l -11 ,15-.1 ~15,17-.O-5,l 0~.0~26,30~]tritriaconta- l(29),2(33),3,5,7,9,22,24,26(30),27-decaene-17,28-diol. To a solution of tert-butyl (2S,4A)-2-((2-(8- (4-(tert-butoxy)-8-fluoro-2-(((2R.7aS)-2-fluorotetrahydro-lH-pyrrolizm-7a(577)-yl)methoxy)pyrido[4,3-J]pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-l- yl)ethoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.24 g, 0.27 mmol) in dichloromethane (20 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane, 3.41 mL, 13.64 mmol) under nitrogen at room temperature. The resulting mixture was stirred at room temperature for 2 h then the reaction was concentrated under reduced pressure. The crude residue was dissolved in THF (100 mL) and treated with diisopropylethylamine (0.95 mL, 5.5 mmol) and bromotris(dimethylamino)phosphonium hexafluorophosphate (0.16 g, 0.41 mmol). The resulting mixture was stirred at room temperature for 18 h, then concentrated. The crude material was purified by column chromatography on silica gel, eluting using a gradient of 0-100% 1:3 ethanol / ethyl acetate (with 2% TEA) in heptane to afford a mixture of isomers. The sample was purified via SFC using a Chiralcel OD. 30 x 250 mm, 5 pm column with a mobile phase of 35% methanol with 0.2% DEA in CO2 using a flowrate of 100 mL / min to generate Peak 1 as (15.S. 17R)-23.33-dinuoro-8-(('(2 / L7a.S)-2- fhiorotetrahy dro- 1 / 7-pyrrolo [ 1.2-a]pyrrol-7a(577)-y l)methoxy)- 19-oxa-3.7,9, l ite traazaheptacyclo[20.7.1.1~2,6~.1~11, 15-.1-15,17~.0~5,10~.0~26,30~]tritriaconta-1(29), 2(33), 3, 5, 7, 9.22, 24.26(30), 27-decaene-17.28-diol (Example 1.005, 50 mg, 0.076 mmol, 28% yield), m / z (ESI): 662.2 [M+H]+. 'H NMR (400 MHz, METHANOL-d^ 5 ppm 9.09 (s, 1H), 7.71 (dd, 1H, J=6.0. 9.1 Hz). 7.32 (d. 1H. .1=2 5 Hz), 7.2-73 (m. 2H), 5.2-5.4 (m. 1H), 5.08 (br d, 1H, .7=13.0 Hz). 4.9-4.9 (m, 1H). 4.2-4.4 (m, 2H). 3.7-3.8 (m, 1H). 3.3-3.5 (m, 3H). 3.1-3.3 (m, 5H). 3.0-3.1 (m, 3H), 2.3-2.4 (in, 1H). 2.1-2.3 (in, 3H). 1.8-2.0 (m, 5H). 1.6-1.8 (m, 5H). 1.57 (br d, 1H, .7=13.0 Hz), 1.47 (br d, 1H. J=13.0 Hz).19F NMR (376 MHz, METHANOL-dj) 5 ppm -120.00 (d, IF, .7=3.9 Hz), - 141.92 (d, IF, .7=7.9 Hz). -173.59 (d, IF, .7=14.5 Hz). Also isolated Peak 2 as (15R,17S)-23,33- difluoro-8-(((2R.7aS)-2-fluorotetrahydro-17f-pyrrolo[l,2-a]pyrrol-7a(577)-yl)methoxy)-19-oxa- 3,7,9,ll-tetraazaheptacyclo[20.7.1.1~2,6~.1~1 l,15~.l~15,17~.0~5,10~.0~26,30~]tritriaconta- l(29),2(33),3,5,7,9,22,24,26(30),27-decaene-17.28-diol (Example 1.006, 15 mg, 0.023 mmol, 8% yield), m / z (ESI): 662.4 [M+H]+. 'HNMR (400 MHz, METHANOL-d^ 5 ppm 9.15 (br s, 1H), 7.6-7.7 (m, 1H), 7.29 (br s, 1H), 7.2-7.3 (m, 1H), 1.2-1.2 (m, 1H), 5.2-5.4 (m, 1H), 5.11 (br d, 1H, .7=13.2 Hz), 4.93 (br s, 1H), 4.7-4.7 (m, 1H), 4.2-4.4 (m, 2H), 3.70 (br d, 1H, .7=13.6 Hz), 3.53 (br d, 1H, .7=11.7 Hz), 3.1-3.3 (m, 6H), 2.9-3.1 (m, 2H), 2.3-2.5 (m, 3H), 2.0-2.3 (m, 4H), 1.8-2.0 (m, 6H), 1.6- 1.7 (m, 4H).19F NMR (376 MHz, METHANOL-d4) 5 ppm -119.18 (br s, IF), -140.38 (br d, IF, J=3.9 Hz), -173.71 (br s, IF).Example 1.007: (13R)-28,37-Difluoro-22-(((2R,7a.S’)-2-fluorotetrahydro-l / 7-pyrrolizin-7a(5 / / )- yl)methoxy)-33-hydroxy-13-methyl-6-oxa-8-aza-2(4,7)-pyrido[4,3-< / ]pyrimidina-l(l,3)- piperidina-3(l ,8)-naphthalenacyclooctaphan-7-one (Example 1.007)

[0288] Step 1. tert- Butyl (R)-3-(((2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate. To a stirred mixture of tert-butyl (3R)-3-amino-3-metliyl-piperidine- 1 -carboxylate (1.5 mL, 7.1 mmol, Pharmablock, Inc.) and DIPEA (1.85 mL, 10.6 mmol) in dichloromethane (10 mL) was added 4-nitrophenyl chloroformate (1.56 g, 7.75 mmol, Ambeed, Inc.) dropwise under nitrogen. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue dissolved in acetonitrile (10 mL) and treated with DIPEA (4.9 mL, 28 mmol) and 2-(2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-l-yl)ethan-l-ol (Intermediate I, 2.65 g, 7.05 mmol). The resulting mixture was heated to 80 °C for 12 h. The reaction was quenched by water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting using a gradient of 0-60% ethyl acetate in heptane, to give tert-butyl (K)-3-(((2-(2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-l-yl)ethoxy)carbonyl)ainino)-3-methylpiperidine-l-carboxylate (1.65 g. 2.68 mmol, 38% yield), m / z (ESI): 639.1 (M+Na)+. ‘HNMR (400 MHz, CDCli) 5 ppm 8.1-8.2 (m, 2H), 7.62 (dd, 1H, J=6.1, 9.0 Hz), 7.4-7.4 (m, 1H), 7.2-7.3 (m, 1H), 6.93 (d, 1H, J=7.8 Hz), 5.26 (s,2H), 4.38 (br d, 2H, .7=7.5 Hz), 3.8-4.0 (m, 4H), 3.53 (s, 3H), 2.89 (br s, 1H), 1.5-1.6 (m, 1H), 1.49 (s, 9H), 1.3- 1.3 (in, 3H), 1.3- 1.3 (in, 3H).

[0289] Step 2. tert- Butyl (R)-3-(((2-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)naphthalen-l-yl)ethoxy)carbonyl)amino)-3-methylpiperidine-l- carboxylate. To a stirred mixture of zert-butyl (R)-3-(((2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate (1.60 g, 2.60 mmol) and bis(pinacalato)diboron (0.92 g, 3.6 mmol), and tris(4-methoxyphenyl)phosphine (91 mg, 0.26 mmol) in ethyl acetate (20 mL) was added palladium (II) acetate (58 mg, 0.26 mmol) and cesium carbonate (1.27 g, 3.89 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 80 °C for 4 h, then the reaction mixture was cooled to room temperature and filtered over through celite, and the filtrate concentrated. The crude material was purified by column chromatography on silica gel, eluting using a gradient of 0-50% ethyl acetate in heptane, to give tert- butyl (R)-3-(((2-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)naphthalen-l-yl)ethoxy)carbonyl)amino)-3 -me thy lpiperidine-1 -carboxy late (1.02 g, 1.65 mmol, 64% yield), m / z (ESI): 639.3 (M+Na)+. *H NMR (500 MHz, CDCl3) 5 ppm 7.63 (dd, 1H, J=5.9, 9.0 Hz), 7.46 (d, 1H, .7=2.7 Hz), 7.43 (d, 1H, J=2.7 Hz), 7.23 (t, 1H, .7=9,0 Hz). 5.3-5.3 (m, 2H). 43-4.3 (m, 1H), 4.2-4.3 (m, 1H), 3.7-3.8 (m, 2H), 3.5-3.6 (m, 5H), 2.9-3.0 (m, 1H), 1.46 (s. 18H). 1 3-1.4 (m, 2H), 1.2-1.3 (m. 10H).19F NMR (471 MHz. CDCI3) 5 ppm -116.71 (br s. IF).

[0290] Step 3. tert- Butyl (R)-3-(((2-(8-(4-(tert-butoxy)-8-fluoro-2-(((2R,7a5)-2- fluorotetrahydro-l / 7-pyrrolizin-7a(517)-yl)methoxy)pyrido[4,3-< / |pyrimidin-7-yl)-2-fluoro-6- (methoxymethoxy)naphthalen-l-yl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate.To a stirred mixture of Zert-butyl (R)-3-(((2-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)naphthalen-l-yl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate (1.00 g, 1.62 mmol) and 4-(Zert-butoxy)-7-chloro-8-fluoro-2-(((2R,7a>S)-2-fluorotetrahydro-17 / - pyrrolizin-7a(577)-yl)methoxy)pyrido[4,3-J|pyrimidine (Intermediate A. 0.80 g, 1.95 mmol) in 2- Me-THF (10 mL) and water (2 mL) was added cataCXium A Pd G3 (0.24 g, 0.32 mmol) and potassium phosphate tribasic (0.86 g, 4.1 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 80 °C for 4 h then the reaction was cooled to room temperature and concentrated. The crude material was purified by column chromatography on silica gel, eluting using a gradient of 0-90% 1:3 ethanol / ethyl acetate (with 2% TEA) in heptane, to give Zert-butyl (R)-3-(((2- (8-(4-(Zert-butoxy)-8-fluoro-2-(((2R.7aS)-2-fluorotetrahydro-177-pyrrolizin-7a(527)- yl)methoxy)pyrido[4.3-<7|pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-l- yl)ethoxy)carbonyl)amino)-3-methylpiperidine-l -carboxylate (0.76 g. 0.88 mmol, 54% yield), m / z (ESI): 867.3 (M+H)+. ’H NMR (400 MHz, CDCl3) 5 ppm 9.13 (d, 1 H, .7=3.9 Hz), 7.74 (dd. 1 H. .7=5.9, 9.0 Hz), 7.54 (d, 1H, .7=2.7 Hz). 7.2-73 (in, 1H). 7.21 (d. 1H. J=2.5 Hz), 5.2-5.5 (m. 3H), 4.5-5.0 (m. 1H), 4.2-4.4 (in, 2H), 3.7-3.9 (in, 4H). 3.53 (s, 3H), 3.2-3.3 (m, 2H), 3.19 (s, 1H), 3.0-3.0 (m, 1H),2.7-2.9 (m, 3H), 2.5-2.7 (m, 1H), 2.3-2.3 (m, 1H), 2.1-2.2 (m, 3H), 1.9-2.0 (m, 4H), 1.82 (s, 9H), 1.7- 1.8 (m, 1H), 1.6-1.7 (m, 1H), 1.5-1.6 (m, 2H), 1.41 (s, 9H), 1.12 (br d, 1H, .7=2.5 Hz).19F NMR (376 MHz, CDCli) 5 ppm -115.3-114.7 (m, IF), -138.5-138.0 (m, IF), -173.1-172.9 (m, IF).

[0291] Step 4. 2-(2-Fluoro-8-(8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-177-pyrrolizin-7a(577)- yl)methoxy)-4-hydroxypyrido[4,3-< / |pyrimidin-7-yl)-6-hydroxynaphthalen-l-yl)ethyl ((R)-3- methylpiperidin-3-yl)carbamate dihydrochloride. To a stirred solution of / m-butyl (R)-3-(((2-(8- (A-(tert -butoxy )-8-fluoro-2-(((2R.7aS)-2-fluorotetrahydro- 1 J7-pyrrolizin-7a(577)- yl)methoxy)pyrido[4,3-J]pyrimidin-7-yl)-2-fluoro-6-(metlioxymetlioxy)naphthalen-l- yl)cthoxy)carbonyl)amino)-3-mcthylpipcridinc-l-carboxylatc (0.75 g, 0.87 mmol) in dichloromcthanc (20 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane, 10.8 mb, 43.2 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 1 h then the reaction mixture was concentrated to give 2-(2-fluoro-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(57 / )-yl)methoxy)-4-hydroxypyrido[4,3-rf]pyrimidin-7-yl)-6-hydroxynaphthalen-l - yl)ethyl ((R)-3-methylpiperidin-3-yl)carbamate dihydrochloride (0.64 g, 0.87 mmol, quantitative yield), m / z (ESI): 667.3 (M+H)+.

[0292] Step 5. (137f)-28,37-Difluoro-22-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-33-hydroxy-13-methyl-6-oxa-8-aza-2(4,7)-pyrido[4,3-< / ]pyrimidina-l(l,3)- piperidina-3(l,8)-naphthalcnacyclooctaphan-7-onc. To a stirred mixture of bromotris(dimethylamino)phosphonium hexafluorophosphate (1.00 g, 2.60 mmol) and DIPEA (2.3 mL, 13 mmol) in THF (200 mL) was added a solution of 2-(2-fluoro-8-(8-fluoro-2-(((2R,7a>S)-2- fluorotetrahydro- l / / -pyrrolizin-7a(577)-yl)methoxy)-4-hydroxypyrido[4,3-<7|pyrimidin-7-yl)-6- hydroxynaphthalen-l-yl)ethyl ((R)-3-methylpiperidin-3-yl)carbamate dihydrochloride (0.64 g, 0.87 mmol) in acetonitrile (20 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 48 h then die reaction was concentrated, and the crude material was purified by chromatography on C18 reversed phase column, eluting using a gradient of 0-80% acetonitrile (0.1% TFA) in water (0.1% formic acid), followed by column chromatography on silica gel. eluting using a gradient of 0-100% 1:3 ethanol / ethyl acetate (with 2% TEA) in heptane, to provide (13R)- 28,37-difluoro-22-(((2R.7a>S)-2-fluorotetrahydro-l / / -pyrrolizin-7a(5 / / )-yl)methoxy)-33-hydroxy-13- methy l-6-oxa-8-aza-2(4.7)-pyrido 14.3 -c / | pyrim idma- 1 (L3)-piperidina-3 (1,8)- naphthalenacyclooctaphan-7-one (Example 1.007, 31 mg. 0.041 mmol, 5% yield), m / z (ESI): 649.3 (M+H)+.!H NMR (400 MHz. METHANOL-d4) 5 ppm 9.39 - 9.06 (m. 1H), 7.84 - 7.67 (m. 1H), 7.39 - 7.32 (m, 2H). 7.30 - 7.20 (m, 1H). 5.74 - 5.48 (m, 1H). 5.41 - 5.20 (m, 1H). 4.42 - 4.31 (m, 1H). 4.25 - 4.17 (m. 1H), 4.16 - 4.07 (m. 1H), 3.69 - 3.47 (m. 2H), 3.30 - 3.12 (m. 4H), 3.08 - 2.96 (m. 2H). 2.42 - 2.10 (m, 4H). 2.08 - 1.95 (m, 4H). 1 .94 - 1 .77 (m, 3H). 1.70 - 1.57 (m, 1H). 1.46 - 1.32 (m, 2H). 1.29 - 1.22 (m, 2H) (2H not observed).19F NMR (376 MHz. METHANOL-d / ) 8 ppm -119.4- -117.7 (m. IF), -141.9-140.5 (m, IF), -173.68 (s, IF).Table 9: Additional Examples 1.016-1.031 and 1.040. Prepared in an Analogous Manner to Example 1.007.Il lTable 10: Additional Data for Examples 1.016-1.031 and 1.040.Table 11: Conditions for Chiral Separation.

[0293] Example 1.008: (l.S'.3R)-l(>-Chloro-29-fluoro-21-(((2R.7a.S)-2-fliiorotetraliy(lro-l / / - pyrrolo[l,2-tf]pyrrol-7a(5 / 7)-yl)methoxy)-5-oxa-16, 20, 22,24- tetraazahexacyclo[22.3.1.1~l, 3-.1-15, 19~.0~9,14~.0~18,23~]triaconta-9, 11, 13, 15(29), 16, 18, 20,22- octaene-3,12-diol (Example 1.008)

[0294] Step 1. tert- Butyl (2.S.4R)-2-((3-(2-chloro-6-ioilo-4-(methoxymethoxy)phenyl)propoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of 3-(2-chloro-6-iodo-4-(methoxymethoxy)phenyl)propan-l-ol (Intermediate F, 0.49 g, 1.37 mmol) and yttrium(III) trifluorometlianesulfonate (0.18 g, 0.34 mmol) in toluene (8 mL) was added tert-butyl (3S,5R)~ l-oxa-7-azadispiro[2.1 ,5s. l3]undecane-7-carboxylate (Intermediate B. 0.54 g, 2.1 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 40 °C for 17 h. The reaction mixture was cooled to room temperature and diluted with sat. aq. solution of sodium bicarbonate 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 a silica gel. eluting with a gradient of 0-80% ethyl acetate in heptane, to give tert-butyl (2S',4R)-2-((3-(2-chloro-6-iodo-4-(methoxymethoxy)phenyl)propoxy)methyl)-2- hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.51 g, 0.83 mmol, 60% yield). m / z (ESI): 632.0 (M+Na)+. *H NMR (400 MHz, CDCIi) 5 ppm 7.51 - 7.43 (m. 1H), 7.15 - 7.07 (m. 1H), 5.18 - 5.08 (m, 2H). 3.69 - 3.56 (m, 2H). 3.53 - 3.46 (m, 5H). 3.36 - 3.29 (m, 2H), 3.29 - 3.25 (m, 2H), 3.06 - 2.93 (m. 2H), 2.92 - 1.T1 (m, 1H), 2.10 - 2.03 (m, 3H), 1.91 - 1.82 (m, 2H), 1.72 - 1.67 (m, 2H), 1.56 - 1.45 (m, 12H).|00295] Step 2. tert- Butyl (2,$,4R)-2-((3-(2-chloro-4-(methoxymethoxy)-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)propoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6- carboxylate. To a stirred mixture of tert-butyl (2S,4R)-2-((3-(2-chloro-6-iodo-4- (methoxymethoxy)phenyl)propoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.51 g,0.83 mmol), bis(pinacolato)diboron (0.32 g, 1.3 mmol) and cesium carbonate (0.55 g, 1.7 mmol) ethyl acetate (3 mL) was added palladium (II) acetate (22 mg, 0.010 mmol) and tris(4- methoxyphenyl)pliosphine (67 mg, 0.19 mmol) at room temperature under nitrogen. The resulting mixture was sparged with nitrogen for 15 minutes and stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite. and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel, eluting with a gradient of 0-80% ethyl acetate in heptane, to give iert-butyl (2S',4R)-2-((3-(2-chloro-4- (methoxymethoxy)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propoxy)methyl)-2- hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.40 g. 0.66 mmol, 79% yield), m / z (ESI): 632.2 (M+Na)1. *H NMR (400 MHz, CDCli) 5 ppm 7.37 - 7.33 (m, 1H). 7.19 - 7.15 (m, 1H), 5.18 - 5.15 (m, 2H), 3.64 - 3.56 (m, 2H), 3.50 - 3.45 (m, 5H), 3.35 - 3.29 (m, 2H), 3.29 - 3.24 (m, 2H). 3.11 - 2.98 (m, 2H), 2.04 - 1.98 (m, 2H), 1.88 - 1.75 (m. 4H), 1.74 - 1.66 (m. 2H), 1.55 - 1.49 (m. 2H), 1.48 - 1.46 (m, 10H), 1.38 - 1.34 (m. 12H).

[0296] Step 3. tert- Butyl (2A,41?)-2-((3-(2-(4-(tert-butoxy)-8-fluoro-2-(((21?,7a5)-2- fluorotetrahydro-l / 7-pyrrolizin-7a(5 / 7)-yl)methoxy)pyrido[4,3-<Z]pyrimidin-7-yl)-6-chloro-4- (methoxymethoxy)phenyl)propoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate. To a mixture of tert-butyl (2S.4R)-2-((3-(2-chloro-4-(methoxymethoxy)-6-(4,4,5.5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.40 g.0.66 mmol). 4-(Zert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-l / 7-pyrrolizin-7a(5 / 7)- yl)methoxy)pyrido[4,3-t / ]pyrimidine (Intermediate A, 0.32 g. 0.78 mmol), potassium phosphate tribasic (0.68 g, 3.2 mmol) and cataCXium A Pd G3 (30 mg. 0.041 mmol) were added 2-Me-THF (4 mL) and water (0.40 mL) under nitrogen. The resulting mixture was sparged with nitrogen for 15 min and stirred at 60 °C for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-60% 1 :3 ethanol / ethyl acetate (with 2% EtsN) in heptane, to give tert-butyl (2S.4R)-2-((3-(2-(4-(tert-butoxy)-8-fluoro-2-(((2R.7a)S)-2-fluorotetrahydro-177- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4.3-<7]pyrimidin-7-yl)-6-chloro-4-(methoxy methoxy )phenyl)propoxy)methyl)-2-hydroxy-6-azaspiro[ 3.5 ]nonane-6-carboxy late (0.36 g, 0.42 mmol, 64% yield), m / z (ESI): 860.2 (M+H)+.!H NMR (400 MHz, DMSO-d6) 5 ppm 9.21 - 9.01 (m, 1H), 7.36 - 7.21 (m, 1H). 7.08 - 6.87 (m, 1H). 5.42 - 5.18 (m, 3H), 4.75 - 4.44 (m, 1H), 4.24 - 4.09 (m. 2H), 3.42 - 3.38 (m, 3H), 3.36 - 3.24 (m, 4H), 3.20 - 3.07 (m, 4H), 3.00 - 2.90 (m, 4H), 2.90 - 2.80 (m, 1H), 2.69 - 2.55 (m, 2H), 2.23 - 2.12 (m, 1H), 2.12 - 2.06 (m, 1H), 2.05 - 2.00 (m, 1H), 1.93 - 1.79 (in, 3H), 1.78 - 1.73 (m, 9H), 1.73 - 1.66 (m, 3H), 1.66 - 1.58 (m, 2H), 1.56 - 1.48 (m, 2H), 1.33 - 1.27 (m, 11H).19F NMR (376 MHz, DMSO-d6') 5 ppm -140.25 (br s, IF), -172.15 (s, IF)).

[0297] Step 4. 7-(3-Chloro-2-(3-(((2S',4R)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)methoxy)propyl)-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((21?,7aA)-2-fluorotetrahydro-17T- pyrrolizin-7a(5 / / )-yl)methoxy)pyrido[4,3-r / ]pyriinidin-4-ol. To a stirred mixture of / er / -butyl (2S.4R)-2-((3-(2-(4-(tert-butoxy)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-lH-pyrrolizin-7a(5 / 7)- yl)methoxy)pyrido[4,3-<7|pyrimidin-7-yl)-6-chloro-4-(methoxymethoxy)phenyl)propoxy)methyl)-2- hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.36 g, 0.42 mmol) in dichlorometliane (9 mb) was added zinc bromide (0.81 g, 3.59 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 17 h then the reaction mixture was diluted with water (10 mL) and stirred for 1 h and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 7-(3-chloro-2-(3-(((2S,4R)-2-hydroxy-6- azaspiro[3.5]nonan-2-yl)methoxy)propyl)-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7aS)-2- lluorotclrahydro- l / / -pvrrolizin-7a(5H)-yl)mcthoxy )pyrido|4.3-<: / |pyrimidin-4-ol (0.30 g, 0.42 mmol, quantitative yield), m / z (ESI): 704.0 (M+H)+.1H NMR (400 MHz, DMSO-de) 5 ppm 9.03 - 8.81 (m, 1H), 7.33 - 7.15 (m, 1H), 7.05 - 6.90 (m, 1H), 5.42 - 5.13 (m, 3H). 4.98 - 4.74 (m, 1H). 4.19 - 4.05 (m, 2H). 3.47 - 3.18 (m, 17H), 3.17 - 3.00 (m. 4H), 2.99 - 2.83 (m. 4H), 2.79 - 2.55 (m. 3H), 2.12 - 2.01 (m. 2H), 1.94 - 1.74 (m, 5H), 1.73 - 1.47 (m, 8H).19F NMR (376 MHz, DMSO-de) 5 ppm - 138.66 - -144.52 (m. IF), -171.95 (br s, IF).

[0298] Step 5. ((15,3R)-10-Chloro-29-fluoro-21-(((2R,7tf5)-2-fluorotetrahydro-17f- pyrrolo[l,2-a]pyrrol-7a(5 / 7)-yl)methoxy)-12-(methoxymethoxy)-5-oxa-16, 20, 22,24- tetraazahexacyclo[22.3.1.1~l, 3-.1-15, 19~.0~9,14~.0~18,23~]triaconta-9, 11, 13, 15(29), 16, 18, 20,22- octaene-3-ol). To a stirred mixture of bromotris(dimethylamino)phosphonium hexafluorophosphate (0.33 g, 0.85 mmol) and MM-diisopropylethylamine (0.75 mL, 4.3 mmol) in acetonitrile (75 mL) was slowly added 7-(3-chloro-2-(3-(((2S,4R)-2-hydroxy-6-azaspiro[3.5]nonan-2-yl)methoxy)propyl)-5- (mcthoxy methoxy )phcnyl)-8-fhioro-2-((T2A'.7a.S)-2-fhiorotctrahydro-l / 7-pyrrolizin-7a(5 / V)- yl)methoxy)pyrido[4.3-<7|pyrimidin-4-ol (0.30 g. 0.42 mmol) as a solution in acetonitrile (12.5 mL) at room temperature under nitrogen. The reaction was shielded from light with aluminum foil and the resulting mixture was stirred at room temperature for 17 h. Additional bromotris(dimethylamino)phosphonium hexafluorophosphate (0.34 g, 0.86 mmol) was added and the resulting mixture was stirred at room temperature for 36 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and washed with sat. aq. sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-100% 1:3 cthanol / cthyl acetate (with 2% EtjN) in heptane, to give ((LS,3R)-10-chloro-29-fhioro-2 l-(((2R,7o$)-2- fluorotetrahy dro- I / / -pvrrolo [ 1 ,2-a]pyrrol-7a(577)-y l)methoxy)- 12-(methoxymethoxy)-5 -oxa- 16,20,22,24-tetraazahexacyclo[22.3.1.1~l,3~.l~15,19~.0~9,14~.0~18,23~]triaconta-9,11,13, 15(29), 16, 18,20, 22-octaene-3-ol) (77 mg, 0.11 mmol, 27% yield), m / z (ESI): 686.2 (M+H)+. ’H NMR (400 MHz, DMSO-d6) 8 ppm 9.26 - 9.10 (m, 1H), 7.36 - 7.23 (m, 1H), 7.23 - 7.08 (in, 1H), 5.44 - 5.17 (m, 3H), 4.86 - 4.26 (m, 2H), 4.24 - 4.11 (m, 1H), 4.11 - 3.99 (m, 1H), 3.45 - 3.39 (m, 3H), 3.34 - 3.30 (m, 3H), 3.16 - 2.98 (m, 4H), 2.89 - 2.78 (m, 3H), 2.56 - 2.53 (m, 5H), 2.18 - 1.95 (m, 4H), 1.91 - 1.57 (m, 9H). ”FNMR (376 MHz, DMSO-d / ) 3 ppm -142.65 (s, IF), -172.15 (s, IF).

[0299] Step 6. (15,3R)-10-Chloro-29-fluoro-21-(((2R,7a5)-2-fluorotetrahydro-lH-pyrrolo[l,2- «]pyrrol-7a(5H)-yl)methoxy)-5-oxa-16,20,22,24- tetraazahexacyclo[22.3.1.1~l,3~.l~15,19~.0~9,14~.0~18,23~]triaconta-9,ll,13,15(29),16,18,20,22- octacnc-3,12-diol (Example 1.008). To a stirred mixture of ((lS,3R)-10-chloro-29-fluoro-21- (((2R,7aS)-2-fluorotetrahydro-l W-pyrrolo| l,2-<7]pyrrol-7a(577)-yl)methoxy)-l 2-(methoxymetlioxy )-5- oxa-16,20,22,24-tetraazahexacyclo[22.3.1.1~l,3~.l~15,19~.0~9,14~.0~18,23~]triaconta- 9,l l,13,15(29),16,18,20,22-octaene-3-ol) (77 mg, 0.11 mmol) in dichloromethane (3 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane, 0.45 mL, 1.8 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC on a Phenomenex Gemini column Cl 8, 100 A, 150 x 30 mm, 5 pm eluting at 45 mL / min with a gradient of 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA). to give (1A3R)-10-chloro-29-fluoro-21 -(((2R.7aN)-2-fluorotetrahydro-lH-pyrrolo[ 1 ,2-a]pyrrol- 7a(5 / 7)-yl)methoxy)-5-oxa-16.20,22.24- tetraazahexacyclo[22.3.1.1~1.3~.l~15,19~.0~9,14~.0~18,23~]triaconta-9.11,13,15(29),16,18,20,22- octaene-3,12-diol bis(2.2.2-trifluoroacetate) (Example 1.008. 54 mg, 0.06 mmol, 55% yield), m / z (ESI): 642.2 (M+H)+.!H NMR (400 MHz. DMSO-de) 8 ppm 11.15 - 10.44 (m, 1H). 10.42 - 9.57 (m. 1H). 9.34 - 9.11 (m, 1H). 7.08 - 6.93 (m, 1H). 6.93 - 6.79 (m, 1H). 5.76 - 5.39 (m, 1H). 4.89 - 4.33 (m, 3H). 4.15 - 3.44 (m, 9H). 3.42 - 3.18 (m, 2H). 2.97 - 2.75 (m, 2H), 2.73 - 2.53 (m, 2H), 2.49 - 2.42 (m. 1H), 2.42 - 2.28 (m, 1H), 2.28 - 2.11 (m, 2H), 2.11 - 1.98 (m, 1H), 1.76 (s. 5H), 1.47 - 1.00 (m, 2H).19F NMR (376 MHz, DMSO-d / ) 8 ppm -74.50 (br s, 5F), -142.78 (s, IF), -172.94 (br s, IF).

[0300] Example 1.009: (15',3R)-29-Fluoro-21-(((2R,7a5)-2-fluorotetrahydro-llT-pyrrolo[l,2- a]pyrrol-7a(5 / / )-yl)methoxy)-10-methyl-5-oxa-16, 20, 22,24- tetraazahexacyclo[22.3.1.1~1, 3~.l~15,19~.0~9,14~.0~18,23~]triaconta-9,l 1,13, 15(29), 16, 18,20,22- octaene-3,12-diol (Example 1.009)

[0301] Step 1. (l3R,93R)-28-Fluoro-22-(((2R,7aS)-2-fluorotetrahydro-17f-pyrrolizin-7a(5H)- yl)methoxy)-35-(methoxymethoxy)-33-methyl-7-oxa-2(4,7)-pyrido[4,3-< / |pyrimidina-l(l,3)- piperidina-3(l,2)-benzena-9(l,3)-cyclobutananonaphan-93-ol. A stirred solution of (l3R,93R)-33- chloro-28-fluoro-22-(((2A,7a>S)-2 -fluorotetr ahydro-lH-pyrrolizin-7a(577)-yl)methoxy)-35- (methoxymethoxy)-7-oxa-2(4,7)-pyrido[4,3-<7|pyrimidina-l(l,3)-piperidina-3(l,2)-benzena-9(l,3)- cyclobutananonaphan-93-ol (48 mg. 0.07 mmol) and methanesulfonato(2-dicyclohexylphosphino- 2',4',6'-tri- / -propyl-l,r-biphenyl)(2'-methylamino-l,r-biphenyl-2-yl)palladium(II) (13 mg, 0.02 mmol, Strem Chemicals, Inc.) in THF (2.5 rnL) at room temperature was sparged with nitrogen for 5 min. To this mixture was added bis(trimethylaluminium)-l,4-diazabicyclo-[2.2.2]octane adduct (37 mg, 0.14 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at 70 °C for 2 h, cooled to room temperature and filtered through celite and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel, eluting using a gradient of 0-100% etlianol / ethyl acetate (1 :3) (2% EtsN) in heptane to provide ( l3R,93R)-28-fhioro-22-(((2R.7a5)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-3'’-(methoxymethoxj')-33-methyl-7-oxa-2(4.7)- pyrido [4,3 -<7| py rim idina- 1(1.3)-piperidina-3 (1 ,2)-benzena-9(l .3)-cyclobutananonaphan-93-ol (40 mg, 0.060 mmol, 87% yield), m / z (ESI): 666.2 (M+H)’.:H NMR (400 MHz, METHANOL-cE) 8 ppm 9.24 - 8.95 (m. 1H), 7.17 - 6.90 (m. 2H), 5.44 - 5.19 (m. 3H), 4.72 - 4.44 (m. 1H), 4.44 - 4.19 (m. 2H), 3.70 - 3.58 (m, 1H). 3.51 - 3.47 (m, 3H). 3.31 - 3.13 (m, 5H). 3.08 - 2.93 (m, 3H), 2.70 - 2.66 (m, 2H), 2.58 - 2.42 (m. 1H), 2.42 - 2.37 (m. 3H), 2.37 - 2.10 (m. 4H), 2.02 - 1.76 (m. 6H), 1.74 - 1.55 (m, 4H), 1.54 - 1.30 (m, 3H).19F NMR (376 MHz, METHANOL-d^ 8 ppm -142.48 - -142.82 (m, IF). -173.41 - -173.84 (m, IF).

[0302] Step 2. (LS',3R)-29-Fluoro-21-(((2R,7aS')-2-tluorotetrahydro-l / / -pynolo[l,2-«|pyiTol- 7a(57f)-yl)methoxy)-10-methyl-5-oxa-16,20,22,24- tetraazahexacyclo[22.3.1.1~l,3~.l~15,19~.0~9,14~.0~18,23~]triaconta-9,ll,13,15(29),16,18,20,22- octaene-3,12-diol. To a stirred mixture of (l3R,93R)-28-fluoro-22-(((2R.7a5)-2-fluorotetrahydro-lH- pyrrolizin-7a(5 / / )-yl)methoxy)-3:’-(methoxymethoxy)-33-methyl-7-oxa-2(4.7)-pyrido[4.3- J|pynmidina-l (1.3)-pipcridina-3( l ,2)-bcnzcna-9(1.3)-cyclobutananonaphan-93-ol (40 mg. 0.06 mmol) in dichloromethane (1.5 mL) at room temperature under ambient atmosphere, was added hydrogen chloride (4.0 M in 1,4-dioxane, 0.2 mL, 0.80 mmol). The resulting mixture was stirred at 25 °C for 10 min then concentrated under reduced pressure. The mixture was purified by prep-HPLC ona Phenomenex Gemini column. C18, 100 A, 150 x 30 mm, 5 pm eluting at 40 mL / min with a gradient of 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to provide (lS.3R)-29-fluoro-21- (((2R.7aS)-2-fluorotetrahydro-177-pyrrolo[l,2-a]pyrrol-7a(5 / 7)-yl)methoxy)-10-methyl-5-oxa- 16,20,22,24-tetraazahexacyclo[22.3.1.1~l,3~.l~15,19~.0~9,14~.0~18,23~]triaconta- 9.11,13.15(29),16.18,20.22-octaene-3,12-diol 2.2,2-trifluoroacetate (Example 1.009, 23 mg. 0.03 mmol, 52% yield), m / z (ESI): 666.2 (M+H)1.:H NMR (400 MHz, DMSO-d,) 5 ppm 11.12 - 10.50 (m, 1H), 9.61 - 9.27 (m, 1H), 9.25 - 9.12 (m, 1H), 6.81 - 6.53 (m, 2H), 5.82 - 5.39 (m, 1H). 5.15 - 4.12 (m, 4H), 4.03 - 3.67 (m, 3H), 3.66 - 2.96 (m. 3H), 2.93 - 2.76 (m. 2H), 2.71 - 2.52 (m. 2H), 2.49 - 2.29 (m, 2H). 2.29 - 2.24 (m, 3H). 2.24 - 1.98 (m, 4H). 1.96 - 1.57 (m, 3H), 1.60 - 1.44 (m, 2H), 1.43 - 1.05 (m, 2H).19F NMR (376 MHz, DMSO-de) 8 ppm -74.11 - -74.46 (m, 3F), -142.54 - - 143.23 (m, IF). -172.51 - -173.51 (m. IF).

[0303] Example 1.042: (13R.41.SR.42R.S.83R)-28-fliioi()-22 (((2R.7aS)-2-fluoroteti ah}(ln)-l H- pyrrolizin-7a(5H)-yl)methoxy)-33-methyl6-oxa-2(4,7)-pyrido[4,3-d]pyrimidina-l(l,3)- piperidina-3(l,2)-benzena-8(l,3)-cyclobutana-4(l,2)- cyclopropanaoctaphane-35,83-diol formate and Example 1.010 & 1.011: (lR.3R.7R.9.S)-30-Fluoro-22-(((2R.7a.S)-2-fluorotetrahy(lro-l / / - pyrrolo[l,2-a]pyrrol-7a(5fl)-yl)methoxy)-ll-methyl-5-oxa-17,21,23,25- tetraazaheptacyclo[23.3.1.1~l,3~.l~16,20~.0~7,9~.(l~10,15~.0~19,24~]hentriaconta-10,12,14,16(30), 17,19,21 ,23-octaene-3,13-diol and (l.S.3R.7.S.9R)-30-fliioi-o-22-(((2R.7a.S)-2- fluorotetrahydro-lH-pyrrolo[l,2-a]pyrrol-7a(5 / / )-yl)methoxy)-ll-methyl-5-oxa-l 7,21 ,23,25- tetraazaheptacyclo[23.3.1.1~l,3~.l~16,20~.0~7,9~.(l~10,15~.0~19,24~]hentriaconta- 10,12,14,16(30),17,19,21,23-octaene-3,13-diol (Examples 1.010 & 1.011)

[0304] Step 1. tert- Butyl (2s.4R)-2-(((( 1 R.S.2.W)-2-(2-bromo-4-(met hoxy met hoxy )-6- methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate.To a stirred mixture of rac-((1R,2S)-2-(2-bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)methanol (Intermediate D, 0.40 g. 1.33 mmol) and yttrium(III) trifluoromethanesulfonate (0.20 g, 0.37 mmol) in toluene (7 mL) was added tert-butyl (3S.5r)-l-oxa- 7-azadispiro[2.1.55. l3]undecane-7-carboxylate (Intermediate B, 0.54 g. 2.12 mmol) at room temperature under nitrogen. The resulting mixture was stirred at 40 °C for 17 h then was cooled to room temperature and diluted with sat. aq. sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, fdtered. and concentrated. The residue was purified by column chromatography on silica gel. eluting with a gradient of 0-80% ethyl acetate in heptane, to give / ert-butyl (2S.4R)-2-((((1RS,2.SR)-2-(2-bromo-4- (methoxy methoxy )-6-methy Ipheny l)cyclopropy l)methoxy )methy l)-2-hy droxy-6-azaspiro[3.5 ]nonane-6-carboxylate (0.54 g, 0.97 mmol, 73% yield), m / z (ESI): 576.0 (M+Na)+. ’H NMR (400 MHz, CDCI3) 5 ppm 7.19 - 7.10 (m, 1H), 6.86 - 6.77 (m, 1H), 5.20 - 5.06 (m, 2H), 3.93 - 3.59 (m, 1H), 3.55 - 3.44 (m, 3H), 3.39 - 3.15 (m, 6H), 2.89 - 2.74 (m, 1H), 2.74 - 2.52 (m, 1H), 2.46 - 2.40 (m, 3H), 2.02 - 1.87 (m, 3H), 1.72 - 1.60 (m, 4H), 1.55 - 1.42 (m, 12H), 1.41 - 1.33 (m, 1H), 1.07 - 0.92 (m, 1H).

[0305] Step 2. tert- Butyl (2s,4R)-2-hydroxy-2-((((lRA’,2\R)-2-(4-(methoxymeth(»xy)-2-methyl- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)methoxy)methyl)-6- azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of tert-butyl (2s,4R)-2-((((lR>S)2SR)-2-(2- bromo-4-(mcthoxymcthoxy)-6-mcthylphcnyl)cyclopropyl)mcthoxy)mcthyl)-2-hydroxy-6- azaspiro [3.5]nonane-6-carboxy late (0.54 g, 0.97 mmol), bis(pinacolato)diboron (0.37 g, 1.47 mmol) and cesium carbonate (0.64 g, 1.96 mmol) in ethyl acetate (5 mL) was added palladium(II) acetate (22 mg, 0.10 mmol) and tris(4-methoxyphenyl)phosphine (45 mg, 0.13 mmol) at room temperature under nitrogen. The resulting mixture was sparged with nitrogen for 15 min and stirred at 80 °C for 3.5 h. After cooling to room temperature, the reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-80% ethyl acetate in heptane, to give Zert-butyl (2S.4R)-2-hydroxy-2- ((((1RS.2SK)-2-(4-(methoxymethoxy)-2-methyl-6-(4, 4,5, 5-tetramethy 1-1,3, 2-dioxaborolan-2- yl)phenyl)cyclopropyl)methoxy)methyl)-6-azaspiro[3.5]nonane-6-carboxylate (0.52 g, 0.87 mmol.90% yield), m z (ESI): 624.2 (M+Na)+. *H NMR (400 MHz, CDC / 3) 6 ppm 7.15 - 6.96 (m, 1H), 6.92 - 6.84 (m. 1H), 5.24 - 5.09 (m. 2H), 3.48 - 3.46 (m. 3H), 3.40 - 3.24 (m. 3H), 3.23 - 3.11 (m. 3H), 3.07 - 2.80 (m, 1H). 2.41 - 2.35 (m, 3H). 1.98 - 1.76 (m, 3H). 1.75 - 1.62 (m, 4H), 1.56 - 1.41 (m, 13H), 1.41 - 1.33 (m, 12H), 1.25 - 1.17 (m, 2H), 0.78 - 0.57 (in, 1H).

[0306] Step 3. tert- Butyl (2s,4R)-2-((((1RA,25R)-2-(2-(4-(tert-butoxy)-8-fluoro-2-(((2R,7a5)-2- fluorotetrahydro-lH-pyrrolizin-7a(5 / 7)-yl)methoxy)pyrido|4,3-i / |pyrintidiri-7-yl)-4- (methoxymethoxy)-6-methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate. To a mixture of tert-butyl (2S',4R)-2-hydroxy-2-((((lRS,2SR)-2- (4-(methoxymethoxy)-2-methyl-6-(4.4.5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclopropyl)methoxy)methyl)-6-azaspiro|3.5|nonane-6-carboxylate (0.52 g, 0.87 mmol), 4- (tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2 -fluorotetrahydro- lrt-pyrrolizin-7a(5 / 7)- yl)methoxy)pyrido[4,3-J|pyrimidine (Intermediate A, 0.40 g. 0.96 mmol), potassium phosphate tribasic (0.56 g, 2.63 mmol) and cataCXium A Pd G3 (33 mg. 0.05 mmol) under nitrogen, 2-Me-THF (4 mL) and water (0.4 mL) were added at room temperature. The resulting mixture was sparged with nitrogen for 15 minutes and stirred at 60 °C for 4 h. After cooling to room temperature, the reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel, eluting with a gradient of 0-80% 1:3 ethanol / ethyl acetate (with 2% EtsN) in heptane, to provide tert-butyl (2S,4R)-2-((((lRS,2,SR)-2-(2-(4-(te / 7-butoxy)-8-fluoro-2 -(((2R, 7a5)-2 -fluorotetr ahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4, 3- J|pyrimidin-7-yl)-4-(methoxyniethoxy)-6-methylphenyl)cyclopropyl)methoxy)methyl)-2 -hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (0.49 g, 0.57 mmol, 66% yield), m / z (ESI): 852.2 (M+H)+.NMR (400 MHz, DMSO-de) 5 ppm 9.13 - 9.08 (m, 1H), 7.05 - 6.97 (m, 1H), 6.90 - 6.81 (m, 1H), 5.43 - 5.21 (m, 1H), 5.21 - 5.16 (m, 2H), 4.79 - 4.63 (m, 1H), 4.23 - 4.12 (m, 2H), 3.34 - 3.30 (m, 3H), 3.26 - 3.05 (m, 7H), 3.05 - 2.96 (m, 3H), 2.90 - 2.79 (m, 1H), 2.49 - 2.43 (m, 3H), 2.24 - 2.13 (m, 1H), 2.13 - 2.01 (m, 3H), 1.94 - 1.74 (m, 15H), 1.61 - 1.53 (m, 2H), 1.49 - 1.40 (m, 3H), 1.40 - 1.27 (m, 11H), 0.77 - 0.48 (m, 1H), -0.27 - -0.68 (m, 1H).19F NMR (376 MHz. DMSO-de) 5 ppm - 138.72 - -139.37 (m, IF), -172.15 (s, IF).

[0307] Step 4. 7-(3-Chloro-2-((l / W,2SR)-2-((((2S;4S)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)methoxy)methyl)cyclopropyl)-5-(methoxymethoxy)phenyl)-8-fluoro-2-(((2R,7a5)-2- fluorotetrahydro-l / 7-pyrrolizin-7a(5 / 7)-yl)methoxy)pyrido[4,3-< / ]pyrimidin-4-ol. To a stirred mixture of tert-butyl (2x,4R)-2-((((1RS,2SR)-2-(2-(4-( / ert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-<7]pyrimidin-7-yl)-4- (methoxymethoxy)-6-methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane- 6-carboxylate (0.49 g, 0.57 mmol) in dichloromethane (11 mL) was added zinc(II) bromide (1.00 g, 4.44 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 36 h then was diluted with sat. aq. sodium bicarbonate solution and stirred for 1 h. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-17 / -pyrrolizin-7a(5 / 7)- yl)niclhoxy)-7-(2-((lR.S'.2.SR)-2-((((2.S'.4.S)-2-hydroxy-6-azaspiro|3.5|nonan-2- yl)methoxy)methyl)cyclopropyl)-5-(methoxymethoxy)-3-methylphenyl)pyrido[4,3-al]pyrimidin-4-ol (0.18 g, 0.26 mmol. 46% yield), m / z (ESI): 696.2 (M+H)+. *H NMR (400 MHz, DMSO-dfi) 5 ppm 8.89 - 8.79 (m. 1H), 7.00 - 6.91 (m. 1H), 6.87 - 6.73 (m. 1H), 5.42 - 5.14 (m. 3H), 4.99 - 4.69 (m. 1H). 4.02 - 3.89 (m, 2H). 3.41 - 3.36 (m, 3H). 3.17 - 3.01 (m, 4H). 3.00 - 2.73 (m, 6H). 2.47 - 2.37 (m, 3H). 2.22 - 1.88 (m, 7H). 1.88 - 1.69 (m, 4H). 1.69 - 1.48 (m, 5H), 1.47 - 1.28 (m, 2H), 0.77 - 0.41 (m. 1H), 0.04 - -0.49 (m, 1H).19F NMR (376 MHz. DMSO-d / ) 8 ppm -141.12 (ddd, J = 16.9, 10.8, 5.2 Hz. IF), -171.90 (br s. IF).

[0308] Step 5. ( l3R,41AT?,42^S',83R)-28-fluoro-22-(((2R,7a5)-2-fluorotetrahydro-17 / -pyrrolizin- 7a(577)-yl)methoxy)-3s-(methoxymethoxy)-33-methyl-6-oxa-2(4,7)-pyrido[4,3-< / ]pyrimidina- 1 (1 ,3)-piperidina-3(l ,2)-benzena-8(l ,3)-cyclobutana-4(l ,2)-cyclopropanaoctaphan-83-ol. To a stirred mixture of AOV-diisopropylcthylaminc (0.5 mL, 2.86 mmol) and bromotris(dimethylamino)phosphonium hexafluorophosphate (0.21 g. 0.55 mmol) in acetonitrile (45 mL) at room temperature under nitrogen, was slowly added 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(577)-yl)methoxy)-7-(2-((lR1S',2>SR)-2-((((25-,41S)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)methoxy)methyl)cyclopropyl)-5-(methoxy methoxy )-3-methylphenyl)pyrido[4,3-<7|pyrimidin-4-ol(0.18 g, 0.26 mmol) as a solution in dimethyl sulfoxide (7.5 mL). The resulting mixture was stirred at room temperature for 45 minutes then concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with sat. aq. solution of sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The combined organic lay ers were 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% 1 :3 ethanol / ethyl acetate (with 2% EtaN) in heptane to give (l3R,41SR,42R.S',83R)-28-fluoro-22-(((2R.7a5)-2-fIuorotetrahydro-lH-pyrrolizin-7a(577)-yl)methoxy)- 3:’-(methoxymethoxy)-33-methyl-6-oxa-2(4.7)-pyrido[4,3-(7|pyrimidina-l(l,3)-piperidina-3(l,2)- benzena-8(l,3)-cyclobutana-4(l,2)-cyclopropanaoctaphan-83-ol (0.10 g, 0.15 mmol. 56% yield), m / z (ESI): 678.2 (M+H)1. ’H NMR (400 MHz, DMSO-d6) 5 ppm 9.29 - 9.03 (m, 1H). 7.38 - 7.20 (m, 1H), 7.16 - 6.96 (m. 1H), 5.43 - 5f.l2 (m, 4H), 4.86 - 4.80 (m, 1H), 4.77 - 4.66 (m, 1H), 4.59 - 4.49 (m. 1H), 4.23 - 3.99 (m. 3H), 3.64 - 3.53 (m, 1H), 3.44 - 3.39 (m, 3H), 3.24 - 3.20 (m, 1H). 3.18 - 2.99 (m, 5H), 2.91 - 2.81 (m, 1H), 2.35 - 2.29 (m. 1H), 2.10 - 1.96 (m. 4H), 1.90 - 1.61 (m. 10H). 1.55 - 1.48 (m, 1H), 1.33 - 1.22 (m, 3H), 0.82 - 0.66 (m, 1H), 0.27 - 0.13 (m, 1H).19F NMR (376 MHz, DMS0-d6) 5 ppm -139.33 (d, J = 10.4 Hz, IF). -172.11 (d, J = 41.6 Hz, IF).

[0309] Step 6. (13R,415R,42R5,83R)-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-vl)methoxy)-33-methyl6-oxa-2(4,7)-pyrido|4,3-6 / ]pyrimidina-l (l,3)- piperidina-3(l,2)-benzena-8(l,3)-cyclobutana-4(l,2)- cyclopropanaoctaphane-35,83-diol formateTo a stirred mixture of ( l3R,41SR,42R.S',83R)-28-fluoro-22-(((2R.7a5)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5 / 7)-yl)methoxy)-3:’-(methoxymethoxy)-33-methyl-6-oxa-2(4.7)-pyrido[4.3-( / ]pyrimidina-l(l,3)- piperidina-3(l,2)-benzena-8(1.3)-cyclobutana-4(l,2)-cyclopropanaoctaphan-83-ol (0.10 g. 0.15 mmol) in dichloromethane (3 mL) at room temperature was added hydrogen chloride (4.0 M in 1,4-dioxane, 0.5 mL, 2.0 mmol) and the reaction mixture was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified by reversed phase column chromatography on a C18 column, eluting with a gradient of 10-90% acetonitrile (0.1% formic acid) in water (0.1% formic acid), to give a racemic (13R,4LSR,42R1S',83R)-28-fluoro-22-(((2R,7aJS)-2- fluorotetrahydro-lH-pyrrolizin-7a(577)-yl)methoxy)-33-methyl6-oxa-2(4,7)-pyrido[4,3-<7]pyrimidina- l(l,3)-piperidina-3(l,2)-benzena-8(l,3)-cyclobutana-4(l,2)- cyclopropanaoctaphane-35,83-diol formate (Example 1.042, 26 mg. 0.039 mmol, 26% yield). m.'z (ESI): 634.2 (M+H)+.!H NMR (400 MHz, DMSO-dd) 6 ppm 9.52 - 9.27 (m, 1H), 9.21 - 9.01 (m, 1H), 8.39 - 7.94 (m, 1H), 7.12 - 6.97 (m, 1H), 6.86 - 6.71 (m 1H), 5.46 - 5.06 (m, 1H), 4.93 - 4.77 (m, 1H), 4.77 - 4.43 (m, 2H), 4.28 - 3.96 (m, 2H), 3.69 - 3.52 (m, 1H), 3.14 - 2.98 (m, 4H), 2.90 - 2.78 (m, 1H), 2.66 - 2.58 (m, 1H), 2.43 - 2.36 (m, 3H), 2.36 - 2.27 (m, 1H), 2.24 - 1.91 (m, 4H), 1.91 - 1.57 (m, 9H), 1.57 - 1.46 (m, 1H), 1.36 - 1.27 (in, 2H), 1.27 - 1.17 (m, 1H), 0.83 - 0.56 (m, 1H), 0.29 - 0.04 (m, 1H).I9FNMR (376 MHz, DMSO-d6) 5 ppm -139.53 (s, IF), -172.06 (s, IF).

[0310] Step 7. (1R,3R,7R,95)-30-Fluoro-22-(((2R,7a5)-2-fluorotetrahydro-lH-pyrrolo[ 1,2- a]pyrrol-7a(5H)-yl)methoxy)-l l-methyl-5-oxa-l 7,21 ,23,25- tetraazaheptacyclo[23.3.1.1~l,3~.l~16,20~.0~7,9~.0~10,15~.0~19,24~]hentriaconta- 10,12,14,16(30),17,19,21,23-octaene-3,13-diol and (l\JRJ5JR)-30-fluoro-22-(((2RJa5)-2- fkiorotetrahydro-lH-pyrrolo[l,2-a]pyrrol-7a(5 / 7)-yl)methoxy)-ll-methyl-5-oxa-l 7,21 ,23,25- tetraaz aheptacyclo[23.3.1.1~l,3~.l~l 6, 20~.0~7,9~.Q~10,15~.0~19,24~]hentriaconta- 10,12,14,16(30),17,19,21,23-octaene-3,13-diol. Example 1.042 was purified using SFC on a Chiralcel OD, 2 x 25 cm, 5 pm column with a mobile phase of 35% MeOH with 0.2% DEA using a flowrate of 80 mL / min to generate 8.9 mg of peak 1 with an ee of >99% and 10.5 mg of peak 2 with an ee of >99%. Peak assignment determined by SFC with Chiralcel OD column with 35% MeOH with 0.2% DEA to give (IA’.3A.7R.9.S)-30-fluoro-22-(((2A.7a.S)-2-fluorotctrahydro-lH-pyrrolo| 1.2- a]pyrrol-7a(5 / / )-yl)methoxy)- 11 -methy 1-5 -oxa- 17,21,23,25- tetraazaheptacyclo[23.3.1.1~1.3~.l~16.20~.0~7,9~.0~10,15~.0~19,24~]hentriaconta-10, 12, 14,16(30), 17, 19,21, 23-octaene-3,13-diol (Example 1.010, 4.5 mg, 7.1 umol, 5% yield). wdz (ESI): 634.2 (M+H)+. *H NMR (400 MHz, METHANOL-d^ 5 ppm 9.21 - 8.96 (m, 1H). 7.18 - 6.97 (m, 1H). 6.91 - 6.73 (m, 1H). 5.54 - 5.18 (m, 1H), 4.99 - 4.89 (m, 1H), 4.74 - 4.64 (m, 1H), 4.44 - 4.33 (m. 1H), 4.27 - 4.16 (m, 1H), 3.72 - 3.60 (m, 1H), 3.41 - 3.35 (m, 1H), 3.32 - 3.18 (m, 3H), 3.18 - 3.08 (m, 1H), 3.08 - 2.98 (m, 1H), 2.88 - 2.78 (m. 1H), 2.59 - 2.50 (m. 1H), 2.50 - 2.43 (m. 3H), 2.42 - 2.21 (m, 2H). 2.20 - 2.08 (m, 2H). 2.07 - 1.98 (m, 3H). 1.98 - 1.76 (m, 5H). 1.73 - 1.62 (m, 2H). 1.55 - 1.40 (m, 2H). 1.37 - 1.27 (m, 1H). 0.92 - 0.81 (m, 1H), 0.27 - 0.18 (m, 1H).19F NMR (376 MHz, METHANOL-dj) S ppm -138.41 - -140.65 (m, IF), -172.77 - -174.71 (m, IF) and (lS,3R,7S.9R)-30-fluoro-22-(((2A,7aS)-2-fluorotetrahydro-l / 7-pyrrolo[ l,2-r / ]pyrrol-7a(5AZ)- yl)methoxy)-l l-methyl-5-oxa-17,21,23,25- tetraazaheptacyclo[23.3.1.1~l,3~.l~16,20~.0~7,9~.0~10,15~.0~19,24~]hentriaconta-10,12,14,16(30),17,19,21,23-octacnc-3,13-diol (Example, 1.011, 10 mg, 0.02 mmol, 11% yield), m / z (ESI): 634.2 (M+H)+.]H NMR (400 MHz, DMSO-d^ 5 ppm 9.56 - 9.26 (m, 1H), 9.17 - 9.08 (m, 1H), 7.05 - 6.99 (in, 1H), 6.79 - 6.72 (m, 1H), 5.40 - 5.14 (m, 1H), 4.98 - 4.79 (m, 1H), 4.78 - 4.63 (m, 1H), 4.60 - 4.44 (m, 1H), 4.16 - 4.04 (m, 2H), 3.65 - 3.53 (m, 1H), 3.25 - 3.18 (m, 1H). 3.15 - 2.97 (m, 4H), 2.91 - 2.76 (m, 1H), 2.66 - 2.57 (m. 1H), 2.43 - 2.35 (m. 3H), 2.35 - 2.27 (m, 1H), 2.16 - 2.10 (m, 1H), 2.07 - 1.92 (m, 3H), 1.89 - 1.74 (m, 4H), 1.71 - 1.48 (m, 5H), 1.37 - 1.20 (m, 4H), 0.76 - 0.61 (m, 1H), 0.24 - 0.09 (m, 1H).19F NMR (376 MHz, DMSO-d6)' 3 ppm -139.35 - - 139.67 (m, IF), -171.98 - -172.28 (m, IF).

[0311] Example 1.033: (13R,£)-28,37-difluoro-22-(((2R,7a5)-2-fluorotetrahydro-lH- pyrrolizin-7a(577)-yl)methoxy)-8-oxa-2(4,7)-pyrido[4,3-J]pyrimidina-l(l,3)-piperidina-3(l,8)- naphthalenacyclononaphan-5-en-33-ol 2,2,2-trifluoroacetate.Example 1.033

[0312] Step 1: 2-(8-Allyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane. To a stirred mixture of 1 -ally 1-2 -fluoro-8-iodo-6-(methoxymethoxy)naphthalene (Intermediate 1-1, step 2; 1.0 g, 2.69 mmol) in THF (7.7 mL) at -78 °C under ambient atmosphere, was added A-butyllithium (2.5 M in hexanes, 1.34 mL, 3.36 mmol). The solution was stirred for 5 minutes, then 2-isopropoxy-4,4,5,5-tetramethyl-l,3.2-dioxaborolane (0.75 mL, 4.03 mmol, Sigma- Aldrich Corporation) was added. The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated, then diluted with sat. aq. solution of ammonium chloride and extracted with EtOAc. 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 0-40% EtOAc in heptane, to provide 2-(8-allyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (0.4 g. 1.1 mmol. 40% yield), nvz (ESI): 373.2 (M+H)+.

[0313] Step 2: 7-(8-Allyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4-(to7-butoxy)-8- fluoro-2-(((2R,7a5)-2- fluorotetrahydro-l / / -pyrrolizin-7a(5 / / )-yl)methoxy)pyrido[4,3- d\ pyrimidine. To a stirred mixture of degassed potassium phosphate (0.52 g. 2.45 mmol), 4-(tert- butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-12f-pyrrolizin-7a(5f0-yl)methoxy)pyrido[4,3-J|pyrimidine (Intermediate A, 0.33 g, 0.80 mmol), and 2-(8-allyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.26 g, 0.70 mmol) in 2-Me-THF (2.5 mL) and water (0.25 mL) was added methanesulfonato(diadamantyl-w- butylpliosphino)-2'-amino-l,l'-biphenyl-2-yl)palladium(II) (0.10 g. 0.14 mmol, Ambeed, Inc.). The resulting mixture was stirred at 80 °C for 2 h. The 2-Me-THF was decanted and the resulting mixture concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-70% in ethanol / EtOAc (1:3) with 1% TEA, to provide 7-(8-allyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-4-(Zert-butoxy)-8-fluoro-2-(((2A.7a5)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-i / |pyrimidine (0.40 g, 0.64 mmol. 92% yield), m / z (ESI): 623.2 (M+H)'.

[0314] Step 3: 7-(8-Allyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aA)- 2-fluorotetrahydro-lH-pyrrolizin7a(5 / 7)-yl)methoxy)pyrido[4,3-rf|pyrimidin-4-ol. To a stirred mixture of 7-(8-allyl-7-fluoro-3-(methoxymetlioxy)naphthalen-l-yl)-4-(Zert-butoxy)-8-fluoro-2- (((2A,7a5)-2-fluorotetrahydro-l / T-pyrrolizin-7a(577)-yl)methoxy)pyrido[4,3-r / ]pyrimidine (0.40 g, 0.64 mmol) in DCM (11.9 mL) at room temperature under nitrogen, was added zinc bromide (0.72 g, 3.21 mmol, Combi-Blocks Inc.). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with DCM. 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 0-20% ethanol / EtOAc (1:3) with 1% TEA in heptane, to provide 7-(8-allyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2A,7aS)-2-fluorotetrahydro-lH-pyrrohzin7a(5 / 7)- yl)methoxy)pyrido[4,3-i / |pyrimidin-4-ol (0.40 g, 0.71 mmol, quantitative yield), m / z (ESI): 567.2 (M+H)+.

[0315] Step 4: 7-(8-Allyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-4-((R)-3- ((allyloxy)methyl)piperidin-l-yl)-8-f'luoro-2-(((2R,7aA')-2-fluorotetrahydro-l W-pyrrolizin- 7a(5 / f)-yl)methoxy)pyrido[4,3-rf]pyrimidine. To a stirred mixture of 7-(8-allyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fhiorotetrahydro-l W-pyrrolizin-7a(5H)- yl)methoxy)pyrido|4,3-i / |pyrimidin-4-ol (33 mg, 0.058 mmol). (A)-3-((allyloxy)methyl)piperidine hydrochloride (Intermediate J, 28 mg. 0.15 mmol) and DIPEA (45 mg, 0.35 mmol) in DMSO (0.39 mL) at room temperature under nitrogen, was added PyBOP (76 mg. 0.15 mmol). The reaction mixture was stirred for 16 h, then diluted with water and extracted with EtOAc. 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 10-90% ACN (0.1% formic acid) in water (0.1% formic acid), to provide 7-(8-allyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-4-((R)-3-((allyloxy)methyl)piperidin-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-l H-pyrrolizin-7a(5 / 7)-yl)methoxy)pyrido[ 4, 3-<: / | pyrimidine (14 mg, 0.020 mmol, 34% yield), m / z (ESI): 704.2 (M+H)+.

[0316] Step 5: ( 13R^)-28,37-difluoro-22-(((2R,7a5)-2-fluorotetrahydro-l H-pyrrolizin- 7a(5Zf)-yl)methoxy)-8-oxa-2(4,7)-pyrido[4,3-< / ]pyrimidina-l(l,3)-piperidina-3(l,8)- naphthalenacyclononaphan-5-en-33-ol 2,2,2-trifluoroacetate. To a stirred mixture of 7-(8-allyl-7- fluoro-3-(methoxy methoxy )naphthalen- 1 -y 1 ) -4 -((R) -3 -((allyloxy)methyl)piperidin- 1 -yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(577)-yl)methoxy)pyrido[4,3-t7|pyrimidine (14 mg, 0.020 mmol) and 4-methylbenzenesulfonic acid hydrate (4.5 mg, 0.024 mmol) in 1,2-DCE (6.9 mL) at room temperature under nitrogen, was added Hovcyda-Grubbs II catalyst (5.0 mg, 7.96 pinol, Sigma-Aldrich Corporation). The resulting mixture was stirred at 80 °C for 5 h. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% methanol in DCM, to provide (13R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetralrydro-lH-pyrrolizin-7a(5FZ)- yl)methoxy)-33-(methoxymethoxy)-8-oxa-2(4,7)-pyrido[4,3-J|pyrimidina-l(l,3)-piperidina-3(l,8)- naphthalenacyclononaphan-5-ene. m / z (ESI): 676.2 (M+H)+.

[0317] Step 5B: The above product was dissolved in 1 mL of DCE and 0.5 mL of TFA was added. The mixture was purified by prep-HPLC, eluting at 20 mL / min with a gradient of 10-90% ACN (0.1% TFA) in water (0.1% TFA), to provide (13A,£)-28,37-difluoro-22-(((2R,7aS)-2- fluorotctrahydro-17 / -pyrrolizin-7a(5 / 7)-yl)mcthoxy)-8-oxa-2(4,7)- pyrido[4,3-d]pyrimidina-l(l,3)- piperidina-3(l,8)-naphthalenacyclononaphan-5-en-33-ol 2,2,2-trifluoroacetate (Example 1.033, 6.0 mg, 8.1 pmol, 40% yield), m / z (ESI): 632.4 (M+H)~.]H NMR (400 MHz, METHANOL-d / ) 5 ppm 9.28 (s, 1H), 7.90 - 7.67 (m, 1H), 7.46 - 7.17 (m, 3H), 5.76 - 5.50 (m, 1H), 5.42 - 5.00 (m, 3H), 4.80 - 4.56 (m. 2H), 4.19 - 3.81 (m, 4H), 3.77 - 3.39 (m, 3H), 3.30 - 3.09 (m, 2H), 3.02 - 2.53 (m, 3H), 2.50 - 2.29 (m, 3H), 2.26 - 1.56 (m, 6H).19F NMR (376 MHz. METHANOL-d / ) 5 ppm -77.14 (TFA), -119.19 (s, IF), -140.05 (s, IF), -174.15 (s, IF).Example 1.034: (13r,73R)-33-Chloro-28-fluoro-22-(((2R,7a5)-2-fluorotetrahydro-l / T-pyrrolizin- 7a(57f)-yl)methoxy)-6(5,2)-oxazola-2(4,7)-pyrido[4,3-rf|pyrimidina-l (1 ,3)-piperidina-3(l ,2)- benzena-7(l,3)-cyclobutanaheptaphane-35,73-diol tris(2,2,2-trifluoroacetate).

[0318] Step 1: l-Bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene. To a stirred mixture of 3-bromo-5-chloro-4-iodophenol (2.65 g. 7.95 mmol) and DIPEA (4.4 mL. 25.2 mmol) in DCM (30 mL) at room temperature under nitrogen, was added bromomethyl methyl ether (1.7 mL. 20.8 mmol). The resulting mixture was stirred at 40 °C for 1 h. The reaction mixture was cooled to room temperature and diluted with sat. aq. solution of sodium bicarbonate (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with sat. aq. solution of sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc in heptane, to give l-bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene (3.0 g, 7.9 mmol, 99% yield). Product did not ionize on LC-MS.(400 MHz, CDCI3) 8 ppm 7.32 - 7.29 (m, 1H), 7.18 - 7.15 (m, 1H), 5.17 - 5.15 (m, 2H), 3.49 - 3.47 (m, 3H).

[0319] Step 2: 4-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)butan-2-one. A stirred mixture of l-bromo-3-chloro-2-iodo-5-(methoxymethoxy)benzene (2.98 g, 7.90 mmol), tetrabutylammonium chloride (2.2 g, 7.92 mmol, Combi-Blocks Inc.), and sodium bicarbonate (1.72 g, 20.47 mmol, Sigma-Aldrich Corporation) in DMF (20 mL) at room temperahire under nitrogen, was sparged with nitrogen for 15 minutes. To this mixture was added palladium (II) acetate (0.17 g, 0.74 mmol, Sigma-Aldrich Corporation) and 3-butcn-2-ol (1.17 g, 1.4 mL, 16.15 mmol, Combi- Blocks Inc.). The resulting mixture was stirred at 65 °C for 19 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 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 0-40% EtOAc in heptane, to provide 4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)butan-2-one (1.68 g, 5.22 mmol, 66% yield). Product did not ionize on LC-MS. ’H NMR (400 MHz, CDCI3) 8 ppm 7.25 - 7.18 (m, 1H), 7.13 - 7.04 (m, 1H), 5.19 - 5.10 (m, 2H), 3.55 - 3.44 (m, 3H), 3.23 - 3.11 (m, 2H), 2.75 - 2.62 (m, 2H), 2.28 - 2.17 (m, 3H).

[0320] Step 3: l-Bromo-4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)butan-2-one. To a stirred mixhire of 4-(2-bromo-6-chloro-4-(nicthoxy methoxy )phenyl)butan-2-one (1.68 g, 5.22 mmol) and chlorotrimethylsilane (0.942 g, 1.1 mL, 8.67 mmol, Sigma-Aldrich Corporation) in THF (17.5 mL) at -78 °C under nitrogen, was slowly added lithium diisopropylamide solution (1.0 M in THF / hexanes, 7.3 mL, 7.30 mmol, Sigma-Aldrich Corporation). The resulting mixhire was stirred at - 78 °C for 1 h. The reaction mixture was diluted with sat. aq. solution of sodium bicarbonate (20 mL) and wanned to room temperature. The mixture was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated, to provide crude material. The crude material was dissolved in THF (17.5 mL) at 0 °C under nitrogen, then sodium bicarbonate (0.66 g, 7.89 mmol, Sigma-Aldrich Corporation) and A-bromosuccinimide(1.05 g, 5.90 mmol, CombiBlocks Inc.) were added at the same temperature. The resulting mixture was allowed to warm to room temperature and stirred for 18 h. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc in heptane, to provide1-bromo-4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)butan-2-one (1.43 g, 3.57 mmol, 68% yield). Product did not ionize on LC-MS. ’H NMR (400 MHz, CDCI3) 5 ppm 7.25 - 7.20 (m, 1H), 7.11 - 7.05 (m, 1H), 5.17 - 5.13 (m, 2H), 4.00 - 3.93 (m, 2H), 3.51 - 3.47 (m, 3H), 3.27 - 3.17 (m, 2H), 2.96 - 2.86 (m, 2H).

[0321] Step 4: l-Azido-4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)butan-2-one. To a stirred mixture of l-bromo-4-(2-bromo-6-chloro-4-(mcthoxymcthoxy)phcnyl)butan-2-onc (1.43 g, 3.57 mmol) in acetone (15 mL) at room temperature under ambient atmosphere, was added sodium azide (0.30 g, 4.64 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was filtered through celite and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc in heptane, to provide l-azido-4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)butan-2-one (1.09 g, 3.01 mmol, 84% yield), m / z (ESI): 384.0 (M+Na)+. *H NMR (400 MHz, CDCI3) 5 ppm 7.24 - 7.20 (m. 1H), 7.11 - 7.06 (m. 1H), 5.16 - 5.13 (m. 2H), 4.03 - 3.99 (m, 2H), 3.51 - 3.47 (m, 3H), 3.26 - 3.18 (m, 2H), 2.76 - 2.67 (m, 2H).

[0322] Step 5: tert-Butyl 2-((4-(2-bromo-6-chloro-4-hydroxyphenyl)-2-oxobutyl)carbamoyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of l-azido-4-(2-bromo-6- chloro-4-(methoxymethoxy)phenyl)butan-2-one (1.09 g, 3.01 mmol), palladium on carbon (0.23 g, 2.14 mmol, Sigma Aldrich Corporation), and ’-toluene sulfonic acid monohydrate (0.67 g, 3.52 mmol, Sigma Aldrich Corporation) in EtOAc (8 mL) and ethanol (8 mL) at room temperature under nitrogen, was slowly added triethylsilane (1.75 g, 2.4 mL, 15.03 mmol, Sigma Aldrich Corporation) over 30 minutes. The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered through celite and the fdtrate concentrated under reduced pressure to provide crude l-amino-4-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)butan-2-one, which was used as is in the next step, m / z (ESI): 336.0 (M+H)+.

[0323] Step 6: 6-(tert-Butoxycarbonyl)-2-hydroxy-6-azaspiro[3.5]nonane-2-carboxylic acid.To a stirred mixture of 2-hydroxy-6-azaspiro[3.5]nonane-2 -carboxylic acid hydrochloride (2.87 g, 12.95 mmol, Enamine) in THF (30 mL) and water (30 mL) at room temperature under nitrogen, was carefully added sodium bicarbonate (2.80 g. 33.3 mmol, Sigma- Aldrich Corporation) and di-ze / 7-bulyl dicarbonate (4.00 g, 4.00 mL, 18.33 mmol, Combi-Blocks Inc.). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (15 mL) and 1 M aq. solution of HC1 (10 mL) until the aqueous phase was pH 2. The biphasic mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, fdtered, and concentrated. The crude material was purified by column chromatography on silica gel, elutingwith a gradient of 0-100% EtOAc in heptane, to provide 6-(tert-butoxycarbonyl)-2-hydroxy-6- azaspiro[3.5]nonane-2-carboxylic acid (3.1 g, 10.86 mmol, 84% yield), m / z (ESI): 308.0 (M+Na)+. ’H NMR (400 MHz, DMSO-d / ) 5 ppm 13.07 - 11.81 (m, 1H), 5.69 - 5.40 (m, 1H), 3.43 - 3.32 (m, 2H), 3.26 - 3.16 (m, 2H), 2.39 - 2.26 (m, 1H), 2.26 - 2.10 (m, 1H), 1.86 - 1.75 (m, 1H), 1.73 - 1.66 (m, 1H), 1.66 - 1.58 (m, 1H), 1.57 - 1.50 (m, 1H), 1.44 - 1.32 (m, 11H).

[0324] Step 7: tert- Butyl 2-((4-(2-bromo-6-chloro-4-hydroxyphenyl)-2-oxobutyl)carbamoyl)-2- hydroxy-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of crude l-amino-4-(2-bromo- 6-chloro-4-(methoxymethoxy)phenyl)butan-2-one, 6-(tert-butoxycarbonyl)-2-hydroxy-6- azaspiro[3.5]nonanc-2-carboxylic acid (0.86 g, 3.01 mmol) and HATU (1.49 g, 3.91 mmol, Combi- Blocks Inc.) in DMF (14 m ) at room temperature under nitrogen was added DIPEA (1.92 g, 2.6 mL, 14.89 mmol). The resulting mixture was stirred at room temperature for 20 minutes. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-60% ethanol / EtOAc (1:3) (2% EtjN) in heptane, to provide tert-butyl 2-((4-(2-bromo-6-chloro-4- hydroxyphenyl)-2-oxobutyl)carbamoyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.90 g, 1.61 mmol, 54% yield), m / z (ESI): 503.0 (M-tBu+H)+. ’H NMR (400 MHz, CDCI3) 5 ppm 7.76 - 7.39 (m, 1H), 7.12 - 6.97 (m, 1H), 6.96 - 6.81 (m, 1H), 5.81 - 5.38 (m, 1H), 4.30 - 4.06 (m, 2H), 3.55 - 3.44 (m, 2H), 3.36 - 3.27 (m, 2H), 3.17 - 3.07 (m, 2H), 2.96 - 2.93 (m, 1H), 2.72 - 2.61 (m, 3H). 2.58 - 2.47 (m, 1H), 2.46 - 2.33 (m, 1H), 1.97 - 1.80 (m. 2H), 1.79 - 1.64 (m. 2H), 1.46 (br d, J = 6.7 Hz, 10H).

[0325] Step 8: tert- Butyl 2-((4-(2-bromo-4-((tert-butyldimethylsilyl)oxy)-6-chlorophenyl)-2- oxobutyl)carbamoyl)-2-((tert-butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of tert-butyl 2-((4-(2-bromo-6-chloro-4-hydroxyphenyl)-2-oxobutyl)carbamoyl)-2- hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (0.90 g, 1.61 mmol) and 2,6-lutidine (0.69 g, 0.75 mL, 6.44 mmol, TCI America) in DCM (8 mL) at 0 °C under nitrogen was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.98 g, 0.85 mL. 3.70 mmol, Oakwood Products, Inc.). The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and purified by column chromatography on silica gel, eluting with a gradient of 0-60% ethanol / EtOAc (1:3) (2% EtsN) in heptane, to yield tert-butyl 2-((4-(2-bromo-4-((tert- butyldimethylsilyl)oxy)-6-chlorophenyl)-2-oxobutyl)carbamoyl)-2-((tert-butyldimethylsilyl)oxy)-6- azaspiro[3.5]nonane-6-carboxylate (0.97 g, 1.23 mmol, 77% yield), m / z (ESI): 787.3 (M+H)+. *H NMR (400 MHz. CDCl3) 5 ppm 7.23 - 7.03 (m, 1H). 7.00 - 6.98 (m, 1H). 6.88 - 6.81 (m, 1H). 4.30 - 4.17 (m. 2H), 3.64 - 3.50 (m, 1H), 3.46 - 3.27 (m, 3H). 3.24 - 3.15 (m, 2H). 2.74 - 2.65 (m, 2H). 2.49 - 2.39 (m. 1H), 2.00 - 1.87 (m. 1H), 1.86 - 1.76 (m. 1H), 1.73 - 1.63 (m. 1H), 1.57 - 1.41 (m. 7H). 1.29 - 1.27 (m, 2H). 1.03 - 0.95 (m, 22H), 0.32 - 0.27 (m. 3H), 0.24 - 0.19 (m. 9H).

[0326] Step 9: tert-Butyl 2-(5-(2-bromo-4-((tert-butyldimethylsilyl)oxy)-6- chlorophenethyl)oxazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of tert-butyl 2-((4-(2-bromo-4-((tert-butyldimethylsilyl)oxy)-6- chlorophenyl)-2-oxobutyl)carbamoyl)-2-((tert-butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6- carboxylate (0.97 g, 1.23 mmol) in 2-Me-THF (6 mL) at room temperature under nitrogen, was added Burgess reagent (1.80 g, 7.55 mmol, Combi-Blocks Inc.). The resulting mixture was stirred at 75 °C for 3 h. The reaction mixture was diluted with sat. aq. solution of sodium bicarbonate (10 mL) and extracted with EtOAc (3 x 15 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 0-50% EtOAc in heptane, to provide tertbutyl 2-(5-(2-bromo-4-((tert-butyldimethylsilyl)oxy)-6-chlorophenethyl)oxazol-2-yl)-2-((tert- butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate (0.58 g, 0.76 mmol. 61% yield), m / z (ESI): 769.2 (M+H)+.]H NMR (400 MHz, CDCty) 5 ppm 7.07 - 6.97 (m. 1H), 6.93 - 6.82 (in. 1H), 6.78 - 6.67 (m, 1H). 3.44 - 3.17 (m, 6H). 2.96 - 2.83 (m, 2H). 2.83 - 2.57 (m, 2H). 2.30 - 2.03 (m, 2H), 1.83 - 1.66 (m. 1H), 1.29 (br s, 21H), 1.02 - 0.99 (m. 9H), 0.25 - 0.23 (m. 6H), -0.04 - -0.12 (m, 6H).

[0327] Step 10: tert- Butyl 2-((tert-butyldimethylsilyl)oxy)-2-(5-(2-chloro-4-hydroxy-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenethyl)oxazol-2-yl)-6-azaspiro[3.5]nonane-6- carboxylate. To a stirred mixture of tert-butyl 2-(5-(2-bromo-4-((tert-butyldimethylsilyl)oxy)-6- chlorophenethyl)oxazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate (0.58 g. 0.76 mmol). B2PHI2 (0.39 g, 1.53 mmol.), cesium carbonate (0.50 g, 1.53 mmol) and tris(4- methoxyphenyl)phosphine (39 mg. 0.11 mmol) in EtOAc (4 mL) at room temperature under nitrogen, was added palladium(II) acetate (19 mg, 0.085 mmol). The resulting mixture was sparged with nitrogen for 5 minutes and stirred at 80 °C for 2 h. The reaction mixture was filtered, concentrated, and purified by column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc in heptane, to give tert-butyl 2-((tert-butyldimethylsilyl)oxy)-2-(5-(2-chloro-4-hydroxy-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenethyl)oxazol-2-yl)-6-azaspiro[3.5]nonane-6-carboxylate (0.20 g, 0.28 mmol, 37% yield), m / z (ESI): 703.4 (M+H)+.!H NMR (400 MHz. CDCty) 5 ppm 7.25 - 7.19 (m. 1H), 7.01 - 6.97 (m, 1H), 6.74 - 6.71 (m, 1H), 6.27 - 6.10 (m, 1H), 3.37 - 3.19 (m, 5H), 2.90 - 2.81 (m, 2H), 2.71 - 2.59 (m, 2H), 2.30 - 2.18 (m, 2H), 1.55 - 1.48 (m. 9H), 1.48 - 1.44 (m. 3H), 1.41 - 1.36 (in, 2H). 1.36 - 1.34 (m, 12H), 0.91 - 0.88 (m, 9H), -0.06 - -0.10 (m, 6H).

[0328] Step 11: tert-Butyl 2-(5-(2-(4-(tert-butoxy)-8-fluoro-2-(((21?,7a5)-2-fluorotetrahydro- lH-pyrrolizin-7a(577)-yl)methoxy)pyrido[4,3-« / ]pyrimidin-7-yl)-6-chloro-4- hydroxyphenethyl)oxazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6- carboxylate. A stirred mixture of tert-butyl 2-((tert-butyldimethylsilyl)oxy)-2-(5-(2-chloro-4- hydroxy-6-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)phenethyl)oxazol-2-yl)-6- azaspiro[3.5]nonane-6-carboxylate (0.20 g, 0.28 mmol), 4-(tert-butoxy)-7-chloro-8-fluoro-2- (((2R,7aS -2-fluorotetrahydro-lH-pyrrolizin-7a(577)-yl)methoxy)pyrido[4,3-<7| pyrimidine(Intermediate A, 0.12 g, 0.29 mmol) and potassium phosphate tribasic (0.18 g, 0.86 mmol) in 2-Me- THF (2 mL) and water (0.20 mL) at room temperature under nitrogen, was sparged with nitrogen for 5 minutes. To this mixture was added cataCXium® A Pd G3 (18 mg, 0.025 mmol). The resulting mixture was stirred at 60 °C for 3 h. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-50% ethanol / EtOAc (1:3) (2% EtsN) in heptane, to give tertbutyl 2-(5-(2-(4-(Zert-butoxy)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-lH-pyrrohzin-7a(5E0- yl)methoxy)pyrido[4,3-t / |pyrimidin-7-yl)-6-chloro-4-hydroxyphenethyl)oxazol-2-yl)-2-((Zert- butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate (0.15 g, 0.15 mmol. 55% yield), m / z (ESI): 953.2 (M+H)+.]H NMR (400 MHz, CDCI3) 5 ppm 9.13 - 9.02 (m. 1H), 7.04 - 6.85 (in. 1H), 6.77 - 6.65 (m, 1H). 6.62 - 6.52 (m, 1H), 5.45 - 5.16 (m, 1H), 4.35 - 4.22 (m, 2H), 3.41 - 3.14 (m, 7H), 3.10 - 2.95 (m. 1H), 2.92 - 2.75 (m. 4H), 2.72 - 2.61 (m, 1H), 2.59 - 2.47 (m, 2H), 2.34 - 2.25 (m. 1H), 2.24 - 2.05 (m, 4H), 2.04 - 1.83 (m, 4H), 1.80 - 1.73 (m, 9H), 1.54 - 1.42 (m, 10H), 1.34 - 1.26 (m, 2H), 0.86 - 0.76 (m, 9H), -0.13 - - 0.25 (m, 6H).19F NMR (376 MHz. CDCI3) 5 ppm - 138.62 (br s. IF). - 172.71 (s, IF).

[0329] Step 12: 7-(2-(2-(2-(2-((tert-Butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonan-2-yl)oxazol- 5-yl)ethyl)-3-chloro-5-hydroxyphenyl)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-177-pyrrolizin- 7a(57f)-yl)methoxy)pyrido[4,3-rf]pyrimidin-4-ol. To a stirred mixture of tert-butyl 2-(5-(2-(4-(tert- butoxy)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro-l / / -pyrrolizin7a(5 / 7)-yl)methoxy)pyrido[4,3- t / |pyrimidin-7-yl)-6-chloro-4-hydroxyphenethyl)oxazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)-6- azaspiro[3.5]nonane-6-carboxylate (0.15 g, 0.15 mmol) in DCM (3.5 mL) at room temperature under ambient atmosphere, was added HC1 (4.0 M in 1,4-dioxane, 53 g, 0.5 mL, 2.00 mmol). The resulting mixture was stirred at room temperature for 1 h 20 min. The reaction mixture was concentrated to give 7-(2-(2-(2-(2-((tert-butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonan-2-yl)oxazol-5-yl)ethyl)-3- chloro-5-hydroxyphenyl)-8-fluoro-2-(((2A,7aS)-2-fluorotetrahydrolH-pyrrolizin-7a(5 / 7)- yl)methoxy)pyrido[4.3-<7|pyrimidin-4-ol (0.12 g. 0.15 mmol, quantitative yield), nvz (ESI): 797.2 (M+H)+.19FNMR (376 MHz, METHANOL-dty 5 ppm -131.10 - -135.83 (m, IF), -174.20 (br d, J = 7.8 Hz, IF).|00330] Step 13: (13r,73R)-33-Chloro-28-fluoro-22-(((2R,7a5)-2-fluorotetrahydro-lH- pyirolizin-7a(5 / / )-yl)methoxy)-6(5,2)-oxazola-2(4,7)-pyrido[4,3-« / ]pyriniidina-l(l,3)-piperidina- 3(1 ,2)-benzena-7(l ,3)-cyclobutanaheptaphane-35,73-diol tris(2,2,2-trifluoroacetate) (Example 1.034). To a stirred mixture of bromotris(dimethylamino)phosphonium hexafluorophosphate (0.18 g, 0.46 mmol) and DIPEA (0.22 g. 0.3 mL. 1.72 mmol) in ACN (27 mL) at room temperature under nitrogen, was added 7-(2-(2-(2-(2-((tert-butyldimethylsilyl)oxy)-6-azaspiro[3.5]nonan-2-yl)oxazol-5- yl)ethyl)-3-chloro-5-hydroxyphenyl)-8-fluoro-2-(((2R,7a.S)-2-fluorotetrahydro-l / 7-pyrrolizin-7a(5J7)- yl)methoxy)pyrido[4,3-J|pyrimidin-4-ol (0.12 g. 0.15 mmol) as a solution in DMSO (4.5 mL). The resulting mixture was stirred at room temperature for 1 h then bromotris(dimethylamino)phosphoniumhexafluorophosphate (62 mg, 0.16 mmol) was added and stirred for 1 h (2 h total reaction time). The reaction was concentrated, and the resulting residue was dissolved in EtOAc (10 mL) and washed with sat. aq. solution of sodium bicarbonate. The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to provide a crude material. To a stirred mixture of the crude material in ACN (2 mL) and THF (2 mL) at 0 °C under nitrogen, was added tetramethylammonium fluoride (0.14 g, 1.50 mmol, AA Blocks LLC). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and concentrated. The resulting material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / EtOAc (1:3) (2% Et3N) in heptane. The mixture was then further purified by prep-HPLC, eluting with a gradient of 10-90% ACN (0.1% TFA) in water (0.1% TFA). The fractions containing product were combined, frozen at -78 °C, and lyophilized to give (13r,73R)-33-chloro-28-fluoro-22-(((2R,7aS -2-fluorotetrahydro-17 / -pyrrolizin- 7a(5 / 7)-yl)methoxy)-6(5.2)-oxazola-2(4,7)-pyrido[4,3-J]pyrimidina-l(l,3)-piperidina-3(L2)-benzena- 7(1.3)-cyclobutanaheptaphane-35,73-diol tris(2,2,2-trifluoroacetate) (Example 1.034, 10 mg, 9.9 pmol, 7% yield), m / z (ESI): 665.2 (M+H)+. *H NMR (400 MHz, METHANOL-d4) 5 ppm 9.20 - 9.12 (m, 1H). 7.11 - 7.03 (m, 1H). 6.96 - 6.90 (m, 1H). 6.68 - 6.64 (m, 1H), 6.69 - 6.62 (m, 1H), 5.69 - 5.52 (m. 1H), 4.75 - 4.65 (m, 2H), 4.11 - 3.83 (m, 4H), 3.54 - 3.46 (m, 1H), 2.95 - 2.86 (m, 2H), 2.83 - 2.53 (m, 4H), 2.52 - 2.32 (m, 3H), 2.30 - 2.11 (m. 2H), 2.10 - 1.90 (m. 6H), 1.89 - 1.70 (m. 3H).19FNMR (376 MHz, METHANOL-d^ 5 ppm -77.45 (s, 9F), -143.16 (s, IF), -174.12 (s, IF).Table 12: Additional Example 1.041. Prepared in an Analogous Manner to Example 1.034.Table 13: Additional Data for Example 1.041.Examples 1.035 and 1.036: (131?,85)-28,37-Difluoro-22-(((21?,7a5)-2-fluorotetrahydro-lH- pyrrolizin-7a(5 / / )-yl)methoxy)-6-oxa-2(4,7)-pyrido|4,3-< / |pyrimidina-l (l ,3)-piperidina-3(l,8)- naphthalenacyclooctaphane-33,8-diol 2,2,2-trifluoroacetate (Example 1.035) and (13R, 81?)- 28,37-difluoro-22-(((2R,7a5)-2-fluorotetrahydro-lll-pyrrolizin-7a(51 / )-yl)methoxy)-6-oxa- 2(4,7)-pyrido[4,3-< / ]pyrimidina-l (l ,3)-piperidina-3(l,8)-naphthalenacyclooctaphane-33,8-diol 2,2,2-trifluoroacetate (Example 1.036).

[0331] Step 1: tert- Butyl (3R)-3-(oxiran-2-yl)piperidine-l-carboxylate. To a stirred mixture of tert-butyl (3S)-3-ethenylpiperidme-l-carboxylate (0.42 g, 1.99 mmol, AstaTech, Inc) in DCM (8 mL) at room temperature under nitrogen, was added 3-chloroperoxybenzoic acid (1.22 g, 70 wt%, 5.0 mmol, Sigma Aldrich Corporation), and stirred at room temperature for 16 h. The mixture was added to 10 mL of 10% Na2S2C>3 solution and stirred for 5 minutes. The DCM was removed under vacuum. The reaction mixture was diluted with 10 wt% aq. solution of sodium carbonate and extracted with heptane (3x). 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 0-60% EtOAc in heptane, to give tert-butyl (3R)-3-(oxiran-2-yl)piperidine- 1 -carboxylate (0.22 g, 0.97 mmol, 49% yield), m / z (ESI): 250.2 (M+Na)'. ’H NMR (400 MHz, CDCl3) 6 ppm 4.23 - 4.03 (m, 1H). 4.00 - 3.67 (m, 1H). 4.35 - 3.53 (m, 1H). 2.98 - 2.73 (m, 3H), 2.68 - 2.45 (m, 1H). 2.01 - 1.68 (m, 2H). 1.64 - 1.53 (m, 2H). 1.48 (s, 12H).

[0332] Step 2: tert- Butyl (3R)-3-(2-(2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)ethoxy)-l-hydroxyethyl)piperidine-l-carboxylate. To a stirred mixture of zc / 7-bulyl (3R)-3- (oxiran-2-yl)piperidine-l -carboxylate (0.11 g, 0.48 mmol) and 2-(2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-l-yl)ethan-l-ol (Intermediate I, 0.15 g, 0.40 mmol) in toluene (0.80 mL) at room temperature under ambient atmosphere, was added yttrium(III) trifluoromethanesulfonate (53 mg, 0.10 mmol). The resulting mixture was stirred at 50 °C for 16 h. The crude material was concentrated and purified by column chromatography on silica gel, eluting with a gradient of 10-90% ACN (0.1% formic acid) in water (0.1% formic acid), to give tert-butyl (3R)-3-(2-(2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethoxy)-l- hydroxyethyl)piperidine-l -carboxylate (0.10 g, 0.17 mmol, 42% yield), m / z (ESI): 626.0 (M+Na)+. *H NMR (400 MHz, CDCI3) 5 ppm 8.13 (d, J = 2.1 Hz. 1H), 7.77 - 7.54 (m. 1H), 7.42 (d, J = 2.5 Hz. 1H). 7.29 - 7.16 (m, 3H). 5.26 (s, 2H), 4.10 - 4.02 (m, 1H), 3.94 - 3.75 (m, 5H). 3.53 (s. 6H), 2.95 - 2.50 (m. 2H), 1.47 (d, J = 6.9 Hz, 19H).

[0333] Step 3: tert-Butyl 4-(2-(2-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l -yl)ethoxy)-l -hydroxyethyl)piperidine-l -carboxylate. To a stirred and degassed mixture of B2Pin2(91 mg, 0.36 mmol), cesium carbonate (0.13 g. 0.41 mmol), tert-butyl 4-(2-(2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethoxy)-l- hydroxyethyl)piperidine-l -carboxylate (0.17 g, 0.28 mmol), and tris(4-methoxyphenyl)phosphine (19 mg, 0.055 mmol) in EtOAc (0.92 mL) under nitrogen, was added palladium(II) acetate (6.2 mg, 0.028 mmol). The resulting mixture was stirred at 80 °C for 4 h. The reaction was filtered and concentrated. 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 4-(2-(2-(2-fluoro-6-(methoxymethoxy)-8-(4.4,5,5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)naphthalen-l-yl)ethoxy)-l -hydroxy ethyl)piperidine-l- carboxylate (0.12 g, 0.20 mmol, 72% yield), m / z (ESI): 626.2 (M+Na)+.

[0334] Step 4: tert- Butyl 4-(2-(2-(8-(4-(tert-butoxy)-8-fluoro-2-(((2R,7a5)-2-fluorotetrahydro- l / 7-pyrrolizin-7a(5 / 7)-yl)methoxy)pyrido[4,3-< / ]pyrimidin-7-yl)-2-fluoro-6- (methoxymethoxy)naphthalen-l-yl)ethoxy)-l- hydroxyethyl)piperidine-l-carboxylate. To a stirred mixture of degassed potassium phosphate (0.15 g, 0.70 mmol), 4-(tert-butoxy)-7-chloro-8- Huoro-2-(((2A,7aS)-2-fluorotetrahydro-l / f-pyrrolizin-7a(5 / 7)-yl)metho.xy)pyrido[4,3-(7|pyrimidine (Intermediate A, 94 mg, 0.23 mmol), and tert-butyl 4-(2-(2-(2-fluoro-6-(methoxymethoxy)-8- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethoxy)-l-hydroxyethyl)piperidine-l- carboxylate (0.12 g, 0.20 mmol) in 2-Me-THF (0.72 mL) and water (0.072 mL) was added methanesulfonato(diadamantyl-Ar-butylphosphino)-2'-amino-l.r-biphenyl-2-yl)palladium(II) (29 mg, 0.040 mmol). The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated and purified by colulmn chromatography on silica gel, eluting with a gradient of 0-70% heptane in ethanol / EtOAc (1:3) with 1% TEA, to give tert-butyl 4-(2-(2-(8-(4-(tert-butoxy)-8-fluoro- 2-(((2A.7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5 / 7)-yl)methoxy)pyrido[4,3-J|pyrimidin-7-yl)-2- fluoro-6-(methoxy methoxy)naphthalen- 1 -y l)ethoxy)- 1 -hydroxy ethyl)piperidine- 1 -carboxy late (0.10 g, 0.12 mmol, 59% yield), m / z (ESI): 854.4 (M+H)+.

[0335] Step 5: 8-Fluoro-7-(7-fluoro-3-hydroxy-8-(2-(2-hydroxy-2-((R)-piperidin-3- yl)ethoxy)ethyl)naphthalen-l-yl)-2-(((2R,7a5)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-rf|pyrimidin-4-ol HC1 salt. To a stirred mixture of tert-butyl (3R)-3-(2-(2- (8-(4-(tert-butoxy)-8-fluoro-2-(((2R,7a>S)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-£ / ]pyrimidin-7-yl)-2-fluoro-6-(methoxymethoxy)naphthalen-l-yl)ethoxy)-l- hydroxyethyl)piperidine-l -carboxylate (0.10 g, 0.12 mmol) in DCM (2.1 mL) at room temperature under ambient atmosphere, was added HC1 (4.0 M in 1,4-dioxane, 0.59 mL, 2.34 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with methanol (0.2 mL) and concentrated and used as is. 8-Fluoro-7-(7-fhioro-3-hydroxy-8-(2-(2-hydroxy- 2-((R)-piperidin-3-yl)ethoxy)ethyl)naphthalen-l-yl)-2-(((2A,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(577)-yl)methoxy)pyrido[4.3-<7|pyrimidin-4-ol HC1 salt was obtained, m / z (ESI): 654.2 (M+H)+.

[0336] Step 6: (13R,85)-28,37-Difluoro-22-(((2R,7a5)-2-fluorotetrahydro-lH-pyrrolizin- 7a(57f)-yl)methoxy)-6-oxa-2(4,7)-pyrido|4,3-rf|pyrimidina-l(l,3)-piperidina-3(l,8)- naphthalenacyclooctaphane-33,8-diol 2,2,2-trifluoroacetate (Example 1.035) and (13R,8R)- 28,37-difluoro-22-(((2R,7a5)-2-fluorotetrahydro-17 / -pyrrolizin-7a(5H)-yl)methoxy)-6-oxa- 2(4,7)-pyrido[4,3-< / ]pyrimidina-l (l ,3)-piperidina-3(l,8)-naphthalenacyclooctaphane-33,8-diol 2,2,2-trifluoroacetate (Example 1.036). To a stirred mixture of bromotris(dimethylamino)phosphonium hexafluorophosphate (0.17 g. 0.44 mmol) and DIPEA (0.15 g, 0.21 mL, 1.18 mmol) in ACN (16.8 mL) at room temperature under nitrogen was added 8-fluoro-7- (7-fluoro-3-hydroxy-8-(2-(2- hydroxy -2-((A)-piperidin-3-y l)ethoxy)ethy l)naphthalen-l-y l)-2-(((2R, 7aS)-2 -fluorotetrahydro- 1 H-py rrolizin7a(5rt)-yl jmethoxy Jpyrido [4,3 -<7|py rimidin-4-ol , HO salt(64 mg, 0.098 mmol) in DMSO (2.8 inL). The reaction mixture was covered and stirred at room temperature for 2 h. The reaction mixture was concentrated, then diluted with water and EtOAc. Then, aq. NaHCOs was added, the layers separated, and the aqueous layer extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% heptane in ethanol / EtOAc (1 :3) with 1% TEA. The product was passed through a NaHCOa cartridge, then further purified by prep-HPLC, eluting with a gradient of 10-90% ACN (0.1% TFA) in water (0.1% TFA) to provide two peaks:

[0337] Peak 1: ( 13R,8S)-28,37-difhioro-22-(((2R,7aS)-2-fhrorotctrahydro-l H-pyrrolizin-7a(5 / 7)- yl)methoxy)-6-oxa-2(4,7)- pyrido|4.3-c / |pyrimidina-l( l,3)-piperidina-3(l,8)- naphthalenacyclooctaphane-33,8-diol 2,2,2-trifluoroacetate (Example 1.035, 8 mg, 10.7 pmol, 11% yield), m / z (ESI): 636.2 (M+H)+. 'HNMR (400 MHz, METHANOL-dA) 8 ppm 9.24 (s, 1H), 7.84 - 7.71 (m, 1H), 7.39 - 7.24 (m, 3H), 5.91 - 5.47 (m. 1H), 5.04 - 4.92 (m. 2H), 4.71 (d, J = 7.9 Hz, 2H), 4.17 - 3.81 (m, 4H), 3.52 (s, 7H), 3.31 - 3.14 (m, 2H). 2.94 - 2.15 (m, 10H), 1.92 - 1.74 (m, 2H), 1.67 - 1.40 (m, 3H).19F NMR (376 MHz. METHANOL-dA) 8 ppm -77.18 (TFA), -117.96 (s, IF), - 143.34 (s, IF), - 174.03 (s, IF).

[0338] Peak 2: (13R,8R)-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5 / 7)- yl)mcthoxy)-6-oxa-2(4,7)-pyrido[4,3-J|pyrimidina-l(l,3)-pipcridina-3(l,8)- naphthalenacyclooctaphane-33,8-diol 2,2,2-trifluoroacetate (Example 1.036, 5 mg, 6.7 junol, 6.8% yield), m / z (ESI): 636.2 (M+H)+.!H NMR (400 MHz, METHANOL-dA 8 ppm 9.30 (s, 1H), 7.84 - 7.69 (m, 1H), 7.39 - 7.00 (m, 3H), 5.77 - 5.30 (m. 1H), 5.18 - 4.96 (m, 2H), 4.71 (d, J = 8.6 Hz, 2H), 4.20 - 3.83 (m, 3H), 3.72 - 3.45 (m, 5H), 3.44 - 3.36 (m, 1H), 3.26 - 3.13 (m, 2H), 2.93 - 2.32 (m, 6H), 2.28 - 2.12 (m, 1H), 2.07 - 1.78 (m, 3H), 1.73 - 1.52 (m, 3H).19F NMR (376 MHz, METHANOL-dA 8 ppm - 77.14 (TFA), -118.49 (s, IF), -142.98 (s, IF), -174.05 (s, IF).SECTION 3: Biochemical and Cellular Assays

[0339] Provided in this section is the biological evaluation of the specific examples provided herein.KRAS G12D Coupled Nucleotide Exchange Assay

[0340] Purified GDP-bound KRAS protein (aa 1-169), containing both G12D and Cl 18A amino acid substitutions and an A- terminal His-tag, was pre-incubated in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCk and 0.01% Triton X-100) with a compound dose-response titration for 2 hours. Following compound pre-incubation. purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 min. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa 1 -149),nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader, using AlphaScreen® technology, and data were analyzed using a 4-parameter logistic model to calculate IC50 values.Phospho-ERKl / 2 MSD Assay

[0341] AsPC-1 (ATCC® CRL-1682™) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and lx penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). Sixteen hours prior to compound treatment. AsPC-1 cells were seeded in 96-well cell culture plates at a density of 25.000 cells / well and incubated at 37 °C, 5% CO2. A compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37 °C, 5% CO2 for 2 hours. Following compound treatment, cells were washed with ice-cold Dulbecco's phosphate- buffered saline, no Ca2+or Mg2+(ThermoFisher Scientific 14190144), and then lysed in RIP A buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 rnM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1 / 2 in compound-treated lysates was assayed using Phospho-ERKl / 2 Whole Cell Ly sate kits (Meso Scale Discovery K151DWD) according to the manufacturer’s protocol. Assay plates were read on a Meso Scale Discovery’ Sector Imager 6000, and data were analyzed using a 4-parameter logistic model to calculate IC50 values.AsPC-1 and SW620 CTG Assay Protocols

[0342] AsPC-1 (human pancreatic adenocarcinoma; ATCC CRL-1682) or SW620 (human colon adenocarcinoma; ATCC CCL-227) cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and lx penicillin / streptomycm / L-glutamine. Cells were seeded in 384-well plates at a density of 3.33E+04 cells / mL and incubated at 37 °C, 5% CO2, overnight. Serially -diluted compound or DMSO was added to the cells, and plates were incubated at 37 °C, 5% CO2 for 72 h. Cell viability was measured using a CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega) according to the manufacturer’s protocol. The luminescence signal of treated samples was normalized to DMSO control, and data were analyzed using a 4-parameter logistic model to calculate IC50 values.Table 3:

[0343] The results presented in Table 3 have been generated with the in vitro assays described above. These assays may be used to test any other compound described herein to assess and characterize a compound’s biological activity. In view of the disclosure provided herein, compormds not specifically tested would be expected to have similar results.

[0344] Compounds showing activity in the coupled exchange assay are useful in the methods provided herein (see Section “METHODS OF USE").REFERENCESDer, C. J.; Krontiris, T. G.; Cooper, G. M. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Han ey and Kirsten sarcoma viruses. Proc Nat Acad Sci 1982, 79, 3637-3640.Vojtek, A. B.; Der, C. J. Increasing complexity of the Ras signaling pathway. J. Biol. Chem. 1998. 273, 19925-19928.Malumbres, M.; Barbacid, M. RAS oncogenes: the first 30 years. Nat Rev Cancer 2003, 3, 459-465.Sridhar, S. S.; Seymour, L.; Shepherd, F. A. Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. The Lancet Oncology 2003, 4, 397-406.Holderfield, M.; Denker, M. M.; McCormick, F.; McMahon, M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer 2014. 14, 455-467.Caunt, C. J.; Sale, M. J.; Smith. P. D.: Cook, S. J. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer 2015. 15, 577-592.Simanshu, D. K.; Nissley, D. V.; McCormick, F. RAS Proteins and Their Regulators in Human Disease. Cell 2017, 170, 17-33.Cox, A. D.; Fesik, S. W.; Kimmelman, A. C.; Luo, J.; Der, C. J. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov 2014, 13, 828-851.O'Bryan. J. P. Pharmacological targeting of RAS: Recent success with direct inhibitors. Pharmacol Res 2019. 139, 503-511.Ostrem, J. M.; Peters, U.: Sos, M. L.; Wells. J. A.; Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013. 503, 548-551.

Claims

What is claimed is:

1. A compound of Formulaor a pharmaceutically acceptable salt thereof, wherein;Z is C-H, C-halogen, C-CN, C-CM alkyl, C-CM haloalkyl, C-CM alkoxy, C-CM haloalkoxy. C-C3-7 cycloalkyl 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; q is 0. 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(RZ)2, CM alkyl. CM deuteroalkyl, CM alkoxy, CM haloalkyl. CM haloalkoxy, CM hydroxyalkylene, C2-4 alkenyl, C2-4 haloalkenyl, 5-7 membered heteroaryl, -S(O)2-Ci-4alkyl. -S(O)2N(RZ)2. -C(O)RZ, -C(O)ORZ. -C(O)N(RZ)2, -CM alkylene-C(O)-CMalkyl. -CM alkylene-C(O)N(Rz)2. CM alkylene-S(O)2-Ci-4alkyl, or -S-CMalkyl;L2is a bond. CM alkylene, -O-CM alkylene. -S-CM alkylene, NRZ, O or S, wherein each CM alkylene, -O-CM alkylene and -S-CM alkylene chain is substituted with 0-2 occurrences of R2;R1is hydrogen, hydroxyl. Ce-io aryl. 5-10 membered heteroaryl. C3-8 cycloalkyl or 4-15 membered heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R3; each R2is independently halogen, deuterium, hydroxyl or Ci -4 alkyl, wherein two geminal groups, together with the atom to which they are attached, form a spiro-Ck- cycloalkyl group substituted with 0-2 occurrences of Rw; or wherein two adjacent R2groups, together with the atoms to which they are attached form a fused-Cj.? cycloalkyl group substituted with 0-2 occurrences of Rw;A is Ce-io aryl substituted with q occurrences of R6;R4is hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy. C1-4 haloalkyl, C2-4 alkenyl. C2-4 alkynyl, C3.- cycloalkyl or cyano; each R5independently is halogen, cyano, oxo. -T-Ry, hydroxyl. -N(RZ)2, C1-4 alkyl, C1-4 haloalkyl. C1-4 alkoxy. =C(RW)2 or -O-C2-4 alkynyl;each R6independently is halogen, hydroxyl, cyano, -b^R^i, -C(O)RZ, -C(O)ORZ, Ci-4 alky l, CM alkoxy, Ci-4 haloalkyl, CM haloalkoxy, C2-4 alkynyl or C3-6 cycloalkyl or two R6taken together on adjacent carbon atoms form a C3-7 cycloalkyl; each Rwindependently is CM alky l, CM alkoxy’, halogen, hydroxy l or CM haloalkyl;T is CM alky lene, -S(O)2-, -C(O)-, -CM alkylene-C(O)-, CM alky lene-S(O)2- or -S-;Ryis CM alkyl, CM haloalkyl, hydroxyl, cyano or -N(RZ)2; and each Rzis independently hydrogen or CM alkyl.

2. A compound of Formula (II) :or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2, L1, R1, R2. R4, R5, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

3. A compound of Formula (III) :or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2. L1, R1, R2. R4. R5, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

4. A compound of Formula (IV) :or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2, L1, R1, R2, R4, R3, R6, Rw, T, Ryand Rzarc as defined above for Formula (I).

5. A compound of Formulaor a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2, L1, R1, R2, R4, R3, R6, Rw, T, Ryand Rzare as defined above for Formula (I)6. A compound of Formulaor a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx. L2, L1, R1, R2, R4, R3, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

7. A compound of Formulaor a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2, L1, R1, R2. R4, R5, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

8. A compound of Formulaor a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2. L1, R1, R2. R4. R5, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

9. A compound of Fonnula (IX) :or a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2. L1, R1, R2. R4. R5, R6, Rw, T, Ryand Rzare as defined above for Formula (I).

10. A compound of Formulaor a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ. p, Rx. L2, L1, R1. R2, R4, R3, R6. Rw. T, Ryand Rzare as defined above for Formula (I).

11. A compound of Formulaor a pharmaceutically acceptable salt of said compound, wherein X is -CH2-, -O- or -S-; andZ, p, Rx, L2, L1, R1, R2, R4, R5, R6, Rw, T, Ryand Rzarc as defined above for Formula (I).

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

13. The compound or salt of any of claims 1-12, wherein L2is -O-methylene, -O-ethylene or -O-n- propylene substituted with 0-2 occurrences of R214. The compound or salt of claim 13, wherein L2is -O-methylene substituted with 0 occurrences of R2.

15. The compound or salt of claim 14, wherein R1is heterocycloalkyl substituted with 0-3 occurrences of R5.

16. The compound or salt of claim 15, wherein R1is 7a-(lrexalrydro-lH-pyrrolizinyl) substituted with one occurrence of R5.

17. The compound or salt of claim 16, wherein R5is halogen, -O-C2-4 alkynyl, =C(RW)2 or C1-4 alkyl.

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

19. The compound or salt of claim 18. wherein R5is fluorine.

20. The compound of any of claims 1-19. wherein p is 0.

21. The compound or salt of claim 20, wherein22. The compound or salt of claim 20. wherein23. The compound or salt of any of claims 1-19, wherein p is 1.

24. The compound or salt of claim 23, wherein each Rxindependently is hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy. C1.4 haloalky 1, C1.4 haloalkoxy.

25. The compound or salt of claim 24. wherein each Rxindependently is hydroxyl or methyl.

27. The compound or salt of any of claims 1-26, wherein A is phenyl or naphthyl.

28. The compound or salt of claim 27. wherein q is 0.

29. The compound or salt of claim 27, wherein q is 1.

30. The compound or salt of claim 29, wherein R6is Ci-4 alkyl, hydroxy l, halogen or Ci-4 haloalky 1.

31. The compound or salt of claim 30, wherein R6is halogen.

32. The compound or salt of claim 31, wherein R6is fluoro or chloro.

33. The compound or salt of claim 27, wherein q is 2.

34. The compound or salt of claim 33, wherein each R6is independently’ C1.4 alkyl, hydroxyl, halogen or CM haloalky 1.

35. The compound or salt of claim 34. wherein one R6is hydroxyl and the other R6is fluoro.

36. The compound or salt of claim 35, wherein one R6is hydroxyl and the other R6is chloro.

37. The compound or salt of claim 36, wherein each R6is independently hydroxyl or methy l.

38. The compound or salt of any of claims 1-26, wherein39. The compound or salt of claim 38, whereinThe compound or salt of claim 38, whereinThe compound or salt of claim 38. wherein42. The compound or salt of any of claims 1 -41 , wherein L1is43. The compound or salt of any of claims 1-42, wherein R4is hydrogen, hydroxyl, halogen, C1-4 alkyl or C1.4 alkoxy.

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

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

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

47. A compound selected from one of the following:

48. A pharmaceutical composition comprising the compound or salt according to any one of claims 1-47 and a pharmaceutically acceptable excipient.

49. A compound or salt according to any one of claims 1-47 or the pharmaceutical composition according to claim 48 for use as a medicament.

50. A compound or salt according to any one of claims 1-47 or the pharmaceutical composition according to claim 48 for use in treating cancer.

51. A compound or salt according to any one of claims 1-47 or the pharmaceutical composition according to claim 48 for use in treating cancer, wherein one or more cells of the cancerexpress a KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutant protein.

52. The compound, salt or pharmaceutical composition for use of claim 50 or 51, 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 / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

53. A use of the compound or salt according to any one of claims 1-47 or the pharmaceutical composition according to claim 48 in the preparation of a medicament for treating cancer.

54. A use of the compound or salt according to any one of claims 1-47 or the pharmaceutical composition according to claim 48 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.

55. The use according to claim 53 or 54, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer ty pes, 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.

56. 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 1-47 or a pharmaceutical composition according to claim 48.

57. 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 1-47 or a pharmaceutical composition according to claim 48, 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 method 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. The method according to claim 56 or 57. 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.

60. The method according to claim 59. wherein the cancer is non-small cell lung cancer.

61. The method according to claim 59, wherein the cancer is colorectal cancer.

62. The method according to claim 59. wherein the cancer is pancreatic cancer.

63. The method according to anyone of claims 56-62, 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.

Images