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

11005-W001-SECMACROCYCLIC 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 / 691,480, filed September 6, 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 of11005-W001-SECKRAS, KRAS G12C, which bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and prevented its subsequent activation (Ostream et al., 2013). This discovery' brought about significant new efforts in the KRAS inhibitor research, which have recently culminated in the entry' of KRAS inhibitors in human clinical trials.

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

[0007] One aspect of the disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt of said compound, wherein;Z is C-R7orN;Q is CH, C-halogen, C-C1-4 alky l, 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. 2 or 3; q is 0. 1. 2 or 3; each Rxis independently hydroxyl, halogen, oxo, cyano, -N(RZ)2. C1-4alkyl. C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkyl, 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. -C1-4alkylene-C(O)-Ci. 4alkyl, -C1-4alkylene-C(O)N(Rz)2, C1-4alkylene-S(O)2-Ci-4alkyl, or -S-C1-4alkyl;L is a bond, C1-4alkylene. -O-Ci-g alkylene, -S-C1-6alkylene, NRZ. O or S, wherein each C1-4alkylene. -O-C1-4alkylene and -S-C1-4alkylene chain is substituted with 0-2 occurrences of R2;-L'-L2- is -L2, -N(RZ)C(O)-L2. -C(O)-L2-, -OC(O)-L2. -C(O)O-L2, -OC(O)-O-L2, -OC(S)-O-L2, -O-L2, -NiRTGOtO-I.2. -OC(O)N(RZ)-L2, -N(RZ)-I.2. -S(O)2-L2, -S-L2, -S(O)-L2, C1-4alkylene-C(O)-L2, C1-4alkylene-C(O)O-L2, -C1-4alkylene-OC(O)O-L2, -C1-4alkylene- OC(O)-L2. -C1-4alkylene-O-L2, -C1-4alkylene-S(O)2-L2, -C1-4alkylene-S-L2, -C1-4alkylene-S(O)-L2, -11005-W001-SEC0-5-6 membered heteroaryl-L2, -C1-4 alkylene-5-6 membered heteroaryl-L2, -C1-4 hydroxyalkylene-5- 6-membered heteroaryl-L2or a 5-6 membered heteroaryl-L2;L2is C1-6alkylene, C1-6 alkylene-O-, C1-6alkylene-O- C1-6alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-7 cycloalkylene, C1-4 alkvlcnc-C, - cycloalkylene, C1-4 haloalkvlcnc-C;,.- cycloalkylene, C3-7 cycloalkylene-Ci-4 alkylene, C1-6hydroxy alkylene or C1-4haloalkylene;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;R2is halogen, hydroxyl, C1-4 alkyl or two R2on the same or adjacent carbon atoms can be taken together to form a C3-7 cycloalkyl;A is Ce-io aryl or 5-10 membered heteroaryl and is substituted with q occurrences of RG; each R5independently is halogen, cyano, oxo. -T-Ry, hydroxyl, -N(RZ)2, C1-4alkyl, C1-4 haloalkyl, C1-4 alkoxy or -O-C2-4 alkynyl; each R6independently is halogen, hydroxyl, cyano. -N(RZ)2. -C(O)RZ, -C(O)ORZ. C1-4alkyl. C1-4 alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4 alkynyl or C3-6 cycloalkyl or two R6taken together on adjacent carbon atoms form a C3-7 cycloalkyl;R is hydrogen, halogen, cyano, C1-4alkyl. C1-4haloalkyl. C1-4alkoxy, C1-4haloalkoxy or C3-7 cycloalkyl;T is C1-4alkylene, -S(O)2-, -C(O)-, -C1-4alkylene-C(O)-, C1-4alkylene-S(O)2- or -S-;Ryis halogen, oxo, C1-4alkyl, C1-4haloalkyl, hydroxyl, cyano or -N(RZ)2; and each Rzis hydrogen or C1-4alkyl.

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

[0009] Yet another aspect of the disclosure provides method of treating cancer in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of the compound or salt of Formula (I) or a pharmaceutical composition comprising the compound or salt of Formula (I).|0010| Still another aspect of the disclosure provides a compound or salt of Formula (1) 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 Fonnula (I), or tire 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,11005-W001-SEC 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 activity7as 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, ampullary7cancer, 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, C3alkyl means an alkyl group that has 3 carbon atoms (e.g., n-propyl or isopropyl). For example, a C1-6alkyl refers to an alkyl group having 1 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a Ci.6alkyl includes alkyl groups having 1, 2. 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5. 1-6. 2-3, 2-4, 2-5, 2-6, 3-4. 3-5. 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges)). A “Ci-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.11005-W001-SEC

[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, Cjalkenyl means the alkenyl group has 3 carbon atoms (e.g., 1-propenyl or 2-propenyl). For example, a C2-6alkenyl refers to an alkenyl group having 2 to 6 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C2-ealken 1 includes alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e g., 2-3, 2-4, 2-5, 2-6. 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges). A C2-4alkenyl includes, for example, ethenyl. 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl. 2-butenyl. or 3-butenyl. Non-limiting examples of alkenyl groups include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2- methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl. 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl. 4-hexenyl, and 5-hexenyl.

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

[0018] The term “cycloalkyl” refers to a saturated, hydrocarbon monocyclic ring, or a saturated, hydrocarbon polycyclic ring system containing the indicated number of carbon atoms as ring members in the ring or ring system. No ring in a cycloalkyl ring or ring system has s double bond, a heteroatom, or is aromatic. When a cycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. For example. 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. 7cycloalkyl includes cycloalkyl groups having 3. 4, 5, 6, or 7 carbon atoms in the ring (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g.. 3-4, 3-5, 3-6, 3-7. 4-5, 4-6. 4-7. 5-6, 5-7, or 6-7 carbon atom ring members, or any combination of the foregoing ranges). Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, norbomyl. decalinyl. and 7,7-dimethylbicyclo[2.2.1]heptanyl.11005-W001-SEC

[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 ary l group that has 10 carbon atoms in the ring system (e.g., naphthyl). When an aryl group is a polycyclic ring system, each ring in the ring system is aromatic, and no ring in the ring system contains a heteroatom. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a Cs-uaryl 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 ary l groups include phenyl, naphthyl, and anthracenyl.

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

[0021] The term “heterocycloalkyl” refers to a saturated, monocyclic ring or saturated, polycyclic ring system comprising carbon atoms and one or more heteroatoms (e.g., one or more of N, O. and S), and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring). When a heterocycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. No ring in a heterocycloalkyl ring or ring system contains a double bond or is aromatic. For example, a heterocycloalkyl group having 5 total atoms and 2 heteroatoms independently selected from N. O, and S, refers to a ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N. O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heterocycloalkyl group having 5-7 total ring atoms and 1-3 heteroatoms independently selected fromN, O, and S includes rings having 5, 6, or 7 total atoms, or any combination of the foregoing, as well as all subgroups in the indicated range (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom independently is selected from N, O, and S. Thus, a heterocycloalkyl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example, 4 carbon atoms and 1 hctcroatom, 3 carbon atoms and 2 hctcroatoms, 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,11005-W001-SEC thiazolidiny 1, oxathiolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, inorpholinyl, thiomorpholinyl, azepanyl, hexahydro-lH-pyrrolizinyl, and 1,4- diazepanyl.

[0022] The term “heteroaryl” refers to a monocyclic aromatic ring comprising carbon and one or more heteroatoms and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring), or a polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) aromatic ring system having one or more heteroatoms and the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring system). When a heteroaryl group is a polycyclic ring system, each ring in the ring system is aromatic. For example, a heteroaryl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to an aromatic ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of die ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S refers to an aromatic ring having a total number of ring atoms in the indicated range (e.g., 5, 6. or 7 total atoms, or any combination of the foregoing), as well as encompassing all subgroups (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom is independently selected from N. O, and S. A heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example. 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms. 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms. 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing independently is selected from N, O. and S. Nonlimiting examples of monocyclic heteroaryl groups include: pyrrolyl, furanyl, thiophene-yl (or thienyl), pyrazolyl. imidazolyl, isoxazolyl. oxazolyl, isothiazolyl, thiazolyl, triazolyl. oxadiazolyl, 1,3,4-oxadiazolyl. thiadiazolyl, tetrazolyl, pyridinyl (or pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. Nonlimiting examples of bicyclic heteroaryl groups include benzofuranyl. benzothienyl, benzimidazolyl, benzoisoxazolyl. benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, furopyridinyl (e.g.. furo[2,3-b]pyridinyl), imidazopyridinyl (imidazo[4,5-b]pyridinyl), imidazothiazolyl (e.g., imidazo[4,5-d]thiazolyl), indolizinyl, indolyl, indazolyl, isobenzo furanyl. isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl (e.g., oxazolo[5,4-b]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (e.g., pyrrolo[2,3-b]pyridyl), quinolinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, cinnolinyl, isoquinolyl, pyrazolopyridinyl (e.g., pyrazolo[3,4-b]pyridinyl), and thiazolopyrindinyl (e.g., thiazolo[5,4-b]pyridinyl). Nonlimiting examples of tricyclic heteroary l groups include carbazolyl, 4,5-benzindolyl, dibenzofuranyl, dibenzothiophene-yl, phenazinyl, and acridinyl.11005-W001-SEC

[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, C3 alkylene means the alkylene group has 3 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, C1 -6, alkylene means an alkylene group having a 1, 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). When the number of carbon atoms in an alkylene group is indicated as “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 C0-6alkylene-OH indicates that the OH group can be directly attached to the compound or through a C1 -6alkylene linker. Examples of alkylene groups include methylene ( — CH2— ), ethylene ( — CH2CH2— ), n-propylene ( — CH2CH2CH2— ), isopropylene (— CH(CH3)CH2— ). 1 -buty lene (— 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 (c.g., CH2F, CH(CH2F)CH3) dihaloalky l (c.g., CHF2, CH(CHF2)CH3), trihaloalkyl (e.g., CF3, CH(CF3)CH3), and polyhaloalky 1 (e.g., CF(CF3)CH3). A haloalky l group may or may not be perhalogenated (e.g., perfluorinated, such as CF(CF3)CF3). For example, the term “ C1-4haloalkyl” refers to a C1-4alkyl, wherein one or more hydrogen atoms is substituted with a halogen. For illustration, C1-4haloalky 1 includes, for example, CH2F, CHF2, CF3, CHFC1, CH2CF3, CFHCF3. CF2CF3, CH(CF3)2, CF(CHF2)2, CH(CH2F)(CF3), CH2C1, CHC12, CCl3. CHFC1, CH2CCl3, CCIHCCl3, CC12CCl3, CH(CCl3)2, CC1(CHCl2)2, CH(CH2C1)CCl3, and CH2CF(CH3)2.

[0026] The term “hydroxy alky lene” or “hydroxylalkylcnc” refers to a saturated straight chain alky lene or saturated branched chain alky lene 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 die same carbon atom. Nonlimiting examples hydroxyalkylene include but are not limited to, hydroxymethylene, 2 -hydroxy ethylene, 2-hydroxypropylene, 3- hydroxypropylene. l-(hydroxymethyl)-2- methylpropylene, 2-hydroxy butylene, 3-hydroxybutylene, 4- hydroxybutylene, 2,3-dihydroxypropylene, l-(hydroxymethyl)-2 -hydroxyethylene, 2,3- dihydroxybutylene, 3,4-dihydroxybutylene and the like.11005-W001-SEC

[0027] The term “oxo” refers to a substituent oxy gen atom connected to another atom by a doubleO If bond (e.g.. =0). For example, an oxo substituent on a cyclopentyd 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 C3alkoxy group means the alkoxy group has 3 carbon atoms (e.g.. OCH2CH2CH3). Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a 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. I -mcthvlcthvloxy (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 “Ci-ihaloalkoxy” refers to a Ci ialkoxy as defined herein, wherein one or more hydrogen atoms is substituted with a halogen. Representative examples of Ci.Jialoalkoxy include OCH2F. OCHF2, OCF3, OCHFC1, OCH2CF3, OCFHCF3, OCF2CF3, OCH(CF3)2, OCF(CHF2)2, OCH(CH2F)(CF3), OCH2C1, OCHC12. OCF3, OCHFC1. OCH2CCl3, OCCIHCCk OCC12CCl3. OCH(CCl3)2, OCC1(CHC12)2, OCH(CH2C1)CCl3, and OCH2CF(CH3)2.

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

[0033] The term “deutero” as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with deuterium (“D” or “2H”). For example, the term “Ci.4deuteroalkyl” refers to a Ci-4alkyl as defined herein, wherein one or more hydrogen atoms are substituted with D. Representative examples of Ci- 4deuteroalkyl include, but are not limited to. -CH2D. -CHD2. -CD3. -CH2CD3. -CDHCD3, -CD2CD3, - CH(CD3)2, -CD(CHD2)2. and -CH(CH2D)(CD3).11005-W001-SEC

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

[0035] The term “alkydamino” 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 indicated number of carbon atoms. For example, a Ci eth cyclohexylene ring cyclohexylene ring can be depicted as, for example.

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

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

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

[0040] The term “vicinal” refers to substituents that are attached to adjacent atoms along a chain orRwithin 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.11005-W001-SEC

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

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

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

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

[0046] The term “pharmaceutically acceptable salt” refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and that is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or formed with organic acids (e.g.. acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid). Pharmaceutically acceptable salts also include, for example, salts formed when an acidic proton present in the parent compound either is replaced by a metal ion (e g., an alkali metal ion. an alkaline earth ion, or an aluminum ion) 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.11005-W001-SEC disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, and preservatives (e.g., antibacterial and antifungal agents).

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

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

[0050] For clarity and avoidance of doubt, the divalent structural elements of -L' -L2- as provided herein are to be inserted into Formula (I) such that the left hand side is attached to the nitrogencontaining heterocycloalkyl group, and the right hand side is attached to the aryl ring. For example,p . .COMPOUNDS OF FORMULA (I)

[0051] Provided herein as Embodiment 1 are compounds of Formula (I):11005-W001-SECor a pharmaceutically acceptable salt of said compound, wherein;Z is C-R7orN;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, 2 or 3; q is 0, 1, 2 or 3; each Rxis independently hydroxyl, halogen, oxo. cyano, -N(RZ)2, C1.4 alkyl, Ci.4deuteroalkyl. C1-4 alkoxy. C1-4 haloalkyl. Ci4haloalkoxy. C1-4 hydroxyalkyl. 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, -C1.4 alkylene-C(O)-Ci.4alkyl. -C1-4 alkj lene-C(O)N(Rz)2. Ci.4alkylene-S(O)2-Ci.4alkyl, or -S-Ci.4alkyl;L is a bond, C1-6alk lene. -O-C1-6alkylene, -S-Ci-g alkylene, NRZ, O or S, wherein each C1-6alky lene, -O-C1-6alkylene and -S-C1-6alkylene chain is substituted with 0-2 occurrences of R2;-S(O)-L2, Ci-4alkylcnc-C(O)-L2, Ci-4alkylcnc-C(O)O-L2, -C1-4 alkylcnc-OC(O)O-L2, -Ci.4alkylcnc- OC(O)-L2, -Ci-4alkylene-O-L2, -Ci.4alkylene-S(O)2-L2, -Ci-4alkylene-S-L2, -C1-4 alkylene-S(O)-L2, - 0-5-6 membered heteroaryl-L2, -C1-4 alkylene-5-6 membered heteroaryl-L2, -C1-4 hydroxyalkylene-5- 6-membered heteroaryl-L2or a 5-6 membered heteroaryl-L2;L2is C1-6alkylene, C1-6 alkylene-O-, C1-6alkylene-O-C1-6alkylene, C2-6 alkenylene, C2.e alkynylene, C3-7 cycloalkylene, Ci-4alkylcnc-CL.- cycloalkylene, Ci-4haloalky lcnc-C,-- cycloalkylene, C3.7 cycloalky lene-Ci.4alkylene, C1-6 hydroxyalkylene or C1-6haloalkylene: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;R2is halogen, hydroxyl, Ci-4alkyl or two R2on the same or adjacent carbon atoms can be taken together to form a C3-7 cycloalkyl;A is Ce-io aryl or 5-10 membered heteroaryl and is substituted with q occurrences of R6; each R independently is halogen, cyano, oxo, -T-Ry, hydroxyl, -N(RZ)2, C1-4alkyl, Ci-4haloalkyl, Ci-4alkoxy or -O-C2.4alkynyl;11005-W001-SEC each R6independently is halogen, hydroxy l, cyano, -N(Rz)2, -C(O)RZ, -C(O)ORZ, C1.4 alkyl, C1-4alkoxy, C1-4 haloalkyl. C1-4haloalkoxy, C2-4 alkynyl or C3-6 cycloalkyl or two R6taken together on adjacent carbon atoms form a C3-7 cycloalkyl;R7is hydrogen, halogen, cyano. C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy or C3-7 cycloalkyl;T is C1-4alkylene, -S(O)2-, -C(O)-, -C1-4alkylene-C(O)-, C1-4alkylene-S(O)2- or -S-;Ryis halogen, oxo. C1-4alkyl. C1-4haloalkyl, hydroxyl, cyano or -N(RZ)2; and each Rzis hydrogen or C1-4alkyl.

[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, NR2or S and Z. p, Rx, L2, L1, R1. R2, R , R5, R6a, R6b, R6c, R7, 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, NR2or S and Z, p, Rx, L2, L1, R1. R2, R4, R5, R6a, R6b, R6c, 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):11005-W001-SECor a pharmaceutically acceptable salt of said compound, wherein X is CH2, O, NR2or S and Z, p. Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, Rw, T, Ryand Rzare as defined above for Formula (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, NR2or S and Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, R', 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 Formula (VI):or a pharmaceutically acceptable salt of said compound, wherein X is CH2, O, NR2or S and Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, 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):11005-W001-SECor a pharmaceutically acceptable salt of said compound, wherein X is CH2, O, NR2or S and Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, Rw, T, Ryand Rzarc as defined above for Formula (IV).

[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, NR2or S and Z, p. Rx, L2, L1. R1, R2, R4, R5. R6a. R6b, R6c, R7. 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, NR2or S and Z, p, Rx, L2, L1, R1. R2, R4, R5, R6a, R6b, R6c, 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):11005-W001-SECor a pharmaceutically acceptable salt of said compound, wherein X is CH2, O, NR2or S and Z. p, Rx. L2, L1, R1. R2. R4, R5, R6a, R6b, R6c, Rw, T. Ryand Rzare as defined above for Formula (IV).

[0061] Provided herein as Embodiment 11 is the compound or salt of any of Embodiments 1-10, wherein Z is C-R7. Provided herein as Embodiment 12 is the compound or salt of Embodiment 11 , wherein R7is hydrogen, fluorine, methyl, trifluoromethyl or chloro. Provided herein as Embodiment 13 is the compound or salt of Embodiment 11. wherein Q is CH. Provided herein as Embodiment 14 is the compound or salt of Embodiment 1 1, wherein R' is chlorine. Provided herein as Embodiment 15 is the compound or salt of Embodiment 11. wherein R7is fluorine. Provided herein as Embodiment 16 is the compound or salt of Embodiment 11, wherein R is methyl.

[0062] Provided herein as Embodiment 17 is the compound or salt of any of Embodiments 1-10. wherein Z is N. Provided herein as Embodiment 18 is the compound or salt of Embodiment 17, wherein Q is CH.

[0063] Provided herein as Embodiment 19 is the compound or salt of any of Embodiments 1-10, wherein Z is N and Q is CH. Provided herein as Embodiment 20 is the compound or salt of any of Embodiments 1-10, wherein Z is CH and Q is CH. Provided herein as Embodiment 21 is the compound or salt of any of Embodiments 1-10, wherein X is C-F and Q is CH. Provided herein as Embodiment 22 is the compound or salt of any of Embodiments 1-10, wherein Z is C-Cl and Q is CH.

[0064] Provided herein as Embodiment 23 is the compound or salt of any of Embodiments 1-22, wherein L3is -O-methylene, -O-ethylene or -O-n-propylene substituted with 0-2 occurrences of R2. Provided herein as Embodiment 24 is the compound or salt of Embodiment 23, wherein L3is -O- methylene substituted with 0 occurrences of R2. Provided herein as Embodiment 25 is the compound or salt of Embodiment 24, wherein R1is heterocycloalkyl substituted with 0-3 occurrences of R5.

[0065] Provided herein as Embodiment 26 is the compound or salt of Embodiment 25, wherein R1is 7a-(hexahydro-lH-pyrrolizinyl) substituted with 0-3 occurrences of R5. Provided herein as Embodiment 27 is the compound or salt of Embodiment 26, wherein R1is unsubstituted 7a- (hexahydro- IH-pyrroliziny 1).

[0066] Provided herein as Embodiment 28 is the compound or salt of Embodiment 26, wherein11005-W001-SECR1is 7a-(liexahydro-lH-pyrrolizinyl) substituted with one occurrence of R5. Provided herein as Embodiment 29 is the compound or salt of Embodiment 28, wherein R5is halogen. Provided herein as Embodiment 30 is the compound or salt of Embodiment 29, wherein R5is fluorine.

[0067] Provided herein as Embodiment 31 is the compound or salt of any of Embodiments 1-30, wherein L is -O-methylene-, -O-ethylene-, -O-n -propylene or -O-isopentanylene and L is substituted with 0-2 occurrences of R2. Provided herein as Embodiment 32 is the compound or salt of Embodiment 31. wherein L is -O-methylene- substituted with 0-2 occurrences of R2. Provided herein as Embodiment 33 is die compound or salt of Embodiment 32, wherein L is -O-methylene substituted with 0 occurrences of R2.

[0068] Provided herein as Embodiment 34 is the compound or salt of any of Embodiments 1-33, wherein R1is heterocycloalkyl substituted with 0-3 occurrences of R5. Provided herein as Embodiment 35 is the compound or salt of Embodiment 34, wherein R1is 7a-(hexahydro-lH- pyrrolizine). 6-(he.xahydro-lH-pyrrolo[2,l-c][l,4]oxazinyl), 2-pyrrolidinyl, l-(7- oxabicyclo[2.2.1]heptanyl), 2-morpholinyl, l-(2-azabicyclo[2.2.2]octanyl) or 3-(2- azabicyclo[3.1.0]hexanyl) substituted with 0-3 occurrences of R5. Provided herein as Embodiment 36 is the compound or salt of Embodiment 35, wherein R1is 7a-(hexahydro-lH-pyrrolizinyl). 6- (hexahydro-lH-pyrrolo[2,l-c][l,4]oxazinyl) or l-(7-oxabicyclo[2.2.1]heptanyl) substituted with 0 occurrences of R5. Provided herein as Embodiment 37 is the compound or salt of Embodiment 36. wherein R1is 7a-(hexahydro-lH-pyrrolizinyl) substituted with 0 occurrences of R5.

[0069] Provided herein as Embodiment 38 is the compound or salt of any of Embodiments 1-33, wherein R1is 7a-(hexahydro-lH-pyrrolizinyl), 6-(hexahydro-lH-pyrrolo[2,l-c][l,4]oxazinyl), 2- pyrrolidinyl, l-(7-oxabicyclo[2.2.1]heptanyl), 2-morpholinyl, l-(2-azabicyclo[2.2.2]octanyl) or 3-(2- azabicyclo[3.1.0]hexanyl) substituted with one occurrence of R5. Provided herein as Embodiment 39 is the compound or salt of Embodiment 38, wherein R5independently is halogen, oxo. methyl, methoxy or -O-(2-propynyl).

[0070] Provided herein as Embodiment 40 is the compound or salt of Embodiment 38, wherein R1is 7a-(hexahydro-lH-pyrrolizinyl) substituted with one occurrence of R5. Provided herein as Embodiment 41 is the compound or salt of Embodiment 40, wherein R5independently is fluoro.

[0071] Provided herein as Embodiment 42 is the compound or salt of any of Embodiments 1-41.11005-W001-SECherein as Embodiment 44 is the compound or salt of Embodiment 43. wherein -L-R1iscompound or salt of Embodiment 44, wherein -herein as Embodiment 46 is the compound or salt of Embodiment 44. wherein -L-R1is. Provided herein as Embodiment 47 is the compound or salt of Embodiment 44, wherein -L-R1is

[0072] Provided herein as Embodiment 49 is the compound or salt of any of Embodiments 1-22. wherein L3is -S-alkylene substituted with 0-2 occurrences of R2. Provided herein as Embodiment 50 is the compound or salt of Embodiment 49, wherein L3is -S-alkylene substituted with 0 occurrences of R2. Provided herein as Embodiment 51 is the compound or salt of Embodiment 0, wherein L3is - S-methylene substituted with 0 occurrences of R2. Provided herein as Embodiment 52 is the compound or salt of Embodiment 51, wherein R1is hydrogen. Provided herein as Embodiment 53 is the compound or salt of any of Embodiments 1-22, wherein -L-R1is11005-W001-SEC

[0073] Provided herein as Embodiment 54 is the compound or salt of any of Embodiments 1-53, wherein B is a 6-10 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S and N. Provided herein as Embodiment 55 is the compound or salt ofEmbodiment 54. whereinProvided herein as Embodiment 56 is the compound or salt of Embodiment 55, whereinProvided herein as Embodiment 57 is the compound or salt of Embodiment 55. whereinProvided herein asEmbodiment 58 is the compound or salt of Embodiment 55, whereinProvidedherein as Embodiment 59 is the compound or salt of Embodiment 55, wherein B-L1is '"i"'Provided herein as Embodiment 60 is the compound or salt of Embodiment 55, wherein B-L1is

[0074] Provided herein as Embodiment 62 is the compound or salt of any of Embodiments 1-61. wherein A is Ce-io aryl (e.g., phenyl or naphthyl). Provided herein as Embodiment 63 is the compound or salt of Embodiment 62, wherein A is phenyl. Provided herein as Embodiment 64 is the compound or salt of Embodiment 63, wherein q is 0.11005-W001-SEC

[0075] Provided herein as Embodiment 65 is the compound or salt of Embodiment 62, wherein q is2. Provided herein as Embodiment 66 is the compound or salt of Embodiment 65, wherein each R6is Ci-4 alkyl, halo (e.g., chloro or fluoro), hydroxyl or cyano. Provided herein as Embodiment 67 is the compound or salt of Embodiment 66, wherein each R6is C 1.4 alkyl or hydroxyl. Provided herein as Embodiment 68 is the compound or salt of Embodiment 67, wherein one R6is hydroxyl and the other R6is methyl.

[0076] Provided herein as Embodiment 69 is the compound or salt of Embodiment 62, wherein A is naphthyl. Provided herein as Embodiment 70 is the compound or salt of Embodiment 69, wherein q is 0.

[0077] Provided herein as Embodiment 71 is the compound or salt of Embodiment 69, wherein q is1. Provided herein as Embodiment 72 is the compound or salt of Embodiment 71. wherein R6is hydroxyl, halo, C1-4 alkoxy or C1.4 alkyl. Provided herein as Embodiment 73 is the compound or salt of Embodiment 72, wherein R6is hydroxyl. Provided herein as Embodiment 74 is the compound or salt of Embodiment 72, wherein R6is halo (e.g., fluorine or chlorine).

[0078] Provided herein as Embodiment 75 is the compound or salt of Embodiment 69, wherein q is2. Provided herein as Embodiment 76 is the compound or salt of Embodiment 75. wherein each occurrence of R6is halogen, hydroxyl, cyano, C1.4 alkoxy or C1-4 alkyl. Provided herein as Embodiment 77 is the compound or salt of Embodiment 76, wherein each occurrence of R6is fluorine, chlorine, cyano, hydroxyl or methoxy.

[0079] Provided herein as Embodiment 78 is the compound or salt of any of Embodiments 1-61,Provided herein as Embodiment 79 is the compound or salt ofEmbodiment 78, wherein. Provided herein as Embodiment 80 is the compound11005-W001-SEC or salt of Embodiment 78, whereinProvided herein as Embodiment 81 is the compound or salt of Embodiment 78, wherein82 is the compound or salt of Embodiment 78. whereinProvided herein asEmbodiment 83 is the compound or salt of Embodiment 78, whereinProvided herein as Embodiment 84 is the compound or salt of Embodiment 78, whereinProvided herein as Embodiment 85 is the compound or salt of Embodiment 78, wherein A-L2isL2OH . Provided herein as Embodiment 86 is the compound or salt of Embodiment 78, wherein

[0080] Provided herein as Embodiment 87 is the compound or salt of any of Embodiments 1-61, wherein A is 5-10 membered heteroaryl. Provided herein as Embodiment 88 is the compound or salt of Embodiment 87. wherein A is 4-indazolyl. Provided herein as Embodiment 89 is the compound or salt of Embodiment 88. wherein q is 0.11005-W001-SEC

[0081] Provided herein as Embodiment 90 is the compound or salt of Embodiment 88, wherein q is 1. Provided herein as Embodiment 91 is the compound or salt of Embodiment 90, wherein R6halo is Ci-4 alkyd, halo, Ci-4 haloalkyl or -C(O)ORZ. Provided herein as Embodiment 92 is the compound or salt of Embodiment 91, wherein R6is halo. Provided herein as Embodiment 93 is the compound or salt of Embodiment 91, wherein R6is fluorine. Provided herein as Embodiment 94 is the compound or salt of Embodiment 91, wherein R6is chlorine.

[0082] Provided herein as Embodiment 95 is the compound or salt of any of Embodiments 1-61, whereinProv ided herein asEmbodiment 96 is the compound or salt of Embodiment 95, whereinProvided herein as Embodiment 97 is tire compound or salt of Embodiment 95, whereinProvided herein as Embodiment 98 is the compound or salt of Embodiment 95, wherein A-L2isProvided herein as Embodiment 99 is the compound or salt of Embodiment 95, yvhcrcin

[0083] Provided herein as Embodiment 100 is the compound or salt of any of Embodiments 1-99, wherein -L'-L2- is -O-C(O)-O-L2. Provided herein as Embodiment 101 is the compound or salt of Embodiment 100, wherein L2is ethylene, n-propylene. 2-methyl-w-propylene, cis-2-propenylene. trans-2-propenylene or -CH2-cyclopropylene. Provided herein as Embodiment 102 is the compound11005-W001-SEC

[0084] Provided herein as Embodiment 105 is the compound or salt of any of Embodiments 1-99. wherein -L’-L2- is -C1.4 alkylene-O-L2. Provided herein as Embodiment 106 is the compound or salt of Embodiment 105. wherein -L’-L2- is -methylene-O-L2. Provided herein as Embodiment 107 is the compound or salt of Embodiment 106, wherein L2is wbutylene-, 2.2-difluoro-n-butvlcnc. trans-2- butenylene, cis-2-butenylene. 3-methyl-w-butylene. -methylene-cyclopropylene-. -ethylene- cyclopropylene- or ethylene-O-methylene. Provided herein as Embodiment 108 is the compound or salt of Embodiment 107, wherein -L'-L2- is. Provided herein as Embodiment 109 is the compound or salt of Embodiment108, wherein -Provided herein as Embodiment 110 is the compound or salt of Embodiment 109, wherein -L’-L2- is. Provided herein as Embodiment 111 is the compound or salt of Embodiment 109,11005-W001-SEC wherein -L1-L2- isProvided herein as Embodiment 112 is the compound or salt ofEmbodiment 109, wherein -L'-L:- is

[0085] Provided herein as Embodiment 113 is the compound or salt of any of Embodiments 1-99, wherein -L1-L2- is -NRZ-C(O)-O-L2. Provided herein as Embodiment 114 is the compound or salt of Embodiment 113, wherein Rzis hydrogen or methyl. Provided herein as Embodiment 115 is the compound or salt of Embodiment 113 or 114, wherein L2is n-propylene, ethylene, -ethylene- cyclopropylene or -methylene-cyclopropylene. Provided herein as Embodiment 116 is the compound117 is the compound or salt Embodiment 116, wherein -L'-L2- is HProvided herein as Embodiment 118 is the compound or salt ofEmbodiment 117. wherein -L'-L2- is. Provided herein as Embodiment 119 is the compound or salt of Embodiment 117, wherein -L’-L2- isherein as Embodiment 120 is the compound or salt of Embodiment 117, wherein -L -L - is11005-W001-SEC oH . Provided herein as Embodiment 121 is the compound or salt of Embodiment117, wherein -

[0086] Provided herein as Embodiment 122 is the compound or salt of any of Embodiments 1-99, wherein -L' -L2- is a 5-6 membered heteroaryl. Provided herein as Embodiment 123 is the compoundherein as Embodiment 125 is the compound or salt of Embodiment 124, wherein -L -L2- is

[0087] Provided herein as Embodiment 126 is the compound or salt of Embodiment 1, wherein the compound is a compound of Table 1 :Table 111005-W001-SEC11005-W001-SEC

[0088] Provided herein as Embodiment 127 is the compound or salt of Embodiment 126, wherein the compound is a compound of Table 1-1:11005-W001-SEC

[0089] Provided herein as Embodiment 128 is the compound or salt of Embodiment 126, wherein(Compound 1,005-1). Provided herein asEmbodiment 129 is the compound or salt of Embodiment 126, wherein the compound is11005-W001-SEC compound or salt of Embodiment 126, wherein the compound i(Compound 1.004-1). Provided herein as Embodiment 131 is the compound or salt of Embodiment126, wherein the compound i(Compound 1.011-1). Provided herein as Embodiment 132 is the compound or salt of Embodiment 126, wherein the compound is(Compound 1.012-1). Provided herein as Embodiment 133 is the compound or salt of Embodiment 126, wherein the compound i(Compound 1.013-1). Provided herein as Embodiment 134 is the compound or salt of Embodimentherein as Embodiment 135 is the compound or salt of Embodiment 126, wherein the compound is11005-W001-SEC(Compound 1.018-1). Provided herein as Embodiment 136 is the compound or salt of Embodiment 126, wherein the compound i(Compound 1.008-1). Provided herein as Embodiment 137 is the compound or salt of Embodiment126. wherein the compound(Compound 1.014-1). Provided herein as Embodiment 138 is the compound or salt of Embodiment 126. wherein the compound isthe compound or salt of Embodiment 126. wherein the compound is11005-W001-SEC(Compound 1.001-1). Provided herein as Embodiment 140 is the compound or salt of Embodiment 126, wherein the compound i(Compound 1.015-1). Provided herein as Embodiment 141 is the compound or salt of Embodiment(Compound 1.019-1). Provided herein as Embodiment 142 is the compound or salt of Embodiment 126, wherein the compound is(Compound 1.009-1). Provided herein as Embodiment 143 is the compound or salt of Embodiment 126, wherein the compound(Compomrd 1.019-1). Provided herein as Embodiment 144 is the compound or salt of Embodiment11005-W001-SEC126. wherein the compound i(Compound 1.022). Provided herein as Embodiment 145 is the compound or salt of Embodiment 126. wherein the compound is(Compound 1.023-1). Provided herein as Embodiment 146 is(Compound 1.025-1). Provided herein as Embodiment 147 is the compound or salt of Embodiment126, wherein the compound(Compound 1.026-1). Provided herein as Embodiment 148 is the compound or salt of Embodiment 126, wherein the compound is11005-W001-SEC(Compound 1.027-1). Provided herein as Embodiment 149 is the compound or salt of Embodiment 126, wherein the compound i(Compound 1.030-1). Provided herein as Embodiment 150 is the compound or salt of Embodiment126, wherein the compound(Compound 1.031-1).

[0090] Provided herein as Embodiment 151 is the compound or salt of Embodiment 1, wherein the compound is a compound of Table 2:11005-W001-SEC11005-W001-SEC11005-W001-SEC

[0091] Provided herein as Embodiment 152 is the compound or salt of Embodiment 151, wherein the compound is a compound of Table 2-1 :11005-W001-SEC

[0092] Provided herein as Embodiment 153 is the compound or salt of Embodiment 151, wherein(Compound 1.005). Provided herein asEmbodiment 154 is the compound or salt of Embodiment 151, wherein the compound is(Compound 1.003). Provided herein as Embodiment 155 is the compound or salt of Embodiment 151, wherein the compound i(Compound 1.004). Provided herein as Embodiment 156 is the compound or salt of Embodiment151, wherein the compound(Compound 1.011 ) . Provided herein as Embodiment 157 is the compound or salt of Embodiment 151, wherein the compound is11005-W001-SEC(Compound 1.013). Provided herein as Embodiment 159 is the compound or salt of Embodimentherein as Embodiment 160 is the compound or salt of Embodiment 151, wherein the compound is(Compound 1.007). Provided herein as Embodiment 161 is the compound or salt of Embodiment 151, wherein the compound i(Compound 1.018). Provided herein as Embodiment 162 is the compound or salt of Embodiment11005-W001-SEC151, wherein the compound(Compound 1.008). Provided herein as Embodiment 163 is the compound or salt of Embodiment 151, wherein the compound is(Compound 1.014). Provided herein as Embodiment 164 is the compound or salt of Embodiment 151, wherein the compound is(Compound 1.017). Provided herein as Embodiment 165 is the(Compound 1 .002). Provided herein as Embodiment 166 is the compound or salt of Embodiment11005-W001-SEC151, wherein the compound i(Compound 1.001). Provided herein as Embodiment 167 is the compound or salt of Embodiment 151, wherein the compound is(Compound 1.015). Provided herein as Embodiment 168 is the compound or salt of Embodiment 151, wherein the compound i(Compound 1.016). Provided herein as Embodiment 169 is the compound or salt of Embodiment151, wherein the compound(Compound 1.009). Provided herein as Embodiment 170 is the compound or salt of Embodiment 151. wherein the compound is11005-W001-SEC(Compound 1.010). Provided herein as Embodiment 171 is the compound or salt of Embodiment 151, wherein the compound i(Compound 1.019). Provided herein as Embodiment 172 is the compound or salt of Embodiment151, wherein the compound(Compound 1.021). Provided herein as Embodiment 173 is the compound or salt of Embodiment 151, wherein the compound is(Compound 1.022). Provided herein as Embodiment 174 is the compound or salt of Embodiment 151, wherein the compound i11005-W001-SEC(Compound 1.023). Provided herein as Embodiment 175 is the compound or salt of Embodiment151, wherein the compound i(Compound 1.024). Provided herein as Embodiment 176 is the compound or salt of Embodiment 151, wherein the compound is(Compound 1.025). Provided herein as Embodiment 177 is the compound or salt of Embodiment 151, wherein the compound i(Compound 1.026). Provided herein as Embodiment 178 is the compound or salt of Embodiment151, wherein the compound(Compound 1.027). Provided herein as Embodiment 179 is the compound or salt of Embodiment 151, wherein the compound is11005-W001-SEC(Compound 1.028). Provided herein as Embodiment 180 is the compound or salt of Embodiment 151, wherein the compound i(Compound 1.029). Provided herein as Embodiment 181 is the compound or salt of Embodiment(Compound 1.030). Provided herein as Embodiment 182 is the compound or salt of Embodiment 1 1, wherein the compound is(Compound 1.031).

[0093] It is understood that selections of values of each variable are those that result in the formation of stable or chemically feasible compounds.Stereoisomers

[0094] The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E / Z)), enantiomers,11005-W001-SEC diastereomers, and atropoisomers. Accordingly, the scope of the present disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, 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.

[0095] 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,NH represents. Similarly, 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.

[0096] The term “stereoisomer” or “stereoisomerically pure” compound refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of 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.

[0097] 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 comprising11005-W001-SEC mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques et al. , Enantiomers, Racemates and Resolutions (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

[0098] As known by those skilled in the art. certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes other tautomers of said structural formula.represents. Similarly, for example, the chemical name (4R,5R)-4- methoxy-5-methyl-4,5.6,7-tetrahydro-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

[0099] 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 and125I. nitrogen, such as13N and1SN, oxygen, such as150,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically -labelled compounds of the compounds disclosed herein, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium11005-W001-SEC(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.1’O and13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. Isotopically- labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying GENERAL SYNTHETIC PROCEDURES and EXAMPLES sections using an appropriate isotopically -labeled reagent in place of the non-labelled reagent previously employed.BIOLOGICAL ACTIVITY

[0100] In some cases, the compounds or salts disclosed herein (such as compounds of Formula (I). Formula (II), Formula (HI), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX) or Formula (X) or compounds listed in Table 1, Table 1-1. Table 2 or Table 2-1 or compounds of Embodiments 1-182, or a pharmaceutically acceptable salt of any of the foregoing), have an IC50 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 Couple Exchange assay. AsPC-1 p-ERK assay, AsPC-1 CTG assay or the SW620 CTG assay, described in “SECTION 3: Biochemical and Cellular Assays.’’ In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50 value of between 0.001 to 0.200 pM.FORMULATION AND ROUTE OF ADMINISTRATION

[0101] 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) or Formula (X) or compounds listed in Table 1, Table 1-1. Table 2 or Table 2-1 or compounds of Embodiments 1-182, 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 ct al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of11005-W001-SECPharmaceutical 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.

[0102] 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, transdcrmally, rcctally, puhnonarily, 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.

[0103] 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 rmit containing a particular amount of the active ingredient.

[0104] Thus, a further aspect of the disclosure is a pharmaceutical composition comprising one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Further provided herein is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, for use as a medicament.

[0105] Provided herein as Embodiment 183 is pharmaceutical composition comprising the compound or salt of any one of Embodiments 1 to 182. and a pharmaceutically acceptable excipient.METHODS OF USE

[0106] The compounds described herein (such as compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX) or Formula (X) or compounds listed in Table 1. Table 1-1, Table 2 or Table 2-1 or compounds of Embodiments 1-182, 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 some11005-W001-SEC 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).

[0107] 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.

[0108] 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), Formula (IX) or Formula (X) or compounds listed in Table 1, Table 1-1, Table 2 or Table 2-1 or compounds of Embodiments 1-182, or a pharmaceutically acceptable salt of any of the foregoing) to a patient.

[0109] 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.

[0110] 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) or Formula (X) or compounds listed in Table 1, Table 1-1, Table 2 or Table 2-1 or compounds of Embodiments 1-182, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein, for use in treating cancer.

[0111] 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.

[0112] 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 of11005-W001-SEC a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0113] In some cases, the cancer disclosed herein is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In some cases, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary', ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is colorectal cancer. In some cases, the cancer is pancreatic cancer.

[0114] Provided herein as Embodiment 184 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 182, or the composition of Embodiment 183.

[0115] Provided herein as Embodiment 185 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 182, or the composition of Embodiment 183. wherein one or more cells express KRAS G12D mutant protein.

[0116] Provided herein as Embodiment 186 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 182. or the composition of Embodiment 183, wherein one or more cells express KRAS G12V mutant protein.

[0117] Provided herein as Embodiment 187 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 182. or the composition of Embodiment 183, wherein one or more cells express KRAS G12A mutant protein.

[0118] 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 182. or the composition of Embodiment 183, wherein one or more cells express KRAS G12S mutant protein.

[0119] Provided herein as Embodiment 189 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the11005-W001-SEC compound according of any one of Embodiments 1 to 182, or the composition of Embodiment 183, wherein one or more cells express KRAS G13D mutant protein.

[0120] 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 182, or the composition of Embodiment 183, wherein one or more cells express KRAS Q61H mutant protein.

[0121] 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 182, or the composition of Embodiment 183. wherein one or more cells express KRAS Q6 IL mutant protein.

[0122] 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 182. or the composition of Embodiment 183, wherein one or more cells express KRAS Q61R mutant protein.

[0123] 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 182. or the composition of Embodiment 183, wherein one or more cells express KRAS G12R mutant protein.

[0124] Provided herein as Embodiment 194 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 182, or the composition of Embodiment 183, wherein one or more cells express KRAS G12C mutant protein.

[0125] Provided herein as Embodiment 195 is the method according to any one of embodiments 184-194, 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, mesodielioma, thyroid cancer, leukemia, or melanoma.

[0126] Provided herein as Embodiment 196 is the method according to Embodiment 195, 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 197 is the method according to Embodiment 196, wherein the cancer is non-small cell lung cancer.11005-W001-SECProvided herein as Embodiment 198 is the method according to Embodiment 196, wherein the cancer is colorectal cancer. Provided herein as Embodiment 199 is the method according to Embodiment 196, wherein the cancer is pancreatic cancer.

[0127] Provided herein as Embodiment 200 is the compound or salt of any one of Embodiments 1 to 182, or the pharmaceutical composition of Embodiment 183 for use as a medicament.

[0128] Provided herein as Embodiment 201 is the compound or salt of any one of Embodiments 1 to 182. or the pharmaceutical composition of Embodiment 183 for use in the treatment of cancer.

[0129] Provided herein as Embodiment 202 is the use of the compound or salt of any one of Embodiments 1 to 182, or the pharmaceutical composition of Embodiment 183. for the manufacture of a medicament for the treatment of cancer.

[0130] Provided herein as Embodiment 203 is the use of the compound or salt of any one of Embodiments 200 to 202, 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.

[0131] Provided herein as Embodiment 204 is the method according to Embodiment 203, wherein die 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 205 is the method according to Embodiment 204, wherein the cancer is non-small cell lung cancer. Provided herein as Embodiment 206 is the method according to Embodiment 204. wherein the cancer is colorectal cancer. Provided herein as Embodiment 207 is the method according to Embodiment 204, wherein the cancer is pancreatic cancer.Combination therapy

[0132] 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) or Formula (X) or compounds listed in Table 1, Table 1-1, Table 2 or Table 2-1 or compounds of Embodiments 1-182, or a pharmaceutically acceptable salt of any of the foregoing). In one aspect, such therapy includes but is not limited to the combination of11005-W001-SEC 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., U.S. Patent No. 10,519,146 B2, issued December 31, 2019; specifically, the sections from column 201 (line 37) to column 212 (line 46) and column 219 (line 64) to column 220 (line 39), which are herewith incorporated by reference.

[0133] 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.

[0134] 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.

[0135] 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- Iluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-lH-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2- methylpiperidine-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-hexaen-13- yl]morpholine), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4- methylthiophen-2-yl)phthalazin-l -amine), MLN8054 (4-[[9-chloro-7-(2,6-difIuorophenyl)-5H- pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(lR,8S)-4-[[4- (cy clobuty lamino)-5 -(trifluorome thy l)py rimidin-2-y 1] amino] - 11 -azatricy clo [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-y lamino)ethy 1] -1,3 -thiazol-2-y l]urea), CY C 116 (4-methy 1-5 -[2-(4-morpholin-4- ylanilino)pyrimidin-4-yl]-l,3-thiazol-2 -amine), TAS-119, BI 811283, and TTP607.11005-W001-SEC

[0136] AKT Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein die second compound is an AKT inhibitor.

[0137] 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)phenyl]-3-phenylimidazo[l,2-b]pyridazine-6-carboxamide), 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]carbazolc-2,10-dicarboxylic acid, 5,7-dihydro-6-mcthoxy-, 2,10-dicthyl 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.

[0138] Arginase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an Arginase inhibitor. Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidargistat and CB 280.

[0139] CDK4 / 6 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an CDK4 / 6 inhibitor. The term “CDK 4 / 6” as used herein refers to cyclin dependent kinases (“CDK”) 4 and 6, which are members of the mammalian serine / threonine protein kinases. The term “CDK 4 / 6 inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of CDK 4 and / or 6.

[0140] Exemplary CDK 4 / 6 inhibitors for use in the methods provided herein include, but are not limited to. abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin- 7(8H)-one. 6-(difluoromethyl)-8-[(lR.2R)-2 -hydroxy -2 -methylcyclopentyl]-2-[[l -(methylsulfony 1)- 4-piperidiny 1] amino] ) .

[0141] 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 occur11005-W001-SEC through modulating or inhibiting kinase enzymatic activity of one or more ErbB family member or by blocking homodimerization or heterodimerization of ErbB family members.

[0142] 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.

[0143] 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.

[0144] In yet another embodiment the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti- HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).

[0145] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody.

[0146] 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 -methy l-3-(4-methy 1- 1 -piperaziny 1)- 1 -butyn- 1 -y 1] -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-fluorophcnyl)mcthoxy]anilino]-3-cyano-7-cthoxyquinolin-6-yl]-4- (dimethylamino)but-2-enamide).

[0147] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3- (trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3- methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-l-yl)methyl)phenyl)-N-(l-phenylethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3-morpholinyhnethyl-[4-[[l-[(3- fluoropheny l)methyl] - 1 H-indazol-5-yl] amino] -5-methylpyrrolo[2, 1 -f| [ 1 ,2,4]triazin-6-yl] -carbamate), and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2- methylsulfony lethy lamino)methy 1] -1,3 -tiriazol-4-y 1] quinazolin-4-amine).

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

[0149] 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]-5-11005-W001-SEC(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.

[0150] 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.

[0151] Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4- yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo-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 -(trifluoromethy l)pyridin -4-yl] amino] -N- methylbenzamide). and APG-2449.

[0152] 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.

[0153] Exemplar,' FGFR inhibitors for use in the methods provided herein include, but are not limited to. futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difhioro-3,5- dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-l-yl]ethanol), AZD4547 (N-[5-[2-(3,5- dimethoxyphenyl)ethyl]-lH-pyrazol-3-yl]-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]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-l-yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453, and HGS1036.

[0154] 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.

[0155] Exemplar}' glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0156] 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.

[0157] Exemplar,' IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab. dalotuzumab, linsitinib, ganitumab. robatumumab. BMS-754807 ((2S)-l-[4-11005-W001-SEC[(5-cyclopropyl-lH-pyrazol-3-yl)amino]pyrrolo[2,l-f|[l,2,4]triazin-2-yl]-N-(6-fluoropyridin-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-metliylthiopliene-2-carboxamide), PL225B, AVE 1642, and BIIB022.

[0158] 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.

[0019] Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, the inhibitors disclosed in US 2020 / 0239441, WO 2020 / 132649, WO 2020 / 132651, and WO 2020 / 132653, each of which is herewith incorporated by reference in its entirety.

[0160] 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.

[0161] 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- fluorophenyl)thieno[2.3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4- pyrimidinyl]methoxy]benzenepropanoic acid), and ABBV-467.

[0162] 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 the second compound is an MEK inhibitor.

[0163] Exemplar}' 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- dih}'droxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4- iodoanilino)-N-(2-h}'drox}'ethoxy)-l,5-dimeth}'l-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-hydroxyethoxy)-5-[(3-oxooxazinan-2- yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)- 8-methylpyrido[2,3-d]pyrimidine-4, 7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4- difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N- (cyclopropylmethoxy)-3.4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodophenylamino)benzamide), PD98059 (2-(2-amino-3-methoxyphenyl)-4H-11005-W001-SEC chromen-4-one), PD334581 (N-[5-[3 , 4-Difluoro-2-[(2 -fluoro-4-iodophenyl)amino]phenyl]- 1,3,4- oxadiazol-2-yl]-4-morpholineethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554. .

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

[0165] 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- (trifhioromethyl)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).

[0166] PD-1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0167] Exemplar,' PD-1 inhibitors for use in the methods provided herein include, but are not limited to. pembrolizumab. nivohimab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210). sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR- 042, WBP-285). INCMGA00012 (MGA012). AMP-224, AMP- 14, 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.

[0168] PD-L1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.

[0169] Exemplar}' 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.

[0170] 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.

[0171] Exemplar,' 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-2-11005-W001-SEC[[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 Isulfony Ibenzimidazol- 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-plienylchroinen-2- yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]- 3-hydroxypropanoate). XL147 (N-[3-(2,l,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-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).

[0172] 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 compormd, wherein the second compormd 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 isofonns (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.

[0173] Exemplaty 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-fhioro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6- yl)phenyl)urea). Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3- (trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide). CEP- 32496 (l-(3-((6.7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(l,l,l-trifluoro-2-methylpropan-2- yl)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).11005-W001-SEC

[0174] 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 die second compound is a SHP2 inhibitor.

[0175] Exemplary 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 dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6- (2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TNO155, (3S,4S)-8-[6-amino-5-(2-amino-3- chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and vociprotafib (RMC-4630 - Revolution Medicine).

[0176] 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-methyl-2 -pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2- oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-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).

[0177] 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)thio]-4-[(3S,4S)-4-amino-3-methyl-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)thio]-6-methylpyrazolo[l,5-a]pyrazin-4-yl]-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0178] 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 -pyridinemethanol (CAS 2238840-54-3), 3-[(lR)-l-amino-8-azaspiro[4.5]dec-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]dcc-8-yl]-6-(2,3-dichlorophcnyl)-5-mcthyl-2-pyridincmcthanol (CAS 2238840-60-1),11005-W001-SEC(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)tliio]-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-pyridinemethanol (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-(hydroxymethyl)pyridin-3-ol.

[0179] 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 an inhibitor disclosed in US 10,590,090 B2, US 2020 / 017517 Al, US 2020 / 017511 Al. or WO 2019 / 075265 Al.

[0180] 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.

[0181] Exemplar}' 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.

[0182] 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 nonrcccptor tyrosine kinase family including: Src, Yes, Fyn, and Fgr (SrcA11005-W001-SEC subfamily); Lek, Hek, Blk, and Lyn (SreB subfamily), and Frk subfamily . The term “Sre 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.

[0183] Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethy 1-2 -oxo-3-((4, 5,6,7- tetrahydro-1H-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- mcthylpipcrazin-l-yl)phcnyl)amino)pyrimidin-4-yl)carbamatc), and KX-01 (N-bcnzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide).

[0184] 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.

[0185] Exemplary chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folinate), 5 -fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil. cyclophosphamide, and methotrexate.GENERAL SYNTHETIC PROCEDURES

[0186] The compounds provided herein can be synthesized according to the procedures described in this and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. It should be appreciated that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner.

[0187] 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 the examples provided herein.11005-W001-SEC

[0188] In general, the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX) or Formula (X) can be synthesized according to Schemes I- IV as shown below:

[0189] In general, the compounds of Formula (I) can be synthesized according to Schemes I- VI as shown below:Scheme I

[0190] Compounds of Formula (I-A) can be prepared according to Scheme I. In step A. compound (1-1) reacts with an alcohol in the presence of a Lewis acid such as Y(OT1 3 or Sc(OTfh in a solvent such as DCM or toluene to give compound (1-2). In step B, compound (1-2) undergoes borylation with a reagent, such as M2(e g.. bis(pinacolato)diboron) under Pd-catalyzed conditions to give compound (1-3). In step C, compound (1-3) is coupled with a halogen (e.g., chloride) on a pyridopyrimidine to give compound (1-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 1,4-dioxane, 2-MeTHF and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (1-4) is hydrolyzed to give the11005-W001-SEC free amine, compound (1-5), using a reagent such as HC1 in 1,4-dioxane or TFA. In step E, compound (1-5) is cyclized under conditions such as Py BroP or BrOP and DIPEA in a solvent such as CH3CN, THF and DMSO to give compounds of Formula (I- A).Scheme II

[0191] Compounds of Formula (II- A) can be prepared according to Scheme II. In step A, compound (II-l) reacts with an alcohol in the presence of a Lewis acid such as Y(OT1)3or Sc(OTl)3in a solvent such as DCM or toluene to give compound (H-2). In step B, compound (II- 2) undergoes borylation with a reagent, such as M2(e.g., bis(pmacolato)diboron) under Pd-catalyzed conditions to give compound (II-3). In step C. compound (II-3) is coupled with a halogen (e.g., chloride) on a pyridopyrimidine to give compound (II-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-Me-THF, 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with11005-W001-SEC or without a base such as potassium phosphate. In step D, compound (II-4) is hydrolyzed to give compound (II-5) using a reagent such as HC1 in 1,4-dioxane or TFA. In step E, compound (II- 5) is cyclized under conditions such as PyBroP or BrOP and DIPEA in a solvent such as CH3CN, THF and DMSO to give compounds of Formula (II- A).Scheme III

[0192] Compounds of Formula (III- A) can also be prepared according to Scheme III. In step A, compound (III-l ) undergoes SNAT reaction with an optionally substituted cyclic amine bearing an alcohol in a solvent such as acetonitrile and in the presence of a base such as Htinig’s base or triethylamine to give compound (III-2). In step B, compound (III-2) undergoes SNAT reaction with a nucleophile having the formula R'-L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig’s base, DBU or NaH to give compound (III-3). In step C, compound (III- 3) is coupled with an organometallic reagent or a boronic acid (ester) (M) attached to an aryl or hetereoaryl bearing a terminal protected alcohol (e.g.. with TBS or TBDPS) to give compound (III-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-MeTHF, THF, 1,4-dioxane and water,11005-W001-SEC and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (III-4) is reacted with CDI, followed by treatment with a desilyating reagent such as TBAF in a solvent such as THF to give compound (III- 5). In step E, compound (HI-5) is hydrolyzed to give compounds of Formula (III- A) using a reagent such as HC1 in 1,4-dioxane or TFA in DCM.Scheme IV11005-W001-SEC

[0193] Compounds of Formula (IV-A) can also be prepared according to Scheme IV. In step A, compound (IV-1) undergoes SNAT reaction with an optionally substituted cyclic amine bearing an alcohol in a solvent such as acetonitrile and in the presence of a base such as Hiinig's base or triethylamine to give compound (IV-2). In step B, compound (IV-2) is coupled with an organometallic reagent or a boronic acid (ester) (M) attached to an aryl or hetereoaryl bearing a terminal protected alcohol (e g., TBS or TBDPS) to give compound (IV-3). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-MeTHF. THF, 1.4-dioxane and water, and a catalyst such as cataCXium A Pd G3. with or without a base such as potassium phosphate. In step C, compound (IV-3) is reacted with CDI, followed by treatment with a desilyating reagent such as TBAF in a solvent such as THF to give compound (IV-4). In step D, compound (IV-4) is reacted with an oxidizing agent such as m-CPBA in a solvent such as DCM to give compound (IV-5). In step E. compound (IV-5) undergoes SNAT reaction with a nucleophile having the formula R‘-L-H in the presence of a base such as DBU. NaH, DIEA or triethylamine in a solvent such as CH3CN, THF. DMF or DMSO to give compound (IV-6). In step F, compound (IV-6) is hydrolyzed to give compounds of Formula (IV-A) using a reagent such as HC1 in 1,4-dioxane or TFA.Scheme V11005-W001-SEC

[0194] Compounds of Fonnula (V-A) can be prepared according to Scheme V. In step A, compound (V-l) reacts with an alcohol in the presence of a Lewis acid such as Y(OTI)3or Sc(OTI)3in a solvent such as DCM or toluene to give compound (V-2). In step B, compound (V-2) undergoes borylation with a reagent, such as M2(e.g., bis(pinacolate)diboron) under Pd-catalyzed conditions to give compound (V-3). In step C, compound (V-3) is coupled with a halogen (e.g.. chloride) on a pyridopyrimidine to give compound (V-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-Me-THF, 1.4-dioxane. THF and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D. compound (V-4) is reacted with an oxidizing agent such as OT-CPBA in a solvent such as DCM to give compound (V-5). In step E, compound (V-5) undergoes SNAT reaction with a nucleophile having the formula R'-L-H in the11005-W001-SEC presence of a base such as DBU, NaH, DIEA or triethylamine in a solvent such as CH3CN, THF, DMF or DMSO to give compound (V-6). In step F, compound (V-6) is hydrolyzed with an acid to give compound (V-7) using a reagent such as HC1 in 1,4-dioxane or TFA in DCM. In step G, compound (V-7) is cyclized under conditions such as PyBroP or BrOP and DIPEA in a solvent such as CH3CN, THF and DMSO to give compounds of Formula (V-A).Scheme VI

[0195] Compounds of Formula (VI- A) can be prepared according to Scheme VI. In step A, compound (VI-1) is activated by reacting with CDI or 4-nitrophenyl chloroformate, then treated by an alcohol in a solvent such as 2-Me-THF in the presence of a base such as Hunig’s base or NaH to give compound (VI- 2). In step B, compound (VI- 2) undergoes borylation with a reagent such as bis(pinacolato)diboron under Pd-catalyzed conditions to give compound (VI- 3). In step C, compound (VI- 3) is coupled with a pyridopyrimidine to give compound (VI-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-Me-THF, 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step D, compound (VI- 4) is hydrolyzed to give compound (VI-5) using a reagent such as HC1 in dioxane or TFA in DCM. In11005-W001-SEC step E, compound (VI-5) is cyclized under conditions such as PyBroP or BrOP and DIPEA in a solvent such as Cl fCN. THF, 2-Me-THF and DMSO to give compounds of Formula (VI- A).

[0196] As can be appreciated by the skilled artisan, the above synthetic scheme and representative examples are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds.

[0197] 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.

[0198] 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

[0199] This section provides specific examples of compounds of Formula (I) and methods of making the same.List of Abbreviations11005-W001-SEC11005-W001-SEC11005-W001-SEC

[0200] Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific examples provided herein.

[0201] Chromatography: Unless otherwise indicated, product-containing residues were purified by passing the material or concentrate through (a) Biotage High Capacity D column or (b) ISCO RediSep Gold High Performance column or (c) ISCO RediSep Rf HP C18 Gold column or (d) Biotage Isolute SCX-2 column; and eluting the product off the column with a solvent gradient as indicated.

[0202] 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 tw o HPLC columns: (a) Phenomenex Gemini column (5 micron, C18. 150 x 30 mm) or (b) Waters X-select CSH column (5 micron. C18, 100 x 30 mm). A typical run through the instrument included: eluting at 45 mL / min with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) over 10 minutes. Conditions can be varied to achieve improved separations.

[0203] Proton NMR Spectra: Unless otherwise 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.

[0204] Mass Spectra (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or exemplary' compounds are reported as mass / charge (m / z), having an [M+H]+molecular ion. The molecular ion reported was obtained by electrospray detection method (commonly referred to as an ESI MS) utilizing a Waters Acquity UPLC / MS system. Compounds having an isotopic atom, such as bromine and the like, are generally reported according to the detected isotopic pattern, as appreciated by those skilled in the art.

[0205] Fluorine-19 NMR Spectra: Unless otherwise indicated, all19F NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz.SECTION 1 : Synthesis of Intermediates11005-W001-SEC

[0206] 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.

[0207] Intermediate A: tert- Butyl (3.S',5R)-l-oxa-7-azadispiro[2.1.5 .13|undecane-7- carboxylate.

[0208] Step 1. (2.S',4R)-2-Cyario-2-((trirncthvlsilyl)oxy)-6-azaspiro[3.5|nonane-6-carboxylate.To a solution of tert-butyl 2-oxo-6-azaspiro[3.5]nonane-6-carboxylate (600 g. 2.51 mol) in tetrahydrofuran (1.50 L) was added TMSCN (353 mL. 2.63 mol) at -70 °C under N2, then n-BuLi (2.5 M in hexanes, 50 mL, 125 mmol) was added dropwise at -78 °C. The mixture was stirred at 20 °C for 2 h. A total of 4 batches were combined for the workup and purification. The reaction mixture was quenched by addition of FLO and extracted with EtOAc. The combined organic layers were dried over Na2SO4. filtered and concentrated under reduced pressure to afford crude tert-butyl 2-cyano-2- ((trimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate (3.6 kg). The crude product was purified by trituration with MTBE at -20 °C to afford (2S,47?)-2-cyano-2-((trimethylsilyl)oxy)-6- azaspiro[3.5]nonane-6-carboxylate (1.4 kg, 41% yield, 4.14 mol).

[0209] Step 2. (2.S’,4R)-2-Hydroxy-6-azaspiro[3.5|nonanc-2-carboxylic acid. A mixture of tertbutyl 2-cyano-2-((trimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate (200 g, 591 mmol) in HC1 (12 M in water, 85 mL, 1.02 mol) was purged with N2. and the resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude (2 ,47?)-2- hydroxy-6-azaspiro[3.5]nonane-2-carboxylic acid (109 g).

[0210] Step 3. 6-(tert-Butoxycarbonyl)-2-hydroxy-6-azaspiro[3.5]nonane-2-carboxylic acid. A stirred mixture of (2S,4 )-2-hydroxy-6-azaspiro[3.5]nonane-2 -carboxylic acid (109 g, crude) was dissolved in water and basified to pH 11 using sodium carbonate. Tetrahydrofuran (1.2 L). NaiCO.(99 g, 1.18 mol), and Boc2O (205 mL, 883 mmol) were then added at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 12 h. The aqueous layer pH was11005-W001-SEC adjusted to pH 4 and extracted with EtOAc. The combined organic layers were dried over Na^SO i. filtered and concentrated under reduced pressure. The crude material was purified by trituration with petroleum ether:EtOAc (10: 1) at room temperature for 60 min to afford (2S,4R)-6-(tert- butoxycarbonyl)-2-hydroxy-6-azaspiro[3.5]nonane-2-carboxylic acid (147 g, 0.52 mol, 87% yield). ’H NMR (400 MHz, DMSO-d^ 5 ppm 3.31 (s, 2 H), 3.20 (s, 2 H), 2.30 (d, J = 12.4 Hz, 2H ), 1.68 (d, J = 13.2 Hz. 2 H), 1.56 - 1.65 (m. 2 H), 1.37 (s, 11 H).

[0211] Step 4. tert- Butyl ( S, 4R)-2-hydroxy-2-(hydroxymethyl)-6- azaspiro [3.5] nonane-6- carboxylate. A solution of (2S,4R)-6-(tert-butoxycarbonyl)-2-hydroxy-6-azaspiro[3.5]nonane-2- carboxylic acid (100 g, 350 mmol, 25.5 mL / min) in 2-McTHF (500 mL) and BH3*DMS (105 mL, 1.05 mol, 4.5 mL / min) were pumped into a flow reactor (residence time 10 min) at 60 °C. The product stream was collected in a flask containing methanol (750 mL) at 0 °C. The product solution was quenched by methanol and concentrated under reduced pressure. The crude mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel. eluting with a gradient of 0 to 100% EtOAc in petroleum ether to afford tert-butyl (2S,4R)-2-hydroxy-2-(hydroxymethyl)-6-azaspiro[3.5]nonane-6-carboxylate (660 g. 2.43 mol, 69% yield). m,z (ESI): 216.1 (M- / -Bu+H)+. *H NMR (400 MHz, DMSO-d,)' 5 ppm 4.72 (s, 1 H). 4.54 (s. 1 H), 3.08 - 3.29 (m. 6 H), 1.91 (d, J= 12.8 Hz, 2 H), 1.56 - 1.62 (m, 2H ), 1.47 (d, J = 13.2 Hz, 2 H). 1.38 (s, 11 H).

[0212] Step 5. tert- Butyl (3S',51?)-l-oxa-7-azadispiro[2.1.55.l3]undecane-7-carboxylate. To a solution of tert-butyl (2S,4R)-2-hydroxy-2-(hydroxymethyl)-6-azaspiro[3.5]nonane-6-carboxylate (10 g. 36.9 mmol) 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, Combi-Blocks Inc.) was then added and the mixture was stirred at room temperature for 40 h. The reaction mixture was washed with water (150 mL), dried over Na2SOi. filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-100% EtOAc in heptane, to give tert-butyl (3>S'.5R)-l-oxa-7-azadispiro|2.1.55.l3|undecane-7-carboxylate (Intermediate A, 5.81 g, 22.9 mmol, 62% yield), m / z (ESI): 372.1 (M+Na)+.!H NMR (400 MHz. CDCl3) 6 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).

[0213] Intermediate B: rac-((l R,25)-2-(2-Bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)methanol.11005-W001-SEC

[0214] Step 1. 2-(3-Bromo-4-iodo- -methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane.To a stirred 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- / ert-butvl-2.2'-bipyridinc (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, 0.05 mmol, Strem Chemicals. Inc.) under a stream of nitrogen. The resulting mixture was sparged with nitrogen for 15 min and stirred at 60 °C for 2.5 h. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica, 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), m / z (ESI): product did not ionize. ’HNMR (400 MHz, ('I)CI,) 5 ppm 8.01 - 7.75 (in, 1H), 7.69 - 7.46 (m, 1H), 2.70 - 2.46 (m, 3H), 1.41 - 1.33 (m, 12H ).

[0215] 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 mL) and water (3 mL) at room temperature under ambient atmosphere, was added sodium perborate tetrahydrate (0.55 g, 3.54 mmol). The resulting mixture was stirred at room temperature for 1 h. 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 Na^SOi. filtered, and concentrated to give 3-bromo-4-iodo-5-methylphenol (0.42 g, 1.36 mmol, quantitive yield), m / z (ESI): product did not ionize.!H NMR (400 MHz, CDC ) 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).

[0216] 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 A(A / -diisopropylethylamine (0.6 mL, 3.44 mmol) in dichloromethane (4 mL) at room temperature under nitrogen, was added bromomethyl11005-W001-SEC methyl ether (0.2 mL, 2.45 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at 40 °C for 30 min. The reaction mixture was cooled to room temperature, diluted with sat. aq. solution of sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with sat. aq. solution of sodium bicarbonate, water, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in heptane to give 1 -bromo-2-iodo-5-(methoxy methoxy )-3- methylbenzene (0.33 g, 0.93 mmol. 81% yield), m / z (ESI): product did not ionize. ’H NMR (400 MHz, CDCl3) 3 ppm 7.26 - 7.18 (m, 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).

[0217] Step 4. rac-Ethyl (1R,2S)-2-(2-bromo-4-(methoxymethoxy)-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 (1R,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 for 15 min and stirred at 100 °C for 21 h. The reaction mixture was filtered through celite, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica, 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), m / z (ESI): 343.0 (M+H)+. ‘HNMR (400 MHz. CDCl3) 8 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).

[0218] Step 5. rac-((lR,2.S’)-2-(2-Bromo-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)methaiiol. To a stirred mixture of rac-ethyl (lR.2S)-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. 3.6 mL. 3.60 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at -78 °C and gradually allowed to warm to room temperature 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 1 h at room temperature. The mixture was extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with brine, dried over Na2SOi. filtered, and concentrated to give rac-((17?.2>S)-2- (2-bromo-4-(methoxymethoxy)-6-methylphenyl)cyclopropyl)methanol (Intermediate B, 0.40 g, 1.33 mmol. 93% yield), m / z (ESI): product does not ionize on LC-MS. 'H NMR (400 MHz. CDCl38 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.11005-W001-SEC3H), 3.05 - 2.93 (in, 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).

[0219] Intermediate C. 4-(tert-Butoxy)-7-chloro-2-(((2R ,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-rf]pyrimidine.

[0220] Step 1. 4-(tert-Butoxy)-7-chloro-2-(((2R ,7aS)-2-fIuorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[2,3-d]pyrimidine. To a stirred mixture of 2.4.7-trichloropyrido[2,3- <7|pynmidinc (0.50 g, 2.13 mmol. Synthonix) in THF (8.5 mL) at -78 °C, was added sodium tert- butoxide (2.0 M in THF. 1.2 mL. 2.40 mmol) and the resulting mixture was stirred at -78 °C. After stirring for 1 h, the reaction allowed to warm to room temperature and continued to stir. After stirring an additional 1 h. the reaction was then absorbed onto silica gel and the crude material was purified via column chromatography on silica gel using a gradient of 0-40% EtOAc in heptane to provide 4- (tert-butoxy)-2,7-dichloropyrido[2,3-d|pyrimidine (0.47 g, 1.73 mmol, 81% yield). m / z(ESI): 216.0 (M+H-t-Bu)+.!H NMR (400 MHz, CDCl3) 5 ppm 8.35 (d, J=8.4 Hz, 1 H), 7.47 (d, J=8.4 Hz. 1 H), 1.78 (s, 9 H).

[0221] Step 2. 4-(tert-Butoxy)-7-chloro-2-(((2R,7aS’)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[2,3-rf]pyrimidine. A reaction vessel was charged with 4-( / ert-butoxy)- 2.7-dichloropy rido|2,3-d | pyrimidine (0.47 g, 1.73 mmol) and ((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methanol (0.50 g. 3.11 mmol, Pharmablock, Inc.), before being suspended in acetonitrile (3.5 mL) and A,A-diisopropylethylamine (0.91 mL. 5.21 mmol) and stirred at 80 °C. After 18 h, the reaction was then concentrated under reduced pressure then purified via column chromatography on silica gel using a gradient of 0-40% of a 3: 1 EtOAc:EtOH mixture (containing 2% triethylamine) in heptane to provide 4-(tert-butoxy)-7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d |pyrimidine (Intermediate C, 0.61 g, 1.54 mmol, 89% yield). m / z (ESI): 395.0 (M+H)+. 'H NMR (400 MHz. CDCl3) 5 ppm 8.25 (d. J=8.2 Hz, 1 H), 7.28 (d, J=3.6 Hz, 1 H), 5.22 - 5.43 (m, 1 H), 4.35 (s, 2 H), 3.11 - 3.41 (m, 3 H), 2.95 - 3.07 (m, 1 H), 2.14 - 2.35 (in, 2 H), 2.03 - 2.13 (in, 1 H), 1.88 - 2.01 (m, 3 H), 1.74 (s, 9 H).11005-W001-SEC

[0222] Intermediate D: 4-(ter / -Butoxy)-6,7-dichloro-2-(((2R ,7aS )-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d ]pyrimidine.

[0223] Step 1. 2-Amino-5,6-dichloronicotinic acid. To a stirred solution of 2-amino-6- chloronicotinic acid (16 g. 93 mmol) in acetonitrile (640 mL) at room temperature under nitrogen, was added A'-chlorosuccmimidc (16.1 g, 121 mmol). The resulting mixture was stirred at 80 °C for 1.5 h. The reaction mixture was poured into ice water (1.8 L), filtered and the filter cake was washed with water. The filtrate was concentrated under reduced pressure to afford 2-amino-5,6- dichloronicotinic acid (15 g, 72.5 mmol. 78% yield), m / z (ESI): 207.1 (M+H)+.

[0224] Step 2. 2-Amino-5,6-dichloronicotinamide. To a stirred solution of 2-amino-5,6- dichloronicotinic acid (40 g, 193 mmol) in tetrahydrofuran (400 mL) at room temperature under nitrogen was added SOCI2 (56 mL, 773 mmol). The resulting mixture was stirred 2 h at 70 °C then concentrated under reduced pressure to afford crude 2-amino-5,6-dichloronicotinoyl chloride (40 g). To a stirred solution of crude 2-amino-5,6-dichloronicotinoyl chloride (40 g) in tetrahydrofuran (400 mL) at room temperature under nitrogen was added an aq. solution of ammonium hydroxide (160 mL). The mixture was stirred at room temperature for 1 h then concentrated under reduced pressure to afford 2-amino-5,6-dichloronicotinamide (50 g). m / z (ESI): 206.0 (M+H)+.

[0225] Step 3. 6,7-Dichloropyrido[2,3-rf]pyrimidine-2,4-diol. To a solution of 2-amino-5.6- dichloronicotinamide (10 g, 48.5 mmol) in toluene (10 mL) at room temperature under nitrogen was added oxalyl chloride (0.7 mL) dropwise. The resulting mixture was stirred at 110 °C for 1 h. The mixture was cooled to room temperature, filtered and the filter cake washed with toluene to afford crude 6.7-dichloropyrido[2,3-t / |pyrimidine-2.4-diol (36.7 g).11005-W001-SEC

[0226] Step 4. 2,4,6,7-Tetrachloropyrido|2,3-d |pyrimidine. To a stirred solution of phosphoryl trichloride (40.2 mL, 431 mmol) in 1,4-dioxane (125 mL) at room temperature under nitrogen was added 6,7-dichloropyrido[2,3-<7|pyriniidine-2,4-diol (12.5 g, 53.9 mmol) portionwise followed by slow addition of MA'-diisopropvIcthvlaminc (46.9 mL. 269 mmol). The resulting mixture was stirred at 100 °C for 2 h. A total of 4 batches were combined for the workup and purification. The reaction mixture was concentrated under reduced pressure and the resulting residue was carefully quenched at 0 °C with sat. aq. solution of sodium bicarbonate and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4. fdtered and concentrated under reduced pressure to afford 2.4.6.7-lctrachloropyrido|2,3-d |pyrimidinc (Intermediate M, 62 g, 231 mmol, 62% yield), m / z (ESI): 269.9 (M+H)1. ’H NMR (400 MHz, CDCl / ) 5 ppm 8.64 (s, 1H).

[0227] Step 5. 4-(tert-butoxy )-2,6,7-trichloropyrido[2,3-d|pyrimidine. To a stirred solution of 2,4,6,7-tetrachloropyrido[2,3-<7|pyrimidine (2.00 g, 7.44 mmol) hi tetrahydrofuran (100 mL) at -60 °C under nitrogen was added potassium iert-butoxide (1.0 M in THF, 8.9 mL, 8.9 mmol). The resulting mixture was stirred at -60 °C for 0.5 h. A total of 3 batches were combined for the workup and purification. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4. filtered and concentrated under reduced pressure. The crude material was purified by trituration with petroleum ether at room temperature for 30 min to afford 4-(tert-butoxy)-2.6.7-lrichloropyrido|2.3-T|pyriinidinc (3.70 g. 12.1 mmol, 54% yield), m / z (ESI): 250.1 (M-t-Bu+H)+.

[0228] Step 6. 4-(tert-Butoxy)-6,7-dichloro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[2,3-d]pyrimidine. To a stirred solution of 4-(tert-butoxy)-2,6,7- lrichloropyrido|2,3-d |pvrimidine (1.28 g, 4.18 mmol) in 1,4-dioxane (26 mL) at room temperature under nitrogen was added ((2R,7aS)-2 -fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methanol (0.67 g. 4.18 mmol) and N,N-diisopropylethylamine (0.73 mL, 4.18 mmol). The resulting mixture was stirred at 80 °C for 10 h. The reaction mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO i. filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 5 / 1 to 2 / 1 petroleum ether in EtOAc to afford 4-(fert-butoxy)-6.7-dichloro-2- (((2 / L 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d | pyrimidine (Intermediate D, 0.92 g, 2.14 mmol. 51% yield), m z (ESI): 429.2 (M+H)+.1H NMR (400 MHz, CDCb) 5 ppm 8.55 (s, 1 H). 5.20 - 5.36 (m, 1H), 4.05 - 4.20 (m, 2H ), 3.00 - 3.35 (m, 3H), 2.80 - 2.85 (m, 1H). 1.85 - 2.25 (m, 3H), 1.75 -1.84 (m, 3H). 1.69 (s. 9H).

[0229] Intermediate E: 7-Chloro-6-fluoro-2-(methylthio)-4-(2- (trimethylsilyl)ethoxy)pyrido|2,3-d |pyrirnidine11005-W001-SEC

[0230] Step 1. 2,6-Dichloro-5-fluoronicotinoyl chloride. To a solution of 2,6-dichloro-5- fluoronicotinic acid (40.0 g, 190 mmol) and DMF (1 mL) in dichloromethane (400 mL) at 0 °C under nitrogen was added oxalyl chloride (19.3 mL, 229 mmol) dropwise. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated rmder reduced pressure to afford crude 2.6-dichloro-5-fluoronicotinoyl chloride (45 g).

[0231] Step 2. Methyl (2,6-dichloro-5-fluoronicotinoyl)carbamimidothioate. To a solution of NaOH (13.6 g, 591 mmol) in water (510 mL) at 0 °C under nitrogen was slowly added 2-methyl-2- thiopseudourea hemisulfate (69.4 g, 250 mmol). The resulting mixture was stirred at 0 °C for 0.5 h. To the reaction mixture was added 2,6-dichloro-5-fluoronicotinoyl chloride (30 g, 131 mmol) as a solution in MTBE (390 mL). The reaction was then allowed to stir at 0 °C for 1.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SOi. filtered and concentrated under reduced pressure. The crude material was purified by trituration with petroleum ether at room temperature for 30 min. The suspension was filtered, and the filter cake was washed with MTBE to afford methyl (2,6-dichloro-5-fluoronicotinoyl) carbamimidothioate (33.0 g, 117 mmol. 89% yield). m / z (ESI): 282.0 (M+H)+.

[0232] Step 3. 7-Chloro-6-fluoro-2-(methylthio)pyrido[2,3-r / |pyrimidin-4-ol. To a solution of methyl (2.6-dichloro-5-fluoronicotinoyl)carbamimidothioate (50.0 g, 177 mmol) in DMF (500 mL) at room temperature under nitrogen was added NaHC'CA, (22.3 g, 266 mmol) then the mixture was stirred at 80 °C for 12 h. A total of 5 batches were combined for the workup and purification. The reaction mixture was diluted with water and adjusted to pH 2 using 6 M aq. solution of HC1 and the resulting mixture was extracted with EtOAc. The combined organic extracts were dried over Na2SOi. filtered and concentrated under reduced pressure. The crude material was purified by trituration with MTBE:petroleum ether (1:1) at room temperature for 20 min to afford 7-chloro-6-fluoro-2- (methylthio)pyrido[2,3-r / |pyrimidin-4-ol (Intermediate Q, 30.2 g, 123 mmol, 14% yield), m / z (ESI): 245.9 (M+H)+.!H NMR (400 MHz, DMSO-d6) 5 ppm 13.09 (s, 1H), 8.36 (d, J=7.6Hz, 1H), 2.57 (s, 3H).19F NMR (376 MHz, DMSO-d6) 5 ppm -122.86 (s, 1 F).11005-W001-SEC

[0233] Step 4. 7-Chloro-6-fluoro-2-(methylthio)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3- d\ yrimidine. To a stirred mixture of 7-chloro-6-fhioro-2-(methylthio)pyrido[2,3-<7|pyrimidin-4-ol (0.50 g, 2.00 mmol), (2-hydroxyethyl)trimethylsilane (0.44 mL, 3.1 mmol, Combi-Blocks Inc.) and triphenylpliosphine (0.80 g, 3.10 mmol) in toluene (14 mL) at room temperature was slowly added diisopropyl azodicarboxylate (1.5 mL, 7.53 mmol. Oakwood Products, Inc.). The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na:SOi. filtered, and concentrated under reduced pressure. The crude material was then purified via column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc hi heptane to provide 7-chloro-6-fluoro-2-(methylthio)-4-(2- (trimethylsilyl)ethoxy)pyrido[2,3-d |pyrimidine (Intermediate E, 0.55 g, 1.59 mmol, 78% yield), m / z (ESI): 346.0 (M+H)+.]H NMR (400 MHz, CDCl / ) 5 ppm 8.06 (d, J=6.9 Hz, 1H), 4.63 - 4.74 (m. 2H ), 2.70 (s, 3H), 1.22 - 1.26 (m, 2H ). 0.14 (s, 9H).

[0234] Intermediate F: 4-(Benzyloxy)-7-chloro-2-(((2R ,7aS)-2-fluorotetrahydro-1H- pyrr()lizin-7a(5W)-yl)methoxv)pyrirnido[4,5-d| pyrimidine

[0235] Step 1. 7-( Vlethylthio)pyrimido|4.5-< / ]pyrimidine-2.4(l / / .3 / / )-dione. To a stirred mixture of ethyl 4-amino-2-(methylthio)pyrimidine-5-carboxylate (2.00 g, 9.38 mmol. Ambeed) in tetrahydrofuran (37.5 mL) at room temperature under nitrogen was added trichloroacetyl isocyanate (2.7 mL, 14.1 mmol. Combi-Blocks Inc.) dropwise. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to half of the original volume under reduced pressure. The resulting suspension was triturated with heptane at room temperature for 15 min and the resulting solid was added to ammonia (7.0 M in MeOH, 20 mL, 140 mmol) at 0 °C under ambient atmosphere. The resulting mixture was stirred at room temperature for 2 h and the reaction mixture was filtered, and the filter cake washed with MeOH to afford 7-(methylthio)pyrimido[4,5- <7|pyrimidine-2,4(l / 7.3 / 7)-dione (2. 10 g. 9.99 mmol, quantitative yield), m / z (ESI): 211 .2 (M+H)+. *H NMR (400 MHz. DMSO-d / ) 5 ppm 8.67 (s, 1H). 7.84 - 6.73 (m, 4H), 2.50 (s, 5H).11005-W001-SEC

[0236] Step 2. 2,4-Dichloro-7-(methylthio)pyrimido[4,5-d |pyrimidine. To a stirred mixture of 7-(methylthio)pyrimido[4,5-<7|pyrimidine-2,4( l / / .3 / / )-dionc (0.93 g, 4.42 mmol) and phosphorus oxide trichloride (3.3 mL, 35.4 mmol) at room temperature under nitrogen, was added N,N- diisopropylethylamine (2.3 mL, 13.3 mmol). The resulting mixture was stirred at 100 °C for 2 h then the reaction mixture was then diluted with EtOAc and carefully quenched with sat. aq. solution of sodium bicarbonate at 0 °C. The resulting mixture was extracted with EtOAc, and 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% heptane in ethyl acetate to afford 2,4-dichloro-7-(methylthio)pyrimido[4,5- c / |pyrimidmc (0.56 g, 1. 1 mmol. 51% yield), m / z (ESI): 247.0 (M+H) ' . ’H NMR (400 MHz, DMSO- d() 5 ppm 9.18 (s, 1H). 2.59 (s. 3H).

[0237] Step 3. 4-(Benzyloxy)-2-chloro-7-(methylthio)pyrimido[4,5-d ]pyrimidine. To a stirred mixture of 2,4-dichloro-7-(methylthio)pyrimido[4,5-d ]pyrimidine (0.50 g, 2.02 mmol) and benzyl alcohol (1.3 mL. 12.1 mmol) in DCE (4.0 mL) at room temperature under ambient atmosphere, was added A.A iisopropy lethy lamine (1.1 mL, 6.07 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel. eluting with a gradient of 0-50% heptane in ethyl acetate. The mixture was further purified by 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 afford 4-(benzyloxy)-2-chloro-7-(methylthio)pyrimido[4,5-<f]pyrimidine (0.55 g, 1.73 mmol, 85% yield), m / z (ESI): 319.2 (M+H)+. ‘HNMR (400 MHz. CDC ) 5 ppm 9.31 (s, 1H). 7.60 - 7.37 (m, 5H), 5.69 (s, 2H ), 2.71 (s, 3H).

[0238] Step 4. 4-(Benzyloxy)-2-(((2R ,7aS )-2-fluorotetrahydro-1H-pyrrolizin-7a(57 / )- yl)methoxy)-7-(methylthio)pyrimido [4, 5-i / | pyrimidine. To a stirred mixture of 4-(benzyloxy)-2- chloro-7-(methylthio)pyrimido[4,5-d ]pyrimidine (0.55 g, 1.73 mmol) and ((2A’.7a.S)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (0.55 g, 3.45 mmol, Pharmablock, Inc.) in acetonitrile (5.7 mL) at room temperature under ambient atmosphere, was added AOV-diisopropylcthylaminc (1.2 mL, 6.90 mmol). The resulting mixture was stirred at 75 °C for 3 h then the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-60% dichloromethane in ethanokethyl acetate (1:3. 1% Et3N) to afford 4-(benzyloxy)-2-(((2 ,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(methylthio)pyrimido[4,5-d |pyrimidine (0.48 g, 1.09 mmol, 63% yield), m / z (ESI): 442.2 (M+H)+. ‘H NMR (400 MHz, CDCl3) 8 ppm 9. 17 (s, 1H), 7.43 (s, 5H). 5.64 (s, 2H ), 5.46 - 5.16 (m. 1H), 4.60 - 4.20 (m. 2H ), 3.53 - 2.95 (m. 4H), 2.69 (s, 3H), 2.41 - 1.90 (m, 6H).11005-W001-SEC

[0239] Step 5. 4-(Benzyloxy)-7-chloro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrimido[4,5-d |pyrimidine. To a stirred mixture of 4-(benzyloxy)-2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5f / )-yl)methoxy)-7-(methylthio)pyrimido[4,5-<7|pyrimidine (0.45 g. 1.02 mmol) in dichlorometliane (5.1 mL) and tetrahydrofuran (5.1 mL) at 0 °C under nitrogen, was added sulfuryl chloride (0.66 mL, 8.15 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was carefully diluted with sat. aq. solution of sodium bicarbonate 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 0-100% dichloromethane in ethanohethyl acetate (1:3. 1% Et3N) to afford 4-(benzyloxy)-7-chloro-2-(((2R,7aS)-2-fluorotetrahydro- 1H- pyrrolizin-7a(5L / )-yl)methoxy)pyrimido[4,5-i / |pyrimidine (Intermediate F, 0.16 g, 0.37 mmol, 37% yield), m / z (ESI): 430.2 (M+H)+. *H NMR (400 MHz. CDCl3) 5 ppm 9.30 (s, 1H). 7.64 - 7.42 (m, 5H), 5.68 (s, 2H ), 5.50 - 5.15 (m. 1H), 4.62 - 4.35 (m. 2H ), 3.65 - 2.82 (m. 4H), 2.50 - 1.91 (m. 6H).

[0240] Intermediate G: tert-Butyl (2S.4R)-2-((((1R S.2.SR)-2-(6-cliloro-l-(tetr ahydro -2H- pyran-2-yl)-4-(4,4,5,5-tetramethyl-l ,3,2-dioxahorolan-2-yl)- 1H-indazol-5- yl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate.

[0241] Step 1: roc- Ethyl ( lR,2,S')-2-(4-hromo-6-chloro-l-(tetrahydro-2 / f-pyran-2-yl)-1H- indazol-5-yl)cyclopropane-l-carboxylate. A stirred solution of 4-bromo-6-chloro-5-iodo-l-(tetrahydro-2 / f-pyran-2-yl)-1H-indazole (0.75 g. 1.70 mmol, Lab Network), rac-ethyl (lR.2S)-2-(tetramethyl-1.3.2-dioxaborolan-2-yl)cyclopropane-l-carboxylate (0.49 mL. 2.04 mmol, Enamine).PdC12(dppf) (0.12 g, 0.17 mmol), potassium phosphate tribasic (1.26 g, 5.95 mmol) in toluene (5 mL) and water (1 mL) at room temperature under nitrogen was stirred at 100 °C for 16 h. The reaction11005-W001-SEC mixture was concentrated under reduced pressure and the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc / heptane to afford rac-ethyl (15,2>S)-2-(4-bromo-6-chloro-l-(tetrahydro-27 / -pyran-2-yl)- 1H-indazol-5-yl)cyclopropane-l- carboxylate (0.24 g, 0.56 mmol, 33% yield), m / z (ESI): 448.8 (M+Na)+.

[0242] Step 2. rac-((l R,25)-2-(4-Bromo-6-chloro-l-(tetrahydro-2H-pyran-2-yl)-l H-indazol-5- yl)cyclopropyl)methanol. To a stirred solution of rac-ethyl (lR,2S)-2-(4-bromo-6-chloro-l- (tetrahy dro-2H -pyran-2-yl)- 1 H-indazol-5-yl)cyclopropane- 1 -carboxy late (0.95 g, 2.23 mmol) in tetrahydrofuran (6 mL) at -78 °C under nitrogen was slowly added diisobutvlahiminiim hydride (1.0 M in DCM, 5.6 mL, 5.6 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was carefully poured into 10% aq. solution of Rochelle’s salt pre-cooled to 0 °C. The mixture was extracted with EtOAc, and the combined organic layers were dried over Na2SO ,. filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-60% EtOAc / heptane to afford rac-((lR,2S)-2-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)methanol (0.69 g, 1.78 mmol, 80% yield), m / z (ESI): 384.8 (M+H)+.

[0243] Step 3. tert-Butyl (2S.4R)-2-((((1RS .2SR )-2-(4-l)romo-6-chloro-l-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6- carboxylate. To a stirred solution of (( lR,2S)-2-(4-bromo-6-chloro-l-(tctrahydro-2J / -pyran-2-yl)-1H- mdazol-5-yl)cyclopropyl)methanol (5.00 g, 13.0 mmol) and tert -butyl (35,5S)-l-oxa-7- azadispiro[2.1.5'.l’]undecane-7-carboxylate (3.28 g, 12.96 mmol) in toluene (100 mL) at room temperature under nitrogen was added yttrium(III) trifluoromethanesulfonate (1.80 g, 3.24 mmol).The reaction mixture w as stirred at 50 °C for 10 h. The reaction mixure was diluted with w ater and extracted with EtOAc. 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 (0.1% NH4OH / water) to afford tert-butyl (2S,4R)-2-((((lR,25)-2-(4-bromo-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methoxy)methyl)-2-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (12.0 g, 17.5 mmol, quantitative yield), m / z' (ESI): 540.0 (M- Boc+H)+.

[0244] Step 4. tert- Butyl (25,4R)-2-((((1R5,25R)-2-(6-chloro-l-(tetrahydro-2H -pyran-2-yl)-4- (4,4,5,5-tctrarncthyl-l,3,2-dioxaborolari-2-yl)-1H-iridazol-5-yl)cyclopropyl)rnctho\y)rnethyl)-2- hydroxy-6-azaspiro[3.5]nonane-6-carboxylate. A stirred solution of tris(4- methoxyphenyl)phosphine (0.18 g, 0.52 mmol), palladium (II) acetate (97 mg, 0.43 mmol), bis(pinacolato)diboron (1.64 g, 6.46 mmol), cesium carbonate (2.80 g, 8.61 mmol), tert-butyl (25, 4R)- 2-(((( 01RS2SR)-2-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)- 1H-indazol-5- yl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (2.75 g. 4.30 mmol) in ethyl acetate (20 mL) at room temperature under nitrogen was heated to 80 °C for 2 h. The11005-W001-SEC reaction mixture was filtered through 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- 100% EtOAc / heptane to afford tert-butyl (2S.4R)-2-((((1RS,2SR)-2-(6-chloro-l-(tetrahydro-2H - pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)methoxy)methyl)-2-hydro.xy-6-azaspiro[3.5]nonane-6-carbox late (Intermediate G, 1.74 g, 2.54 mmol, 59% yield), rn / z (ESI): 659.8 (M+Na)+. ’H NMR (400 MHz, CDCl3) δ ppm 8.12 - 7.93 (m, 1H), 7.70 - 7.51 (m, 1H), 5.74-5.56 (m, 1H), 4.07 - 3.97 (m, 1H), 3.88 - 3.68 (m, 2H ), 3.52 - 3.13 (m. 6H), 2.88 - 2.61 (m. 2H ), 2.59 - 2.39 (m. 1H), 2.19 - 2.11 (m, 2H ), 1.92 - 1.57 (m, 10H), 1.55 - 1.38 (m, 14H).

[0245] Intermediate H: 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H - pyran-2-yl)-4-(4,4,5,5-tetramethyl-l ,3,2-dioxahorolan-2-yl)-1 H-indazole.Intermediate H

[0246] Step 1. 3-(4-Bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)propanal.To a stirred solution of 4-bromo-6-chloro-5-iodo- l-(tetrahydro-2h-pyran-2-yl)- IH-inda / olc (3.00 g, 6.80 mmol, Lab Network), sodium bicarbonate (1.43 g, 17.0 mmol), TBACI (1.95 h, 6.82 mmol) in N,N-dinicthylfonnamidc (14 mL) at room temperature under nitrogen was added palladium(II) acetate (77 mg, 0.34 mmol) and allyl alcohol (0.7 mL, 10 mmol). The reaction mixture was stirred at 50 °C for 8 h. The reaction was diluted with sat. aq. solution of ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SOi. filtered and concentrated under reduced pressure. The crude material was purified via column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc / EtOH (3:1) in heptane to afford 3-(4-bromo-6- chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)propanal (2.12 g. 5.70 mmol, 84% yield), m / z (ESI): 371.0 (M+H)+.11005-W001-SEC

[0247] Step 2. 3-(4-Bromo-6-chloro-l-(tetrahydro-2E / -pyran-2-yl)-lE / -indazol-5-yl)propan-l- ol. To a stirred mixture of 3-(4-bromo-6-chloro-l -(tctrabydro-2 / / -pyran-2-yl)-l / / -indazol-5- yl)propanal (1.06 g, 2.86 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) at 0 °C under nitrogen was slowly added sodium borohydride (0.11 g, 2.86 mmol) in portions. The resulting mixture was stirred at 0 °C for 30 min. The reaction was carefully quenched 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 under reduced pressure to afford 3-(4- bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)propan-l-ol (1.03 g, 2.76 mmol, 97% yield).

[0248] Step 3. 4-Bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2 / f- pyran-2-yl)-l / / -indazole. To a stirred solution of3-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)- 1H-indazol-5-yl)propan-l-ol (1.03 g, 2.76 mmol) and A,A-diisopropylethylamine (0.53 mL, 3.00 mmol) in dichloromethane (10 mL) at 0 °C was added tert-butyldimethylsilyl chloride (0.46 g, 3.03 mmol) and 4-(dimethylamino)pyridine (34 mg, 0.28 mmol). The resulting mixture was stirred at 0 °C for 2 h and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-30% EtOAc / EtOH (3:1) in heptane to afford 4-bromo-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H- indazole (1.12 g, 2.30 mmol, 83% yield). m,z (ESI): 487.1 (M+H)1.

[0249] Step 4. 5-(3-((ter / -Butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2E / -pyran-2- yl)-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-vl)-1H-indazole. To a solution of 4-bromo-5-(3- (( / ert-butyldimethylsilyl)oxy)propyl)-6-chloro- 1 -(tetrahydro-2H -pyran-2-yl)- 1H-indazole (3.40 g, 7.00 mmol) and bis(pinacolato)diboron (8.85 g, 34.8 mmol) in 1,4-dioxane (80 mL) and water (10 mL) was added PdC12(dppl (0.51 g, 0.70 mmol) and CS2CO3 (6.81 g, 20.9 mmol). The reaction mixture was flushed with nitrogen and heated at 120 °C for 5 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 10-100% EtOAc in petroleum ether, to afford 5-(3-((Zert- butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2f / -pyran-2-yl)-4-(4,4,5.5-tetramethyl-l,3,2- dioxaborolan-2-yl)- 1H- indazole (Intermediate H, 3.30 g, 6.20 mmol, 88% yield), m / z (ESI): 535.3 (M+H)+.

[0250] Intermediate I: l-Amino-4-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H- indazol-5-yl)butan-2-one.11005-W001-SECIntermediate I

[0251] Step 1. 4-(4-Bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)butan-2- one. To a solution of 4-bromo-6-chloro-5-iodo-l-(tetrahydro-2H -pyran-2-yl)-1H-indazole (2.04 g, 4.62 mmol, Pharmablock, Inc ), sodium bicarbonate (0.97 g, 11.6 mmol) and TBAC1 (1.28 g. 4.62 mmol) in A,A-dimethyl formamide (10 mL) at room temperature under nitrogen was added palladium(II) acetate (52 mg, 0.23 mmol) and 3-buten-2-ol (0.6 mL, 6.9 mmol). The resulting mixture was stirred at 65 °C for 68 h. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over Na^SOi. filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in heptane to afford 4-(4-bromo-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)butan-2-one (1.42 g. 3.68 mmol, 80% yield). m / z (ESI): 406.9 (M+Na)+.

[0252] Step 2. l-Bromo-4-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5- yl)butan- 2-one. To a stirred solution of lithium diisopropylamide (1 M in THF / hexanes. 4.1 mL. 4.1 mmol) in tetrahydrofuran (35 mL) at -78 °C under nitrogen was slowly added 4-(4-bromo-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)butan-2-one (1.33 g. 3.45 mmol) in THF (8 mL). The reaction mixture was stirred at -78 °C for 30 minutes before chlorotrimethylsilane (0.70 mL, 5.5 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for an additional 30 min. The reaction mixture was diluted with sat. aq. solution of sodium bicarbonate and allowed warm to room temperature. The mixture was extracted with EtOAc, and the organic extracts were dried over Na^SOi. filtered and concentrated under reduced pressure. The crude product was dissolved in THF (10 mL) and cooled to 0 °C. Sodium bicarbonate (0.44 g, 5.17 mmol) and A-bromosuccinimide (0.61 g, 3.45 mmol) were then added and the mixture was stirred at room temperature for 15 h. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with 0-100% EtOAc in heptane, to afford 1-11005-W001-SEC bromo-4-(4-bromo-6-chloro- 1 -(tctraliydro-2 / -pyran-2-y 1)- 1 H-indazol-5-y l)butan-2-one (1.16 g, 2.50 mmol, 72% yield), m / z (ESI): 462.8 (M+H)+.

[0253] Step 3. l-Azido-4-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5- yl)butan- 2-one. To a stirred solution of 1 -bromo-4-(4-bromo-6-chloro- l-(tetrahydro-2H -pyran-2-yl)- 1H-indazol-5-yl)butan-2-one (1.16 g, 2.50 mmol) in acetone (10 mL) was added sodium azide (0.21 g, 3.30 mmol). The resulting mixture was stirred at room temperature for 2 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in heptane, to afford l-azido-4-(4-bromo-6-chloro-l-(tctrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)butan-2-onc (0.70 g, 1.64 mmol, 66% yield), m / z (ESI): 448.0 (M+Na)+.

[0254] Step 4. l-Amino-4-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-l H-indazol-5- yl)butan- 2-one. To a suspension of 5% Pd on activated carbon (5.00 g. 46.9 mmol) in ethanol (1 L) was added l-azido-4-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)butan-2-one (20.0 g, 46.9 mmol) and HO (4 M in 1,4-dioxane, 8.0 mL, 32 mmol). The suspension was purged with hydrogen and the resulting mixture was stirred under 15 psi of hydrogen at room temperature for 15 min. The reaction was filtered tiirough celite, and the filtrate concentrated under reduced pressure. The crude material was triturated with ethyl acetate to afford l-amino-4-(4-bromo-6-chloro-l- (tctrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)butan-2-onc (Intermediate I, 8.50 g, 19.4 mmol, 42% yield).

[0255] Intermediate J: tert- Butyl (2S,4R)-2-(5-(2-(6-chloro-l-(tetrahydro-2H -pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate.11005-W001-SEC

[0256] Step 1. tert- Butyl 2-cyano-2-((trimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate.To a solution of tert-butyl 2-oxo-6-azaspiro[3.5]nonane-6-carboxylate (200 g, 836 mmol) in tetrahydrofuran (500 mL) was added TMSCN (118 mL, 878 mmol) at -78 °C under N2, then w-BuLi (2.5 M in hexanes, 16.71 mL, 41.8 mmol) was added dropwise at -78 °C. Then the mixture was stirred at room temperature for 12 h. A total of 2 batches were combined for the workup and purification. The reaction mixture was quenched by addition of H2O and extracted with EtOAc. The combined organic layers were dried over Na2SOi. filtered and concentrated under reduced pressure to afford lert- butyl 2-cyano-2-((trimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate (560 g, crude). ' H NMR (400 MHz, DMSO-d6) 5 ppm 3.44 (s, 1 H), 3.30 (s, 1 H). 3.18 - 3.25 (m, 2 H). 2.51 - 2.57 (m, 1 H). 2.46 (s, 1 H), 2.11 - 2.20 (m, 1 H), 2.02 - 2.09 (m, 1 H), 1.61 - 1.69 (m, 1 H), 1.52 - 1.59 (m. 1 H), 1.37 - 1.43 (m, 11 H), 0.18 - 0.23 (m. 9 H).

[0257] Step 2. 2-Hydroxy-6- azaspiro [3.5] nonane-2-carboxylic acid. A mixture of tert-butyl 2- cyano-2-((trimethylsilyl)oxy)-6-azaspiro[3.5]nonane-6-carboxylate (57 g. 168 mmol) in HC1 (12 M in water, 85 mL, 1.02 mol) was purged with N2, and the resulting mixture was stirred at 50 °C for 2 h. A total of 6 batches were combined for the workup and purification. The reaction mixture was concentrated under reduced pressure. The resulting solid was dissolved in water and basified to pH 11 using solid sodium carbonate. The aqueous solution of 2-hydroxy-6-azaspiro[3.5]nonane-2-carboxylic acid was used in the next step without further purification.

[0258] Step 3. 6-(tert-Butoxycarbonyl)-2-hydroxy-6-azaspiro[3.5]nonanc-2-carboxylic acid.To a stirred mixture of 2-hydroxy-6-azaspiro[3.5]nonane-2 -carboxy lie acid (aq. solution, 500 mL, 168 mmol), and NaHCOs (28.3 g, 337 mmol) in tetrahydrofuran (300 mL) at room temperature under nitrogen was added BOC2O (59 mL, 253 mmol). The resulting mixture was stirred at room temperature for 16 h. A total of 6 batches were combined for the workup and purification. The aqueous layer pH was adjusted to pH 4 and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by trituration with petroleum etherEtOAc (10: 1) at room temperature for 60 min to afford 6-(tert- butoxycarbonyl)-2-hydroxy-6-azaspiro[3.5]nonane-2 -carboxylic acid (200 g, 704 mmol. 70% yield). m / z (ESI): 284.2 (M-H)’.11005-W001-SEC

[0259] Step 4. Methyl 2-hydroxy-6-azaspiro[3.5]nonane-2-carboxylate. To a solution of 6-(tert- butoxycarbonyl)-2-hydroxy-6-azaspiro[3.5]nonane-2-carboxylic acid (15.0 g, 52.6 mmol) in methanol (150 inL) at 0 °C under nitrogen was added SOCf (7.7 mL, 105 mmol) dropwise. The mixture was stirred at room temperature for 4 h. A total of two batches were combined for the workup and purification. The reaction mixture was concentrated under reduced pressure to afford methyl 2- hydroxy-6-azaspiro[3.5]nonane-2-carboxylate (18 g, crude).

[0260] Step 5. (25,4R)-2-Hydroxy-6-azaspiro[3.5]nonane-2,6-dicarboxylate. A solution of methyl 2-hydroxy-6-azaspiro[3.5]nonane-2 -carboxylate (18.75 g. 94 mmol) in water (37.5 mL) was basificd to pH 11 using solid ICCCh. To the resulting mixture w as added tetrahydrofuran (113 mL), Na:CCh (20.0 g, 188 mmol) and BOC2O (33 mL, 141 mmol). The reaction mixture was stirred at room temperature for 12 h. A total of 4 batches were combined for the workup and purification. The reaction mixture was diluted with w ater and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO.. filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 5 / 1 to 1 / 1 petroleum ether in ethyl acetate. The product was further purified by prep HPLC on a Welch Xtimate 250 mm x 100 mm, C18 column, eluting with a gradient of 10-50% MeCN in water (10 inM NH4HCO3) to afford (2S.4R)-2-hydroxy-6-azaspiro[3.5]nonane-2,6-dicarboxylate (52 g, 174 mmol, 47% yield). *H NMR (400 MHz, CDCL) 5 ppm 3.84 (s, 3H). 3.41 (s, 3H), 3.29 - 3.32 (m, 2H ). 2.45 - 2.48 (m, 2H ), 1.89 - 1.92 (m. 2H ), 1.72 - 1.75 (m, 2H ), 1.48 - 1.51 (m, 2H ). 1.46 (s, 9H).

[0261] Step 6. 6- (tert- Butyl) 2-methyl (25,4R)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane- 2,6-dicarboxylate. To a stirred solution of 6-( / ert-butyl) 2-methyl (2S,4R)-2-hydroxy-6- azaspiro[3.5]nonane-2.6-dicarboxylate (23.5 g, 78 mmol) and MX-diisopropylcthylaniinc (62 mL, 353 mmol) in dichloromethane (235 mL) at room temperature under nitrogen was added bromomethyl methyl ether (26 mL, 314 mmol). The resulting mixture was stirred at 40 °C for 12 h. A total of 3 batches were combined for the workup and purification. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over NajSCL. filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 10 / 1 to 0 / 1 petroleum ether in EtOAc to afford 6-(ter / -butyl) 2-methyl (2S.4R)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-2.6-dicarboxylate (50 g. 146 mmol, 97% yield).

[0262] Step 7. (25',4^?)-6-(tert-Butoxycarbonyl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-2- carboxylic acid. To a stirred solution of 6-( / ert-butyl) 2-methyl (2.S'.4R)-2-(mcthoxymcthoxy)-6- azaspiro[3.5]nonane-2.6-dicarboxylate (25 g, 72.8 mmol) in tetrahydrofuran (250 mL) and water (25 mL) at room temperature was added LiOH*lLO (12.2 g, 291 mmol). The resulting mixture was stirred at 40 °C for 2 h. A total of 3 batches (25 g, 25 g and 15 g) were combined for the workup and purification. The reaction mixture was diluted with water and extracted with EtOAc. The combined11005-W001-SEC organic extracts were washed with brine, dried over Na^SO i. filtered and concentrated under reduced pressure to afford f2.S'.4R)-6-f / ert-butoxy carbony l)-2-(methoxymethoxy)-6-azaspiro [3.5]nonane-2- carboxylic acid (60 g, 182 mmol, quantitative yield), m / z (ESI): 328.2 (M-H)’.

[0263] Step 8. tert- Butyl (2 ,47f)-2-((4-(4-bromo-6-chIoro-l -(tetrahydro- 2H -pyran-2-yl)-1H- indazol-5-yl)-2-oxobutyl)carbamoyl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate.To a solution of (2S,4R)-6-(ter / -butoxycarbonyl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-2- carboxylic acid (5.00 g, 15.18 mmol), l-amino-4-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)- lJ / -indazol-5-yl)butan-2-one (Intermediate I, 6.08 g, 15.18 mmol) and PyBOP (8.69 g, 16.70 mmol) in DMF (50mL) at room temperature was added A'. / -diisopropylcthylaminc (5.89 g, 45.5 mmol). The resulting mixture was stirred at room temperature for 4 h. A total of 4 batches were combined for the workup and purification. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 3 / 1 to 2 / 1 petroleum ether in EtOAc to afford ZerZ-butyl (2S,4R)-2-((4-(4-bromo-6- chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)-2-oxobutyl)carbamoyl)-2-(methoxymethoxy)- 6-azaspiro[3.5]nonane-6-carboxylate (48 g, 67 mmol, 63% yield).

[0264] Step 9. tert- Butyl (2S.4R)-2-(5-(2-(4-bromo-6-chIoro-l-(tetrahydro-2H -pyran-2-yl)-1H- indazol-5-yl)cthyl)oxazol-2-yl)-2-(mcthoxymcthoxy)-6-azaspiro[3.5]nonanc-6-carboxylate. To a solution of tert-butyl (2S,4 / ?)-2-((4-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5- yl)-2-oxobutyl)carbamoyl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate (6.00 g, 8.43 mmol) in toluene (60 mL) at room temperature was added Burgess Reagent (12.1 g, 50.6 mmol). The resulting mixture was stirred at 110 °C for 2 h. A total of 2 batches were combined for the workup and purification. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over NaiSOi. filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel. eluting with a gradient of 5 / 1 to 3 / 1 petroleum ether in EtOAc to afford ZerZ-butyl (2.S',4R)-2-(5-(2-(4-bromo-6-chloro-l-(tetrahydro-2H - pyran-2-yl)-lL / -indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6- carboxylate (8.00 g, 11 mmol, 68% yield).

[0265] Step 10. tert- Butyl (2>S',4R)-2-(5-(2-(6-chloro-l-(tetrahvdro-2H -pyran-2-vl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6- azaspiro[3.5]nonane-6-carboxylate. To a stirred solution of tert-butyl (2S.4R)-2-(5-(2-(4-bromo-6- chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6- azaspiro[3.5]nonane-6-carboxylate (4.00 g, 5.76 mmol) in 1,4-dioxane (80 mL) and water (10 mL) at room temperature under nitrogen was added CS2CO3 (5.63 g, 17.3 mmol). PdCL(dppf) (0.42 g, 0.58 mmol) and bis(pinacolato)diboron (7.32 g, 28.8 mmol). The resulting mixture was stirred at 100 °C for 1 h. A total of 4 batches (4 g, 4 g, 2.3 g, 1 g) were combined for the workup and purification. The11005-W001-SEC reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na^SOi. filtered and concentrated under reduced pressure. The crude material was purified by reversed phase MPLC to afford tert-butyl (2S.4R)-2-(5-(2-(6-chloro-l-(tetrahydro-2H -pyran-2-yl)- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1H-indazol-5-yl)ethyl)oxazol-2-yl)-2- (methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate (Intermediate J, 9.30 g, 12.6 mmol, 61% yield), m / z (ESI): 714.4 (M+H)+. ’HNMR (400 MHz, CDCl3) 5 ppm 8.36 (s, 1H), 7.76 (s, 1H), 6.78 (s, 1H), 5.65 - 5.68 (m. 1H), 4.60 (s, 2H ), 3.98 - 4.01 (m. 1H), 3.71 - 3.77 (m, 1H), 3.45 - 3.49 (m, 2H ), 3.31 (s, 5H), 3.24 (s, 2H ), 2.88 - 2.92 (m, 2H ), 2.66 - 2.69 (m, 2H ), 2.46 - 2.55 (m, 1H). 2.13 - 2.19 (m, 3H), 2.05 - 2.07 (m. 1H), 1.65 - 1.78 (m, 5H), 1.50 - 1.57 (m, 2H ), 1.36 - 1.41 (m, 21 H).

[0266] Intermediate L: tert-Butyl (3R)-3-(((2-((lR.S’,2R.S')-2-(6-chloro-l-(tetrahydro-2H -pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y])-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate

[0267] Step 1. rac-(1R ,2S)-2-(4-Bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5- yl)cyclopropane-l-carbaldehyde. To a solution of rac-((1R,2S)-2-(4-bromo-6-chloro)-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methanol (Intermediate K, 5.00 g, 13.0 mmol) in dichloromethane (75 mL) was added Dess-Martin periodinane (11.0 g, 25.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The mixture was filtered, and tire filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 5-10% EtOAc in petroleum ether to afford rac-(1R,2S)-2-(4- bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)cyclopropane-l-carbaldehyde (4.16 g, 10.9 mmol, 85% yield).

[0268] Step 2. rac-4-Bromo-6-chloro-5-((1S,2R )-2-((Z)-2-methoxyvinyl)cyclopropyl)-l- (tetrahydro-2H -pyran-2-yl)-l / / -indazole. To a mixture of (methoxymethyltriphenylphosphonium (24.0 g, 78 mmol) in tetrahydrofuran (200 mL) at 0 °C under nitrogen was added t-BuOK (1.0 M in THF, 78 mL, 78 mmol) dropwise. The reaction mixture was stirred at 0 °C for 30 min before rac- (1R,2.S)-2-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)cyclopropane-l-11005-W001-SEC carbaldehyde (10.0 g, 26.1 mmol) was added dropwise as a solution in tetrahydrofuran (200 mL). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a gradient of 5-10% EtOAc in petroleum ether to provide rac-4-bromo-6-chloro-5-((lS,2 )-2-((Z)-2-methoxyvinyl)cyclopropyl)-l-(tetrahydro-27T-pyran-2-yl)- IH-indazolc (9.62 g. 23 mmol, 90% yield).

[0269] Step 3. Rac-2-((15',25)-2-(4-Bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)acetaldehyde. To a mixture of rac-4-bromo-6-chloro-5-((lS,2 )-2-((Z)-2- methoxyvinyl)cyclopropyl)-l -(tetrahydro-2Ef-pyran-2-yl)-l / / -indazole (33 g, 80 mmol) in 1,4- dioxane (790 mL) and water (130 mL) at room temperature was added pyridine 4- methylbenzenesulfonate (32.4 g, 128 mmol). The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried overNa2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 5-10% EtOAc in petroleum ether to provide rac-2-((lS.2S)-2-(4-bromo-6-chloro-l-(tetrahydro-2Lf-pyran-2- yl)-lLf-indazol-5-yl)cyclopropyl)acetaldehyde (20.0 g. 50.3 mmol, 63% yield).

[0270] Step 4. Rac-2-(( l.S.2.S)-2-(4-Bromo-6-chloro-l-(tcti ah}(ln)-2H -pyran-2-)l)-l H-indazol- 5-yl)cyclopropyl)ethan-l-ol. To a mixture of rac-2-(( lS,2S)-2-(4-bromo-6-chloro- 1 -(tctrabydro-2 / / - pyran-2-yl)-lL7-indazol-5-yl)cyclopropyl)acetaldehyde (20.0 g, 50.3 mmol) in ethanol was added NaBH4(3.23 g, 85 mmol) at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction mixture was carefully quenched with sat. aq. solution of ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 20-35% EtOAc in petroleum ether to provide rac-2-((l>S',2S)-2-(4- bromo-6-chloro- 1 -(tetrahy dro-2H -py ran-2-y 1)- 1H-indazol-5-yl)cy clopropy l)ethan- 1 -ol (Intermediate L, 19.1 g, 48.0 mmol, 95% yield), m / z (ESI): 401.0 (M+H)+. *H NMR (400 MHz. DMSO-d6) 5 ppm 8.06 (s, 1H), 7.99 (s. 1H), 5.87 (dd. J = 9.6, 2.4 Hz, 1H). 4.29 - 4.33 (m, 1H). 3.85 - 3.88 (m, 1H). 3.76 - 3.77 (m, 1H). 3.36 - 3.41 (m, 2H ). 2.29 - 2.38 (m, 1H). 1.97 - 2.03 (m, 3H), 1.84 - 1.86 (m, 1H), 1.69 - 1.73 (m. 1H), 1.54 - 1.60 (m. 2H ), 1.38 - 1.48 (m. 1H), 1.31 - 1.37 (m. 1H), 0.80 - 0.92 (m, 1H), 0.20 - 0.26 (m, 1H).

[0271] Intermediate O: (Z)-4-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3-en-l-ol.11005-W001-SECIntermediate 0

[0272] 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-(mcthoxymcthoxy)bcnzcnc (1.87 g, 4.95 mmol), 3-butyn-l-ol (0.49 mL, 6.44 mmol) and TEA (7.0 mL, 49.5 mmol) in DMA (10 m ) was added bis(triphenylphosphine)palladium(II) dicliloride (57 mg, 0.081 mmol) and copper(I) iodide (28 mg, 0.15 mmol) at room temperature under N2 (degassed for 5 min). The resulting mixture was stirred at 80 °C for 90 min. After cooling to room temperature, the reaction mixture was diluted with sat. aq. solution of ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with sat. aqueous solution of lithium chloride, then 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% EtOAc 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, CDCI3) 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).

[0273] Step 2. (Z)-4-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)but-3-en-l-ol(Intermediate O). 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 Schwartz’s reagent (3.23 g, 12.5 mmol) under N2. 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 EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give (Z)-4-(2-bromo- 6-chloro-4-(methoxymethoxy)phenyl)but-3-en-l-ol (Intermediate O, 0.49 g. 1.52 mmol, 49% yield). m / z (ESI): 343.0 (M+Na)+. *H NMR (400 MHz. CDCI3) 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 ).

[0274] Intermediate P: 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-1 -carboxylate.11005-W001-SEC

[0275] Step 1. tert- Butyl (R)-3-methvl-3-(((4-nitrophcnoxy)carbonyl)arni no) pi peridi ne-1- carboxylate. To a stirred mixture of DIPEA (0.31 mL, 1.8 mmol) and tert-butyl (3R)-3-amino-3- methyl-piperidine-1 -carbox late (0.38 mL, 1.8 mmol) in ACN (3.5 mL) was added 4-nitrophenyl chloroformate (0.38 g, 1.9 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 1 h. The resulting solution was used as is in the next step. m'z (ESI): 402.0 (M+Na)+.

[0276] Step 2. tert-Butyl (R,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 O, 0.45 g, 1.40 mmol) and DIPEA (0.61 mL, 3.50 mmol) in ACN (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 chromatography, eluting using a gradient of 5-100% ACN (0.1% formic acid) in water (0.1% formic acid), to give tert-butyl (R,Z)-3-((((4-(2-bromo-6-chloro-4-(methoxy methoxy )phenyl)but-3-en- 1 -yl)oxy)carbonyl)amino)-3-methylpiperidine- 1 -carboxy late (0.30 g, 0.53 mmol, 31% yield), m / z (ESI): 583.0 / 585.0 (M+Na)+. *H NMR (400 MHz, CDCl3) 5 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 (m, 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).[002H ] Step 3. 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-11005-W001-SEC carboxylate. To a stirred and degassed mixture of palladium(II) acetate (17 mg, 0.077 mmol), cesium carbonate (0.37 g, 1.20 mmol), tert-butyl (7?,Z)-3-((((4-(2-bromo-6-chloro-4-(methoxy methoxy )phenyl)but-3-en- 1 -yl)oxy)carbonyl)amino)-3-methylpiperidine- 1 -carboxy late (0.43 g, 0.77 mmol) and tris(4-methoxyphenyl)phosphine (54 mg, 0.15 mmol) in EtOAc (1.5 mL) under N2, was added bis(pinacolato)diboron (0.25 g, 1.00 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% EtOAc 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 P, 0.34 g. 0.56 mmol, 73% yield), m / z (ESI): 631.2 (M+Na)+.

[0278] Intermediate R: r«c-((lR,2 )-2-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl) methanolIntermediate R

[0279] 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) and DIPEA (1.6 mL. 9.0 mmol) in DCM (10 mL) at room temperature under N2was added MOM-Br (0.5 mL, 6.0 mmol). The resulting mixture was stirred at 40 °C for 1 h. then diluted with sat. aq. solution of sodium bicarbonate and extracted with EtOAc. The combined organic extracts were washed with sat. aq. solution of sodium bicarbonate, water, and 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). m,'z (ESI): 377.8 (M+H)+. 'HNMR (400 MHz, DMSO-d 5 ppm 7.53 - 7.35 (m, 1H), 7.34 - 7.22 (m, 1H), 5.35 - 5.16 (m, 2H ), 3.38 (s, 3H).11005-W001-SEC

[0280] Step 2. rac-Ethyl (lR,25)-2-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropane-l-carboxylate. To a stirred mixture of l-bromo-3-chloro- 2-iodo-5-(methoxymethoxy)benzene (1.80 g, 4.77 mmol), rac-cis -ethyl (lR,2S)-2-(tetramethyl-l,3,2- dioxaborolan-2-yl)cyclopropane-l-carboxylate (1.48 g, 6.20 mmol), potassium phosphate (3.04 g, 14.3 mmol) and Pd(dppl)C12 (0.35 g, 0.48 mmol) at room temperature under N2 was added toluene (10 mL) and water (2 mL). The resulting mixture was sparged with N2for 15 min and stirred at 100 °C for 6 h. The resulting reaction mixture was cooled to room temerature. filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel. eluting using a gradient of 0-50% EtOAc in heptane, to give rac -ethyl (lR.2,S)-2-(2-bronio-6-chloro-4-(methoxymethoxy)phenyl)cyclopropane-l -carboxylate (0.98 g, 2.69 mmol, 56% yield), m / z (ESI): 362.9 (M+H)+.!H NMR (400 MHz, DMSO-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).

[0281] Step 3. rac-((1R,2S)-2-(2-Bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl) methanol (Intermediate R). 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 N2was added 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 resulting mixture was cooled to 0 °C and carefully diluted with sat. aq. solution of Rochelle’s salt (10 mL), then stirred for 15 min. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over sodium sulfate, fdtered, and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting using a gradient of 0- 80% EtOAc in heptane, to give rac-((lA,2S)-2-(2-bromo-6-chloro-4-(methoxymethoxy)phenyl)cyclopropyl) methanol (Intermediate R. 0.70 g, 2.17 mmol, 81% yield). m / z (ESI): 342.9 (M+Na)+. *H NMR (400 MHz, DMS0-d6) 8 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).

[0282] Intermediate S: tert- Butyl (2A',4R)-2-((((l S',2.$R)-2-(2-chloro-4-(mcthoxymethoxv)-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.11005-W001-SECIIntermediate S

[0283] Step 1 : tert-Butyl (2.S,4R)-2-(((( 1RS,2SR )-2-(2-bromo -6-chloro)-4-(methoxymethoxy)phenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6- carboxylate. To a stirred mixture of rac-((17?,2>S)-2-(2-bromo-6-chloro-4-(methoxy methoxy )phenyl)cyclopropyl)methanol (Intermediate R, 0.70 g, 2.2 mmol) and yttrium(III) trifluoromethanesulfonate (0.29 g, 0.54 mmol) in toluene (11 mL) was added tert-butyl (3S,5R)-1- oxa-7-azadispiro[2.1.53.l3]undecane-7-carboxylate (Intermediate A, 0.83 g, 3.3 mmol) at room temperature under N2. The resulting mixture was stirred at 40 °C for 24 h. then cooled to room temperature. The resulting mixture was diluted with sat. aq. solution of sodium bicarbonate and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with a gradient of 0-80% EtOAc in heptane, to give tert-butyl (2S,4R)-2- (((( 1 R.S'.2.S7 )-2-(2-bromo-6-chloro-4-(mctlio,xy 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, CDCl3) 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 ).

[0284] Step 2: tert- Buty l (2.S',4R)-2-((((1 RS,2SR,SR)-2-(2-chloro-4-(metho\y nicthoxy)-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 (Intermediate S). To a stirred mixture of rac -tert-butyl (2S.4R)-2-((((1RS,2SR)-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), B2Pin 20.57 g, 2.20 mmol) and cesium carbonate (0.96 g, 2.95 mmol) in EtOAc (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 N2. The resulting mixture was sparged with N2for 15 min, stirred at 80 °C for 2 h, then cooled to room temperature. The resulting mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with a gradient of 0-80% EtOAc in heptane, to give tert-butyl (2>S’.4R)-2-((((lRiS’,2>SK)-2-(2-chloro-4-(methoxymethoxy)-6-(4.4.5,5-tetramethyl- 1 ,3,2-11005-W001-SEC dioxaborolan-2-yl)plicnyl)cyclopropyl)mcthoxy)nicthyl)-2-liydroxy-6-azaspiro|3.5|nonanc-6- carboxylate (Intermediate S, 0.79 g, 1.3 mmol, 86% yield), m'z (ESI): 644.2 (M+Na)+.1H NMR (400 MHz, DMSO-d6) 8 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 ).

[0285] Intermediate T: 3-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yI)propan-l-olIntermediate T11005-W001-SEC dried over anhydrous Na2SOi. filtered, and concentrated. 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)+.

[0287] 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 MOM-CI (1.1 mL 14 mmol) in portions at 0 °C under N2. The reaction mixture was stirred at 15 °C for 12 h. The mixture was then poured into 0 °C water, stirred for 20 min, then extracted with EtOAc. The combined organic phases were washed with brine, dried with anhy drous Na2SO4, filtered, and concentrated. 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).

[0288] Step 3: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoromethanesulfonate. To a mixture of 7-fhioro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)naphthalen-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. 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, and the aqueous phase was extracted with DCM. The combined organic phases were dried with anhydrous Na2SO4, filtered, and concentrated. 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).

[0289] 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 potassium acetate (1.38 g, 14.0 mmol), B2Pin2(2.37 g, 9.35 mmol) and Pd(dppf)Cl2(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 at 45 °C. The residue was poured into ice water and extracted with EtOAc, and the combined organic phases were dried with anhydrous Na2SO4. filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 2-10% EtOAc in petroleum ether, to give ((2-fhioro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (1.20 g, 2.34 mmol, 50% yield). m / z (ESI): 513.2 (M+H)+.11005-W001-SEC

[0290] Step 5. ((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-l,3,2-dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (30.0 g, 58.5 mmol) in DMF (600 rnL) and toluene (300 mL) was added Cui (16.7 g, 88 mmol), K2CO3 (16.2 g, 117 mmol) and A'-iodosuccinimidc (15.8 g, 70.2 mmol) at room temperature in sequence, and the mixture was stirred at 110 °C for 2 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO i. fdtered, and concentrated to give ((2-fluoro-8- iodo-6-(methoxymethoxy)naphthalen-l-yl)ethynyl)triisopropylsilane (30 g. crude).

[0291] Step 6: l-Ethynyl-2-fluoro-8-iodo-6-(methoxymcthoxy)naphthalenc. To a solution of ((2-fhioro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethynyl)triisopropylsilane (50 g, 98 mmol) in DMF (500 mL) was added cesium fluoride (74.1 g, 488 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h, then cooled to room temperature. The resulting residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 10-100% EtOAc in petroleum ether. The product was triturated with petroleum ether (20 mL) at room temperature for 10 min. The suspension was filtered, and the filter cake was concentrated to give l-ethynyl-2-fhioro-8-iodo-6- (methoxymethoxy)naphthalene (29.0 g. 81.5 mmol, 85% yield over 2 steps).

[0292] Step 7. 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 DCM (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 diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SOi. filtered, and concentrated. The crude residue was purified by column chromatography on silica gel, eluting using a gradient of 0-20% EtOAc / lieptane, to give 2-fhioro-8-iodo-6-(methoxymethoxy)-l-vinylnaphthalene (4.00 g, 11.2 mmol, 40% yield). ’H NMR (400 MHz, CDC / ^ o 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).

[0293] Step 8: 2-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)ethan-l-ol. To a solution of 2-fluoro-8-iodo-6-(methoxymethoxy)-l-vinylnaphthalene (1.00 g, 2.79 mmol) in THF (10 mL) was added dropwise borane dimethylsulfide (10 M in THF, 1.4 mL, 14 mmol) at 0 °C. The mixture was degassed and purged with N2, then wanned to room temperature and stirred for 12 h under N2. The mixture was cooled again to 0 °C, followed by dropwise addition of 4 N aq. NaOH solution (4.7 mL, 18.6 mmol) under N2at 0 °C. Then, 30% aq. H2O2 (2.9 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. Na2SO3 (20 mL) was added dropwise to the mixture at 0 °C under N2. and11005-W001-SEC stirred for 20 min. The mixture was extracted w ith EtOAc, the combined organic layers were dried over Na2SOi and filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 10-100% EtOAc in petroleum ether. The product was triturated with petroleum ether:EtOAc 5:1 (50 mL) at room temperature for 30 min. The suspension was filtered, and the filter cake was concentrated to give 2-(2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-l-yl)ethan-l-ol (0.27 g, 0.71 mmol, 26% yield), m / z (ESI): 377.0 (M+H)+. ’H NMR (400 MHz, DMSO-d6) 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, DMSO-d6) 5 ppm -113.29 (s, 1 F).

[0294] Step 9: 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 (1.62 g, 4.31 mmol) in DCM (29 mL) at 0 °C under ambient atmosphere, was added Dess-Martin periodinane (2.74 g, 6.46 mmol). The resulting mixture was warmed to room temperature and stirred for 2 h. then 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- (methoxy methoxy )naphthalen-l- yl)acetaldehyde (1.28 g, 3.42 mmol, 79% yield), m / z (ESI): 397.0 (M+Na+).!H NMR (400 MHz, CDCl3) 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).

[0295] Step 10: l-Allyl-2-fluoro-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 N2 was added lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 3.8 mL, 3.8 mmol). The resulting mixture was stirred at -78 °C for 30 min and then warmed to 0 °C for 30 min. The solution was cooled back to -78 °C, followed by addition of 2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l- yl)acetaldehyde (1.28 g, 3.42 mmol) 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 1-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).

[0296] Step 11: 3-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-l-yl)propan-l-ol(Intermediate T). To a stirred mixture of l-allyl-2-fhioro-8-iodo-6-(methoxymethoxy)naphthalene (1.14 g, 3.06 mmol) in THF (10.2 mL) at 0 °C under N2was added 9-borabicyclo[3.3.1]nonane solution (0.5 M in THF, 12.6 mL, 6.3 mmol). The resulting mixture was warmed to room temperature11005-W001-SEC and stirred for 4 h. The reaction was cooled to 0 °C and 10 M sodium hydroxide solution (2.0 mL, 20 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, fdtered, 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-fhioro-8-iodo-6-(methoxymethoxy)naphthalen- l-yl)propan-l-ol (Intermediate T, 0.96 g, 2.46 mmol. 80% yield), nv'z (ESI): 412.8 (M+Na)+. ’H NMR (400 MHz, CDCl3) 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).

[0297] Intermediate U: 7-C hloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrimido[4,5-d ]pyrimidin-4-ol.

[0298] Step 1: 4-(Benzyloxy)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(methylthio)pyriinido [4,5-d ] pyrimidine. A mixture of 4-(benzyloxy)-2-chloro-7- (methylthio)pyrimido[4,5-d ]pyrimidine (Step 4 of Intermediate F. 13 g, 40.8 mmol), DIPEA (21.4 mL, 122 mmol) and ((2R,7aS)-2-fhiorotetrahydro-lLf-pyrrolizin-7a(5H)-yl)methanol (9.74 g, 61.2 mmol) in 1,4-dioxane (130 mL) was degassed and purged with N2(3x). then stirred at 80 °C for 3 h. The resulting mixture was quenched by addition of water (200 mL), then extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated. The crude residue was triturated with pet ether (20 mL) at room temperature for 20 min to provide 4-(benzyloxy)-2-(((2R,7aS)-2 -fluorotetrahydro- 1 / f-pyrrolizin- 7a(5H)-yl)methoxy)-7-(methylthio)pyrimido[4,5-d |pyrimidine (12 g, 27.2 mmol, 67 % yield), m'z (ESI): 442.1 (M+H)+. ’H NMR (400 MHz. CDCl3) δ ppm 9.16 (s. 1 H), 7.47 - 7.52 (m. 2H ), 7.38 - 7.46 (m. 3 H), 5.62 (s, 2 H), 5.20 - 5.39 (m, 1 H), 4.29 - 4.39 (m, 2 H), 3.23 - 3.32 (m, 2H ), 3.18 (s, 1 H), 2.95 - 3.03 (m, 1 H), 2.68 (s, 3 H). 2.25 (d. J=2.7 Hz. 1 H), 2.15 - 2.21 (m. 1 H), 2.06 - 2.12 (m. 1 H), 1.88 - 2.01 (m, 3 H).11005-W001-SEC

[0299] Step 2: 7-Chloro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrimido[4,5-d ]pyrimidin-4-ol (Intermediate U). To a solution of 4-('bcnzylo.xy)-2- (((27?,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(methylthio)pyrimido[4,5- ( / |pvrimidinc (2.00 g, 4.53 mmol) in THF (16 mL) and DCM (16 mL) was added sulfuryl dichloride (6.11 g, 45.3 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h, then concentrated. The crude residue was triturated with ACN (10 mL) at room temperature for 60 min, the resulting mixture was filtered, and the filter cake was concentrated to provide 7-chloro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5F / )-yl)methoxy)pyrimido[4,5-t / |pyrimidin-4-ol (Intermediate U. 1.60 g). ’H NMR (400 MHz, D2O) 5 ppm 9.26 (s, 1 H). 5.51 - 5.70 (m, 1 H). 4.80 (br s. 2 H), 3.77 - 3.99 (m, 3 H). 3.43- 3.54 (m. 1 H), 2.53 - 2.73 (m. 2 H), 2.28 - 2.47 (m. 3 H), 2.06 - 2.21 (m. 1 H).

[0300] Intermediate V: tert- Butyl 3-(((((Z)-4-(6-chloro-l -(tetrahydro- 2H -pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxahorolan-2-yl)-l W-indazol-5-yl)hut-3-en-l- yl)oxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate

[0301] Step 1. 4-(4-Bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)but-3-yn- l-ol. A mixture of 4-bromo-6-chloro-5 -iodo- l-(tetrahydro-2H -pyran-2-yl)- 1H- indazole (20.0 g, 45.3 mmol), TEA (63 mL, 453 mmol), but-3- n-l-ol (4.13 g, 58.9 mmol), copper(I) iodide (0.86 g, 4.50 mmol) and Pd(PPh3)2C12 (3.18 g, 4.53 mmol) in DMF (120 mL) was degassed and purged with N2, then stirred at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over11005-W001-SECNa S04, filtered, and concentrated. The crude product was purified by chromatography, eluting with a gradient of 30-60% ACN in water, to give 4-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H- indazol-5-yl)but-3-yn-l-ol (12.3 g, 32.2 mmol, 71% yield).

[0302] Step 2. (Z)-4-(4-Bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-l H-indazol-5-yl)but-3- en-l-ol. To a suspension of PtO2(1.95 g) in THF (220 mL) was added 4-(4-bromo-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)but-3-yn-l-ol (11.0 g, 28.7 mmol) under argon. The reaction mixture was stirred under H2(15 psi) at room temperature for 1.5 h, then filtered, and the filtrate concentrated. The resulting residue was purified by chromatography, eluting with a gradient of 35-67% ACN in water (10 mM NH4HCO3), to provide (Z)-4-(4-bromo-6-chloro-l -(tetrahy dro-2H - pyran-2-yl)- l / / -indazol-5-yl)but-3-cn- l-ol (7.85 g, 20.4 mmol, 71% yield), m'z (ESI): 387.0 / 385.0 (M+H)+. >H NMR (400 MHz, CDCI3) 5 ppm 8.00 (s, 1 H), 7.69 (s, 1 H), 6.45 (d, J= 11.2H z, 1 H), 5.99 - 6.03 (m, 1 H), 5.66 (dd, J =9.2, 2.8 Hz, 1 H), 4.01 - 4.04 (m, 1 H), 3.76 - 3.78 (m, 1 H), 3.65 - 3.68 (m, 2 H), 2.49 - 2.52 (m, 1 H), 2.12 - 2.24 (m, 4 H), 1.74-1.77 (m, 3 H).

[0303] Step 3: ( )-4-(4-Bromo-6-chloro-l-(tetrahydro-2Z / -pyran-2-yl)-1H-indazol-5-yl)but-3- en-l-yl (4-nitrophenyl) carbonate. To a solution of (Z)-4-(4-bromo-6-chloro-l -(tetrahy dro-2H - pyran-2-yl)-1H-indazol-5-yl)but-3-en-l-ol (383 mg, 1 mmol) in THF (3.8 mL) was added TEA (0.71 mL, 5.2 mmol) and 4-nitrophenyl chloroformate (0.36 g, 1.80 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 3 h to provide (Z)-4-(4-bromo-6-chloro-l-(tctrahydro-2J7-pyran- 2-yl)-l / / -indazol-5-yl)but-3-cn-l -yl (4-nitrophenyl)carbonate (2.18 g), which was used in the next step without further purification.

[0304] Step 4: tert- Butyl (Z)-3-((((4-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-l H- indazol-5-yl)but-3-en-l-yl)oxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate. To a mixture of (Z)-4-(4-bromo-6-chloro- 1 -(tetrahy dro-2F / -py ran-2-y 1)- 1 H-indazol-5 -y l)but-3 -en- 1 -y 1 (4- nitrophenyl) carbonate (0.55 g, 1.00 mmol) in THF (5.5 mL) was added / er / -butyl 3-amino-3- methylpiperidine-1 -carboxylate (0.28 g, 1.30 mmol). The mixture was purged with N:(x3), then stirred at 80 °C for 12 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL), and the combined organic lay ers were dried over Na2SCL. filtered and concentrated. The resulting residue was purified by chromatography, eluting with a gradient of 60%- 90% ACN in H2O, to obtain tert -butyl (Z)-3-((((4-(4-bromo-6-chloro-l -(tetrahy dro-2 / f-py ran-2-yl)- 1H-indazol-5-yl)but-3-en- 1 -yl)oxy)carbonyl)amino)-3-methylpiperidine-l -carboxy late (2.00 g, 3.10 mmol, 79% yield), m / z (ESI): 647.2 (M+Na)+.

[0305] Step 5: tert- Butyl 3-((((4-(6-chloi o-1-(tetrahydro-2H -pyran-2-yl)-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)but-3-en-l-yl)oxy)carbonyl)amino)-3- methylpiperidine-l-carboxylate (Intermediate V). To a solution of / er / -butyl (Z)-3-((((4-(4-bromo- 6-chloro-l -(tetrahy dro-2H -pyran-2-yl)-LH-indazol-5-yl)but-3-cn-l-yl)oxy)carbonyl)amino)-3-11005-W001-SEC methylpiperidine- 1 -carboxylate (0.40 g, 0.60 mmol) in 1,4-dioxane (7.3 mL) and H2O (0.7 niL) was added B2Pin2 (0.70 g, 3.0 mmol), cesium carbonate (0.60 g, 1.70 mmol) and Pd(dppf)Cl2(40 mg, 0.06 mmol). The resulting mixture was stirred at 100 °C for 1 h, then diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The resulting residue was purified by chromatography, eluting with a gradient of 55- 85% ACN in water, to obtain tert-butyl 3-((((4-(6-chloro-l-(tetrahydro-2H -pyran-2-yl)-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)- 1H-indazol-5-yl)but-3-en-l-yl)oxy)carbonyl)amino)-3- methylpiperidine-1 -carboxylate (Intermediate V, 1.53 g, 2.30 mmol, 73% yield), m / z (ESI): 673.4 (M+H)+.SECTION 2: Synthesis of Example Compounds

[0306] (1S,3R,7S,9R)-22-(((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol-7a(5H)- yl)methoxy)-ll-methyl-5-oxa-21,23,25,30- 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),1 ,19,21,23-octaene-3,13-diol and (1R ,3R,7R?,9S)-22-(((2R ,7aS)-2- fluorotetrahydro-1H-pyrrolo| l ,2-«|pyrrol-7a(5H)-yl)methoxy)-l l-methyl-5-oxa-21,23,25,30- 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 (Examples 1.001 and 1.002)11005-W001-SECExample 1.001 Example 1.002

[0307] Step 1. tert- Butyl (2s.4R)-2-((((lR.S.2.SR)-2-(2-bromo-4-(iiiellio\ymetho\y)-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 A. 0.70 g, 2.32 mmol) and yttrium(III) trifluoromethanesulfonate (0.32 g, 0.59 mmol. Combi-Blocks Inc.) in toluene (12 mL) at room temperature under nitrogen, was added tert-butyl (3S,5R )-l-oxa-7-azadispiro[2.1.55.l3]undecane-7- carboxylate (Intermediate B, 0.89 g, 3.52 mmol). 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 (15 mL) and extracted with ethyl acetate (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, eluting with a gradient of 0-80% ethyl acetate in heptane to give / ert-butyl (2S,47?)-2-((((17?S,2>SK)-2-(2-bromo-4-(mcthoxymcthoxy)-6- methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.89 g, 1.60 mmol, 69% yield), mz (ESI): 576.0 (M+Na)+.]H NMR (400 MHz, CDCl3) 5 ppm 7.17 - 7.09 (m, 1H), 6.83 - 6.78 (m, 1H), 5.15 - 5.11 (m, 2H ), 3.50 - 3.47 (m, 3H), 3.41 - 3.20 (m, 6H). 2.91 - 2.59 (m, 2H ), 2.45 - 2.40 (m, 3H), 2.02 - 1.88 (m. 3H), 1.72 - 1.69 (m. 1H), 1.68 - 1.57 (m, 4H), 1.55 - 1.42 (m, 12H ), 1.41 - 1.33 (m, 1H), 1.16 - 0.81 (m, 1H).11005-W001-SEC

[0308] Step 2. tert- Butyl (2s,4R)-2-hvdroxv-2-((((1RS,2SR )-2-(4-(methoxymethoxv)-2-rnethvl- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)methoxy)methyl)-6- azaspiro[3.5]nonane-6-carboxylate, Intermediate N. To a stirred mixture of tert-butyl (2s,4R)-2- (((( 1 RS,2SR)-2-(2-bromo-4-( methoxy methoxy )-6-methylphenyl)cyclopropyl)methoxy)metliyl)-2- hy droxy-6-azaspiro[3.5]nonane-6-carboxylate (0.89 g, 1.60 mmol), bis(pinacolato)diboron (0.61 g, 2.41 mmol, Combi-Blocks Inc.) and cesium carbonate (1.10 g, 3.38 mmol, Ambeed, Inc.) in ethyl acetate (6 mL) at room temperature under nitrogen, was added palladium(II) acetate (37 mg, 0.17 mmol, Sigma-Aldrich Corporation) and tris(4-methoxyphenyl)phosphine (69 mg, 0.20 mmol, Combi- Blocks Inc.). The resulting mixture was sparged with nitrogen for 15 min and stirred at 80 °C for 3 h. The reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure. The crude material was purified by column chromatography on silica, eluting with a gradient of 0-80% ethyl acetate in heptane to give tert-buty l (2s,4R)-2-hydroxy-2-((((1RS,2SR)-2-(4- (methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2- yl)phenyl)cyclopropyl)methoxy)methyl)-6-azaspiro[3.5]nonane-6-carboxylate (Intermediate N, 0.89 g, 1.48 mmol, 92% yield), m / z (ESI): 624.2 (M+Na)+. *H NMR (400 MHz, CDCl3) 5 ppm 7.13 - 6.97 (m, 1H). 6.93 - 6.85 (m, 1H). 5.28 - 5.06 (m, 2H ). 3.51 - 3.44 (m, 3H), 3.40 - 3.11 (m, 6H), 3.03 - 2.80 (m. 1H), 2.42 - 2.33 (m, 3H), 2.03 - 1.79 (m, 2H ), 1.78 - 1.63 (m, 4H), 1.55 - 1.42 (m, 12H ), 1.41 - 1.35 (m, 10H), 1.29 - 1.27 (m, 3H), 1.27 - 1.25 (in, 3H). 0.77- 0.56 (m, 1H).

[0309] Step 3. tert-Butyl (2s,4R)-2-((((1RS,2SR )-2-(2-(4-(tert-butoxy)-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)rnethoxy)pyrido[2,3-i / |pyTimidin-7-yl)-4- (methoxymethoxy)-6-methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate. To a mixture of tert-buty l (2x,47?)-2-hydroxy-2-((((1RS,2SR)-2- (4-(methoxymethoxy)-2-methyl-6-(4,4,5,5-tetramethyl-1.3,2-dioxaborolan-2- yl)phenyl)cyclopropyl)methoxy)methyl)-6-azaspiro[3.5]nonane-6-carboxylate (0.25 g. 0.42 mmol). 4- (tert-butoxy)-7-chloro-2-(((2R,7aS)-2-fhiorotetrahydro-1H-pyrrolizin-7a(57 / )-yl)methoxy)pyrido[2.3- <7| pyrimidine (Intermediate C, 0.18 g, 0.46 mmol), potassium phosphate tribasic (0.28 g, 1.32 mmol. Sigma-Aldrich Corporation) and CataCXium A Pd G3 (34 mg, 0.05 mmol, Sigma-Aldrich Corporation) under nitrogen, 2-methyltetrahydrofuran (3 mL) and water (0.30 mL) were added at room temperature. The resulting mixture was sparged with nitrogen for 15 min and stirred at 60 °C for 1.5 h. The reaction mixture was filtered though celite and the filtrate concentrated under reduced pressure. The crude material was purified by column chromatography on silica, eluting with a gradient of 0-80% ethanol / ethyl acetate (1:3) (2% Et3N) in heptane to give tert-butyl (2x.4R)-2- ((((1RS,2SR)-2-(2-(4-(tert-butoxy)-2-(((2R,7aS)-2-fluorotctrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-d |pyrimidin-7-yl)-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.26 g, 0.32 mmol, 76% yield), m / z (ESI): 834.0 (M+H)+.]H NMR (400 MHz, DMSO-d6) δ ppm 8.36 - 8.2711005-W001-SEC(m, 1H), 7.71 - 7.41 (m, 1H), 7.07 - 6.89 (m, 2H ), 5.49 - 5.10 (m, 3H), 4.84 - 4.53 (m, 1H), 4.29 - 4.11 (m, 2H ), 3.43 - 3.35 (m. 3H), 3.27 - 2.92 (m, 1 OH), 2.91 - 2.82 (m, 1H), 2.49 - 2.43 (m, 3H), 2.30 - 2.00 (m, 4H), 1.93 - 1.65 (m, 15H), 1.61 - 1.50 (in, 2H ), 1.49 - 1.37 (in, 3H), 1.37 - 1.21 (in, 10H), 0.83 - 0.56 (m, 1H), -0.23 - -0.65 (m, 1H).19F NMR (376 MHz, DMSO-d.) 5 ppm -167.18 - - 175.67 (m, IF).

[0310] Step 4. 2-(((2R ,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5- hydroxy-2-((lR.S',2>SR)-2-((((2\,4.S')-2-hydroxy-6-azaspiro|3.5|nonan-2- yl)methoxy)methyl)cyclopropyl)-3-methylphenyl)pyrido[2,3-rf]pyrimidin-4-oL To a stirred mixture of tert-butyl (2x,4R)-2-((((lRS,2SR)-2-(2-(4-( / e / -t-butoxy)-2-(((2R,7a*S)-2-fluorotctrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[ 2, 3-<7|pyrimidin-7-v l)-4-(mcthoxy methoxy )-6- methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.26 g, 0.32 mmol) in dichloromethane (7 mL) at room temperature under ambient atmosphere, was added hydrogen chloride solution (4.0 M in 1,4-dioxane, 1.1 mL, 4.40 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure to give 2-(((2A,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5-hydroxy-2-((17?S,2>SK)-2-((((2S,45)-2-liydroxy-6-azaspiro[3.5]nonan-2- yl)methoxy)methyl)cyclopropyl)-3-methylphenyl)pyrido[2,3-rf|pyrimidin-4-ol (0.20 g, 0.32 mmol. 100% yield), m / z (ESI): 634.2 (M+H)1.!H NMR (400 MHz. MeOD-dt) 5 ppm 9.23 - 8.91 (m. 1H), 7.98 - 7.78 (m, 1H). 7.08 - 6.92 (m, 1H). 6.90 - 6.77 (m, 1H), 5.77 - 5.49 (m, 1H), 5.01 - 4.91 (m, 1H), 4.08 - 3.86 (m. 3H), 3.57 - 3.44 (m. 1H), 3.30 - 3.16 (m. 1H), 3.14 - 3.00 (m, 5H), 2.83 - 2.59 (m. 3H), 2.58 - 2.51 (m. 3H), 2.51 - 2.33 (m, 3H), 2.33 - 2.12 (m, 3H), 1.91 - 1.74 (m, 5H). 1.73 - 1.53 (m, 1H). 1.11 - 0.85 (m, 1H), 0.01 - -0.61 (m, 1H).19F NMR (376 MHz, MeOD-d4) 5 ppm - 174.03 - -174.26 (m. IF).

[0311] Step 5. ( l.S.3R.7.S.9R)-22-(((2R,7aS)-2-Fluorotetraliydi ()-1H-pyrrolo|1.2-< / |pyrrol- 7a(5H)-yl)methoxy)-l 1 -methyl-5-oxa-21 ,23,25,30- 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 (1R,31?,71?,95)-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-ll-methyl-5-oxa-21,23,25,30- 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. To a stirred mixture of MN-diisopropy lethy lamine (0.6 mL, 3.44 mmol, Sigma-Aldrich Corporation) and bromotris(dimethylamino)phosphonium hexafluorophosphate (0.36 g, 0.92 mmol, Oakwood Products. Inc.) in acetonitrile (57 mL) at room temperature under nitrogen, was slowly added 2-(((27?.7a*S)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(5-hydroxy-2-((lR1S’,2S7?)-2-((((2.v,4S)-2-hydroxy-6-a / aspiro[3.5]nonan-2- yl)methoxy)methyl)cyclopropyl)-3-methylphenyl)pyrido[2,3-<7|pyrimidin-4-ol (0.20 g. 0.32 mmol) as a solution in dimethyl sulfoxide (9.50 mL). The resulting mixture was stirred at room temperature for11005-W001-SEC30 min. Additional bromotris(dimethylamino)phosphonium hexafluorophosphate (0.15 g, 0.39 mmol, Oakwood Products, Inc.) was added and the reaction allowed to stir for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and washed with sat. aq. solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by reversed phase chromatography on a C18 column, eluting with a gradient of 10-100% acetonitrile (0.1% formic acid) in water (0.1% fonnic acid). The combined fractions were concentrated under reduced pressure. The resulting mixture was neutralized with sat. aq. solution of sodium bicarbonate and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The product was further purified via SFC using an OD 5 micron, 30 x 150 mm column with a mobile phase of 35% MeOH + 0.2% DEA using a flowrate of 100 mL / min. to generate 19.5 mg of peak 1 with 99% LC purity and 26.2 mg of peak 2 with 99% LC purity. Peak assignment determined by SFC with an OD 5 micron, 30 x 150 mm column with 35% MeOH + 0.2 % DEA to generate (LS,,3R,7.S',9R)-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[ l,2-a]pyrrol-7a(5H)-yl)methoxy)-l l-methyl-5-oxa-21,23,25,30- 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, 20 mg, 0.03 mmol, 11% yield), m / z (ESI): 616.4 (M+H)+. ’H NMR (400 MHz, MeOD-d) 5 ppm 8.46 - 8.30 (m, 1H), 7.67 - 7.53 (m.1H), 7.08 - 6.97 (m, 1H). 6.84 - 6.76 (m, 1H). 5.53 - 5.17 (m, 1H). 4.82 - 4.67 (m, 1H). 4.51 - 4.33 (m, 2H ). 4.32 - 4.20 (m, 1H). 3.63 - 3.50 (m, 1H). 3.44 - 3.38 (m, 1H), 3.29 - 3.26 (m, 1H), 3.16 - 3.02 (m. 3H), 2.69 - 2.57 (m, 1H), 2.52 - 2.40 (m, 4H), 2.39 - 2.27 (m, 2H ), 2.27 - 2.13 (m, 2H ), 2.10 - 1.99 (m, 2H ), 1.99 - 1.81 (m, 3H), 1.81 - 1.68 (m, 3H), 1.68 - 1.59 (m, 2H ), 1.46 - 1.37 (m, 2H ), 1.35 - 1.24 (in, 4H), 0.87 - 0.72 (m, 1H), 0.30 - 0.18 (m, 1H).19FNMR (376 MHz, MeOD-d4) 5 ppm -173.57 (br s, IF) and (lR,3R,7R,9S)-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2-«]pyrrol- 7a(5J7)-yl)mcthoxy)-l l-mcthyl-5-oxa-21,23,25,30- 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, 26 mg, 0.04 mmol, 13% yield), m / z (ESI): 616.4 (M+H)+.]H NMR (400 MHz, MeOD-d / ) 5 ppm 8.43 - 8.36 (m, 1H), 7.65 - 7.56 (m, 1H), 7.05 - 6.98 (m, 1H), 6.81 - 6.76 (m, 1H), 5.49 - 5.17 (m, 1H), 4.84 - 4.74 (m, 1H), 4.44 - 4.36 (m, 1H), 4.32 - 4.22 (m, 2H ), 3.61 - 3.52 (m, 1H), 3.44 - 3.37 (m, 1H), 3.29 - 3.15 (m, 3H). 3.14 - 2.99 (m, 2H ), 2.67 - 2.60 (m, 1H), 2.51 - 2.42 (m. 4H), 2.42 - 2.29 (m. 2H ), 2.29 - 2.25 (m. 1H), 2.25 - 2.12 (m, 2H ), 2.05 - 1.82 (m, 5H), 1.81 - 1.72 (m, 2H ), 1.71 - 1.57 (m, 3H), 1.47 - 1.38 (m, 2H ), 1.34 - 1.25 (m, 2H ), 0.87 - 0.74 (m, 1H), 0.34 - 0.18 (m, 1H).19F NMR (376 MHz, MeOD-d / ) 5 ppm -173.63 (s, IF).11005-W001-SEC

[0312] (165)-36-Chloro-22-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5Z7)-yl)methoxy)-16-methyl-31f / -7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3-d |pyrimidina-3(4,5)- indazolacydononaphan-8-one (Example 1.003).

[0313] Step 1. (5)-4-(2,7-Dichloropyrido[2,3-^pyrimidin-4-yl)-6-methyl-l ,4-oxazepan-6- ol. To a solution of 2.4.7-tricliloropyrido|2.3-<r / |pyiiinidinc (2.00 g. 8.53 mmol) in acetonitrile (14 mL) was added DIEA (4.47 mL, 25.6 mmol) and (S)-6-methyl- 1.4-oxazepan-6-ol hydrochloride (1.43 g. 8.53 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 h and the reaction mixture was quenched by addition of H2O (50 mL) and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na?SO.. fdtered and concentrated under reduced pressure. The crude product was triturated with petroleum ether, the suspension was fdtered to give the product (»S)-4-(2.7- dichloropyrido|2,3-d |pyrimidin-4-yl)-6-mctliyl-1.4-oxazcpan-6-ol (2.40 g, 7.31 mmol. 85% yield). m>z (ESI): 329.1, 331.0 (M+H)+.!H NMR (400 MHz. CDCL) 5 ppm 8.71 (d. J= 8.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.61-4.66 (m, 1 H), 4.37 (d, J = 15.2 Hz, 1 H), 4.24 (s. 1 H), 4.02-4.08 (m, 1 H), 3.90-3.95 (m, 1 H). 3.54-3.72 (m, 4 H), 1.33 (s, 3 H).

[0314] Step 2. (.S)-4-(7-( ldoro-2-(((2R,7aS)-2-fluorotetraliydro-1H |)yrroliziii-7a(5H)- yl)mcthoxy)pyrido[2,3-( / |pyrimidin-4-yl)-6-methyl-l,4-oxazepan-6-ol. To a solution of (S)-4-(2.7- dichloropyrido[2,3-<7]pyrimidin-4-yl)-6-methyl-l,4-oxazepan-6-ol (2.00 g, 6.08 mmol) in 1,4-dioxane11005-W001-SEC(20 mL) was added DIEA (3.14 g, 24.3 mmol) and fi2R,7aS)-2-fluorotctrahydro-l / / -pyrrolizin- 7a(5H)-yl)methanol (0.97 g, 6.08 mmol) at room temperature. The mixture was stirred at 100 °C for 12 h then quenched by addition of H2O (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na^SOi. fdtered and concentrated under reduced pressure. The crude product was purified by reversed phase MPLC to give 6S)-4-(7-chloro-2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-t / ]pyrimidin-4-yl)-6-methyl-l,4- oxazepan-6-ol (0.38 g, 0.85 mmol, 14% yield), m / z (ESI): 452.3 (M+H)+.!H NMR (400 MHz, CDCls) 8 ppm 8.28-8.30 (m. 1 H), 7.19-7.21 (m, 1 H). 5.51 (s. 1 H), 5.14-5.27 (m, 1 H). 4.36-4.50 (m. 1 H), 4.29-4.32 (m, 1 H), 4.14-4.23 (m, 2 H). 3.80-3.84 (m, 1 H), 3.58-3.71 (m. 3 H). 3.37-3.45 (m, 2H ), 3.08-3.20 (m, 3 H), 2.87-2.93 (m, 1 H). 2.06-2.15 (m, 2 H), 1.83-1.94 (m. 4 H). 1.32 (s, 3 H).

[0315] Step 3. (65)-4-(7-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro- 2H -pyran-2-yl)-1H-indazol-4-yl)-2-(((2R,7a.$')-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-rf|pyrimidin-4-yl)-6-methyl-l,4-oxazepan-6-ol. To a solution of (S)-4-(7- chloro-2-(((27?,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2.3-< / ]pyrimidin-4- yl)-6-methyl-l,4-oxazepan-6-ol (1.80 g, 3.98 mmol) in 1,4-dioxane (36 mL) and water (3.6 mL) was added K3PO4 (4.23 g, 19.91 mmol), 5-(3-(( / er / -butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro- 2H -pyran-2-yl)-4-f4.4.5.5-lctramethyl-l ,3.2-dioxaborolan-2-yl)-1H-indazolc (2.13 g. 3.98 mmol) and CataCXium A Pd G3 (0.29 g. 0.40 mmol) at room temperature under N?. Then the mixture was stirred at 1 10 °C for 1 h then the reaction mixture was quenched by addition of H2O (50 mL) and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of petroleum ether / EtOAc 10 / 1 to 0 / 1 to give (6.S)-4-(7- (5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-4-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-<7]pyrimidin-4-yl)-6- methyl- l,4-oxazepan-6-ol (1.50 g, 1.82 mmol. 46% yield), m / z (ESI): 824.5 (M+H)+.

[0316] Step 4. (6S)-4-(7-(5-(3-((tert-Butyldimethylsilyl)oxy)propyI)-6-chloro-l-(tetrahydro- 2H -pyran-2-yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-d|pyrimidin-4-yl)-6-niethyl-l,4-oxazepan-6-yl-1H-imidazole-l- carboxylate. To solution of (6S)-4-(7-(5-(3-(( / er / -butyldimethylsilyl)oxy)propyl)-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-<7|pyrimidin-4-yl)-6-methyl-l,4-oxazepan-6-ol (0.50 g, 0.61 mmol) in tetrahydrofuran (10 mL) was added CDI (0.39 g, 2.43 mmol) then the mixture was stirred at 80 °C for 4 h to give crude (6S)-4-(7-(5-(3-((ter / -butjTdimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H - pyran-2-yl)-1H-indazol-4-yl)-2-(((27?.7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5T / )- yl)methoxy )pyrido[2, 3- fi|pyriniidiii-4-yl)-6-methyl-l.4-oxazepan-6-y 1-1H-imidazole- 1 -carboxy late which was used directly in the next step.11005-W001-SEC

[0317] Step 5. (165l)-36-Chloro-22-(((2R ,7aS )-2-fluorotetrahydro-l£T-pyrrolizin-7a(5H)- yl)methoxy)-16-methyl-31-(tetrahydro-2H -pyran-2-yl)-31 / / -7,9-dioxa-l(4,6)-oxazepana-2(4,7)- pyrido[2,3-rf]pyrimidina-3(4,5)-indazolacyclononaphan-8-one. To solution of (6S)-4-(7-(5-(3- (( / ert-butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-4-yl)-2- (((2A.7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d |pyrimidin-4-yl)-6- methyl- l,4-oxazepan-6-yl I H-imidazolc- 1 -carboxylate (crude from last step used directly) in tetrahydrofuran (50 mL) was added TBAF (1 M in THF. 0.82 mL, 0.82 mmol) then the mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of petroleum ether / EtOAC 1 / 0 to 0 / 1 to give (165)-36-chloro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5F7)-yl)methoxy)-16-methyl-3 l-(tetrahydro-2H -pyran-2-yl)-31 / 7-7, 9-dioxa-l (4,6)- oxazepana-2(4.7)-pyrido[2.3-i / ]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.20 g. 0.27 mmol, 45% yield over 2 steps), m / z (ESI): 736.5 (M+H)+.

[0318] Step 6. (16>S)-36-Chloro-22-(((2R,7a.$’)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-16-methyl-31H-7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3-d ]pyrimidina-3(4,5)- indazolacyclononaphan-8-one (Example 1.003). To solution of (16S)-36-chloro-22-(((2A.7aS)-2- fluorotetrahydro-lff-pyrrolizin-7a(5H)-yl)methoxy)-16-methyl-31-(tetrahydro-2H -pyran-2-yl)-3 IH- 7.9-dioxa-l (4.6)-oxazcpana-2(4.7)-pyrido|2,3-d |pyrimidina-3(4.5)-indazolacyclononaphan-8-one (0.25 g, 0.34 mmol) in dichloromethane (5 mL) was added TFA (2.5 mL) at 0 °C. Then the mixture was stirred at room temperature for 1 h then concentrated under reduced pressure. The mixture was adjusted to pH 9 using NH3H2O then purified by prep-HPLC (NH3H2O, column: WePure Biotech XP tC18, 7 micron, 150 x 40; mobile phase: [A: H2O (0.05% NH3H2O + 10 mM NH4HCO3); B: ACN]; B%: 30.00%-60.00%, 8.00 min) to give (16S)-36-chloro-22-(((27?,7a$)-2-fhiorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-16-methyl-31 / 7-7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3- <7|pyrimidina-3(4,5)-indazolacyclononaphan-8-one (Example 1.003, 35 mg, 5.4 pmol). / « z (ESI): 652.3 (M+H)+. ’HNMR (400 MHz, CDCl3) 5 ppm 8.38-8.41 (m, 1 H), 7.81 (s, 1 H), 7.64 (s, 1 H), 7.36-7.38 (m, 1 H), 5.54-5.58 (m, 1 H), 5.22-5.36 (m, 1 H), 4.41-4.61 (m, 1 H), 4.27-4.30 (m, 3 H),4.05-4.06 (m, 1 H), 3.64-3.67 (m, 2 H), 3.56-3.60 (m, 2 H), 3.50-3.52 (m, 1 H), 3.26-3.29 (m, 2H ),3.19-3.20 (m, 1 H), 2.83-2.96 (m. 1 H), 2.67-2.75 (m, 1 H), 2.50-2.60 (m, 1 H), 2.36-2.40 (m, 3 H),2.00-2.13 (m, 3 H), 1.80-1.89 (m. 1 H), 1.68-1.70 (m, 3 H), 1.55 (s, 3 H).19F NMR (376 MHz,CDC / j) 5 ppm -172.41 (s, 1 F).

[0319] (16.S)-36-( hloro-26-fliioro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-16-methyl-31 / 7-7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3-d ]pyrimidina-3(4,5)- indazolacydononaphan-8-one (Example 1.004).11005-W001-SEC

[0320] Step 1. 2,6-Dichloro-5-fluoronicotinoyl chloride. To a solution of 2,6-dichloro-5- fluoronicotinic acid (40 g, 190 mmol) and DMF (1 mL) in DCM (400 mL) was added oxalyl dichloride (29.0 g, 229 mmol) dropwise at 0 °C over 0.1 h. After addition, the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give 2.6- dichloro-5-fluoronicotinoyl chloride (45 g, the crude was used directly in the subsequent step).

[0321] Step 2. Methyl (2,6-dichloro-5-fluoronicotinoyl) carbamimidothioate. To a solution of NaOH (13.59 g, 591 mmol) in water (510 mL) was added 2-methyl-2-thiopseudourea hemisulfate (69.4 g, 250 mmol) in portions at 0 °C then the mixture was stirred at 0 °C for 0.5 h under N2. To the mixture was added dropwise the solution of 2,6-dichloro-5-fluoronicotinoyl chloride (30 g. 131 mmol) in MTBE (390 mL) at 0 °C. Then the mixture was stirred at 0 °C for 1.5 h under N2atmosphere. The reaction mixture was quenched by addition of H2O (300 mL) and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SOi. filtered and11005-W001-SEC concentrated under reduced pressure. The crude product was triturated with petroleum ether (100 mL) and the suspension was filtered and the filter cake was washed with MTBE to give methyl (2,6- dichloro-5-fluoronicotinoyl) carbamimidothioate (33 g, 89% yield, 117 mmol), m z (ESI): 282.0 (M+H)+.

[0322] Step 3. 7-C hloro-6-fluoro-2-(methvlthio)pyrido[2,3-d |pyrimidin-4-ol. To a solution of methyl (2,6-dichloro-5-fluoronicotinoyl)carbamimidothioatc (10 g, 35.4 mmol) in DMF (100 mL) was added CS2CO3 (17.44 g, 53.2 mmol) in one portion then the mixture was stirred at 100 °C for 3 h under nitrogen. The reaction mixture was quenched by addition of H2O (300 mL) and dien extracted with EtOAc. The organic layers were discarded, and the aqueous layer was adjusted to pH 4 with 1 M HC1, then extracted with EtOAc, the combined organic layers dried over Na2SO4, filtered and concentrated under reduced pressure to give 7-chloro-6-fluoro-2-(methylthio)pyrido[2,3-t / ]pyrimidin- 4-ol (5 g, crude).

[0323] Step 4. 4,7-DichIoro-6-fluoro-2-(methylthio)pyrido [2, 3-< / | pyrimidine. To a solution of phosphor l trichloride (24.3 mL, 261 mmol) in 1,4-dioxane (80 mL) was added 7-chloro-6-fluoro-2- (methylthio)pyrido[2,3-<7|pyrimidin-4-ol (8.00 g, 32.6 mmol) in portions at room temperature over 20 min then to the mixture was added dropwise A-clhy 1-A-isopropy lpropan-2 -amine (28.4 mL, 163 mmol) at room temperature over 20 min. Then the mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was quenched by addition of sat. NaHCCh (500 mL) at 0 °C and then 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 petroleum ether / EtOAc 20 / 1 to 5 / 1 to give 4.7-dichloro-6-fluoro-2-(methylthio)pyrido[2,3- 9.50 mmol). 'H NMR (400 MHz. CDCls) 5 ppm 8.17 (d, J = 6.8 Hz, 1 H). 2.72

[0324] Step 5. (.S')-4-(7-Chloro-6-f'luoro-2-(mcthylthio)pyrido[2,3-i / |pyrirnidin-4-yl)-6-rnethyl- l,4-oxazepan-6-ol. To a solution of 4,7-dichloro-6-fluoro-2-(methylthio)pyrido[2,3-i / |pyrimidine (4.00 g. 15.15 mmol) in acetonitrile (28 mL) was added DIEA (7.93 mL, 45.47 mmol) and (.S)-6- methyl-l,4-oxazepan-6-ol hydrochloride (2.54 g, 15.15 mmol) at 0 °C. Then the mixture was stirred at 0 °C for 3 h, then the reaction mixture was quenched by addition of H2O (30 mL) and then 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 (20 mL) and the suspension was filtered and the filter cake was washed with MTBE and concentrated under reduced pressure to give (tS)-4-(7-chloro-6-fluoro-2-(methylthio)pyrido[2,3- r / ]pyrimidin-4-yl)-6-methyl-l,4-oxazepan-6-ol (5.00 g. 92% yield, 13.96 mmol), m z (ESI):11005-W001-SEC359.1 / 361.1 (M+H)+. ’H NMR (400 MHz, CDCl3) 5 ppm 8.45-8.46 (m, 1H), 4.50 (s, 1H), 4.23-4.27 (m, 1H), 3.90-3.97 (m, 2 H), 3.48-3.65 (m, 4 H), 2.62 (s, 3 H), 1.30 (s, 4 H).

[0325] Step 6. (65)-4-(7-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro- 2H -pyran-2-yI)-1H-indazol-4-yl)-6-fluoro-2-(methylthio)pyrido[2,3-d ]pyrimidin-4-yI)-6-methyl-1.4-oxazepan-6-ol. To a solution of (S)-4-(7-chloro-6-fluoro-2-(methylthio)pyrido[2,3-rf|pyrimidin- 4-yl)-6-methyl-l,4-oxazepan-6-ol (5.00 g. 14.06 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was added the solution of K3PO4 (14.79 g, 70.3 mmol), 5-(3-((te / - / -butyldimethylsilyl)oxy)propyl)-6- cliloro-l -(tctrahydro-2H -pyran-2-yl)-4- / 4.4.5.5-tctramcthyl-l.3.2-dioxaborolan-2-yl)-l / / -indazolc (7.45 g, 14.06 mmol) and CataCXium A Pd G3 (1.02 g, 1.41 mmol) at room temperature under N2. Then the mixture was stirred at 110 °C for 1 h under N2. The reaction mixture was quenched by addition of H2O (150 mL) and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SOi. filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of petroleum ether / EtOAc 3 / 1 to 1 / 1 to give (6S)-4-(7-(5-(3-((terZ-butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H - pyran-2-yl)-l / / -indazol-4-yl)-6-fluoro-2-(mctliylthio)pyrido|2.3-c / |pyriinidin-4-yl)-6-mclhyl-l .4- oxazepan-6-ol (7.00 g. 9.60 mmol, 69% yield), m / z (ESI): 731.3 (M+H)+.

[0326] Step 7. ((6S)-4-(7-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro- 2H -pvran-2-yl)-1H-indazol-4-yl)-6-fluoro-2-(mcthylthio)pyrido[2,3-( / ]pvrimidin-4-yl)-6-methvl-1.4-oxazepan-6-yl IH-imidazole-l -carboxylate. To solution of (6S)-4-(7-(5-(3-((Zerf- butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-4-yl)-6-fluoro-2- (methylthio)pyrido[2,3-or|pyrimidin-4-yl)-6-methyl-l,4-oxazepan-6-ol (1.60 g, 2.19 mmol) in tetrahydrofuran (8 mL) was added CD1 (1.42 g, 8.75 mmol) at room temperature and purged with nitrogen. Then the mixture was stirred at 80 °C for 4 h. The crude product ((6S)-4-(7-(5-(3-(( / ert- butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-4-yl)-6-fluoro-2- (methylthio)pyrido[2,3-d |pyrimidin-4-yl)-6-methyl-L4-oxazepan-6-yl IH-imidazolc-l -carboxylate (8 mL, crude) was used in the next step without work up. m / z (ESI): 825.4 (M+H)+.

[0327] Step 8. (16.S)-36-Chloro-26-fluoro-16-methyl-22-(methylthio)-31-(tetrahvdro-2H - pyran-2-yl)-31H-7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3-rf]pyrimidina-3(4,5)- indazolacyclononaphan-8-one. To solution of (6S)-4-(7-(5-(3-(( / er / -butyldimethylsilyl)oxy)propyl)- 6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-4-yl)-6-fluoro-2-(methylthio)pyrido[2,3- <: / |pyrimidin-4-yl)-6-mcthyl-l ,4-oxazcpan-6-yl IH-imidazole-l -carboxylate (8 mL, crude, used directly) in tetrahydrofuran (160 mL) was added TBAF (1 M in THF, 2.91 mL, 2.91 mmol) at room temperature and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica11005-W001-SEC gel eluting with a gradient of petroleinn ether / EtOAc 10 / 1 to 1 / 1 to give (16S)-36-chloro-26-fluoro- 16-metliy l-22-(methy lthio)-31 -(te trahy dro-2 / / -py ran-2-y l)-3 I / / -7.9-dio.xa- 1 (4,6)-oxazepana-2(4,7)- pyrido|2.3-c / |pyrimidina-3(4.5)-indazolacyclononaphan-8-onc (0.67 g, 1.04 mmol, 48% yield over 2 steps), m / z (ESI): 643.2 (M+H)+.

[0328] Step 9. (16A')-36-Chloro-26-fluoro-16-mc4hvl-22-(methvlsulfonvl)-31-(tetrahydro-2 / f- pyran-2-vl)-31 / f-7,9-dioxa-l (4,6)-oxazepana-2(4,7)-pyrido[2,3-d |pvrimidina-3(4,5)- indazolacyclononaphan-8-one. To solution of (16.S)-36-chloro-26-fluoro-16-methyl-22- (methylthio)-31 -itctrahydro-2 / / -pyran-2-yl)-31H-7.9-dio.xa- 1 (4,6)-oxazepana-2(4,7)-pyrido[2,3- i / ]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (1.10 g, 1.71 mmol) and sodium te / 7-butoxide (0.16 g, 1.71 mmol) in ethyl acetate (44 mL) was added / w-CPBA (0.63 g, 3.08 mmol) in portions at 0 °C. Then the mixture was stirred at 0 °C for 1 h. The mixture was poured into sat. Na^SO, (100 mL) slowly at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of petroleum ether / EtOAc 3 / 1 to 1 / 1 to give ( 16S)-36-chloro-26-fhioro- 16-methy l-22-(methy Isulfony l)-31 -(tetrahy dro-2H -pyran-2-y l)-31H-7,9- dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3-i / ]pyrimidina-3(4.5)-indazolacyclononaphan-8-one (0.40 g, 0.59 mmol, 35% yield), m / z (ESI): 675.3 (M+H)+.

[0329] Step 10. ((165)-36-Chloro-26-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5W)-yl)rnethoxy)-16-rncthyl-31-(tetrahydro-2H -pyran-2-vl)-31 / / -7,9-dioxa-l(4,6)-oxazepana- 2(4,7)-pyrido[2,3-^pyrimidina-3(4,5)-indazolacyclononaphan-8-one. To solution of (16S)-36- chloro-26-fluoro- 16-methyl-22-(methylsulfonyl)-31 -(tetrahydro-2 / f-pyran-2-yl)-3 l / / -7.9-dioxa- l(4.6)-oxazepana-2(4,7)-pyrido[2,3-i / ]pyrimidina-3(4.5)-indazolacyclononaphan-8-one (0.45 g, 0.67 mmol) and ((2A.7aS)-2 -fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methanol (0.11 g. 0.67 mmol) in toluene (14 mL) was added sodium / ert-butoxide (0.13 g, 1.33 mmol) at 0 °C and purged with nitrogen and stirred at 0 °C for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over NazSOi. filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 10 / 1 to 1 / 1 petroleum ether / EtOAc to give ((16S)-36-chloro-26-fluoro-22-(((2R,7aS)-2- fluoro tetrahydro- 1H-pyrrolizin-7a(5f / )-yl)methoxy)- 16-methyl-31 -(tetrahy dro-2H -py ran-2-yl)-3 IH- 7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3-<7|pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.23 g, 0.30 mmol, 45% yield), m / z (ESI): 754.3 (M+H)+.

[0330] Step 11. (165)-36-Chloro-26-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-16-methyl-31 / / -7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyi ido[2,3-d|pyi iniidina- 3(4,5)-indazolacyclononaphan-8-one. To solution of (16.S)-36-chloro-26-fluoro-22-(((2R,7aS)-2- fluoro tetrahy dro- 1H-pyrrolizin-7a(5f / )-yl)methoxy)- 16-methyl-31 -itetrahy dro-2H -py ran-2-y l)-3 IH-11005-W001-SEC7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3-<7|pyrimidina-3(4,5)-indazolacyclononaphan-8-one (0.45 g, 0.60 mmol) in dichloromethane (9 mL) was added TFA (4.5 mL) at 0 °C. Then the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the mixture was adjusted to pH 9 with NH, H;O. The reaction mixture was concentrated and purified by prep-HPLC (Waters Xbridge BEH 10 micron, C 18. 250 x 50 mm column; mobile phase: [A: H2O (10 mM NH4HCO3); B:ACN]; B%: 30.00%-70.00%, 10 min) to give (16S)-36-chloro- 26-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-16-methyl-3 lH-7,9- dioxa-l(4.6)-oxazepana-2(4,7)-pyrido[2,3-or|pyrimidina-3(4,5)-indazolacyclononaphan-8-one (Example 1.004, 0.10 g, 0.18 mmol, 30% yield), m / z (ESI): 670.3 (M+H)+.!H NMR (400 MHz, CDCls) 5 ppm 8.12 (d. J= 8.8 Hz, 1 H). 7.70 (s. 1 H), 7.57 (s, 1 H), 5.50 (d, J= 17.2 Hz, 1 H). 5.27 (d, J= 54.0 Hz, 1 H), 4.54 (d, J= 12.8 Hz, 1 H), 4.40 (d. J= 10.8 Hz, 1H), 4.25-4.31 (m, 2H ). 3.96- 4.00 (m, 1 H). 3.52-3.67 (m, 4 H), 3.18-3.34 (m, 5 H). 2.99-3.01 (m, 1 H), 2.82-2.84 (m. 2H ). 2.09- 2.28 (m, 3 H). 1.81-1.94 (m, 4 H), 1.68-1.70 (m, 1 H). 1.54 (s, 3 H).19F NMR (376 MHz, CDCl3) 8 ppm -125.12 (s, 1 F), -172.26 (s, 1 F).

[0331] (265)-18-Chloro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2-«]pyrrol-7a(5J7)- yl)methoxy)-23, 25, 28-trioxa-l ,3,5,14,15,32- hexaazahexacyclo [24.4.1.1-6,10-.0-2,7~.0~11 ,19~.0~12,16~] dotriaconta-2,4,6,8,10(32),ll,13,16,18-nonaen-24-one (Example 1.005).

[0332] Step 1. (65)-4-(7-(5-(3-((ter / -Butyldiphenylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro- 2H -pyran-2-yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-11005-W001-SEC yl)methoxy)pyrido[2,3-rf|pyrimidin-4-yl)-l,4-oxazepan-6-ol. To a stirred mixture of 2,4,7- trichloropyrido[2,3-r / |pyrunidine (0.72 g, 3.06 mmol, Ambeed, Inc.) and l,T-dimethyltriethylamine (2.7 mL, 15.5 mmol) in acetonitrile (12.3 mL) at 0 °C, was added (S)-l,4-oxazepan-6-ol hydrochloride (0.47 g, 3.05 mmol, Pharmablock, Inc.) and the resulting mixture was stirred at 0 °C. After 30 min ((2A,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (0.88 g, 5.51 mmol, Pharmablock, Inc.) was added and the reaction was heated to 80 °C. After stirring 21 h, the reaction was concentrated under reduced pressure to afford crude product. The crude was purified via column chromatography on silica gel using a gradient of 0-50% of a 3 : 1 EtOAc:EtOH mixture (containing 2% triethylamine) in heptane to provide (.S)-4-(7-chloro-2-(((2A,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5T / )-yl)methoxy)pyrido[2,3-r / ]pyrimidm-4-yl)-l,4-oxazepan-6-ol (0.30 g, 0.69 mmol, 22% yield). m / z (ESI): 438.0 (M+H)+.

[0333] Step 2. (65)-4-(7-(5-(3-((terCButyldiphenylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro- 2H -pyran-2-yl)-1H-indazol-4-yl)-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- y I) methoxy) py ndo |2, 3-< / | py rimidi n-4-y l)-l ,4-oxazepan-6-ol. A reaction vessel was charged with palladium(II) acetate (31 mg. 0.14 mmol, AK Scientific, Inc.), (S)-(-)-2-(diphenylphosphino)-2- methoxy-l-.l-binaphthyl(S)-MOP (0.13 g, 0.27 mmol. Combi-Blocks Inc.), potassium phosphate (0.36 g, 1.71 mmol). 5-(3-((Zert-butyldiphenylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2Ef-pyran-2- yl)-4-(4,4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indazole (0.68 g, 1.03 mmol), and (S)-4-(7- chloro-2-(((27?,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5 / f)-yl)methoxy)pyrido[2.3-< / ]pyrimidin-4- yl)-1.4-oxazepan-6-ol (0.30 g, 0.69 mmol) before being suspended in 2-methyltetrahydrofuran (6.1 mL) and water (1.5 mL) sparged for 5 min and stirred at 80 °C. After 3 h. the reaction was concentrated under reduced pressure and the crude material was purified via column chromatography on silica gel using a gradient of 0-60% of a 3:1 EtOAc:EtOH mixture (containing 2% triethylamine) in heptane to provide (6S)-4-(7-(5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro- 2H -pyran-2-yl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fhiorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-d ]pyrimidin-4-yl)-l,4-oxazepan-6-ol (0.44 g, 0.47 mmol, 68% yield), m / z (ESI): 934.0 (M+H)+.|00334] Step 3. (265)-18-Chloro-4-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolo|l,2-a|pyrrol- 7a(5H)-yl)methoxy)-23,25,28-trioxa-l,3,5,14,15,32- hexaazahexacyclo [24.4.1.1 ~6,10~.0~2,7~.0~l 1 ,19~.0~l 2 , 16~] dotriaconta- 2,4,6,8,10(32),ll,13,16,18-nonaen-24-one. To a stirred mixture of (6S)-4-(7-(5-(3-((tert- butyldiphenylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-4-yl)-2-(((21?,7aS)- 2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2.3-r7|pyrimidin-4-yl)-l,4-oxazepan-6-ol (0.33 g, 0.36 mmol) in tetrahydrofuran (7.1 mL) at room temperature, xvas added 1,1'- carbonyldiimidazole (64 mg, 0.39 mmol) and the resulting mixture was stirred at room temperature. After 2 h, the reaction was then diluted with THF (63 mL) and tetrabutylammonium fluoride solution11005-W001-SEC(1.0 M in THF, 0.89 mL, 0.89 mmol, Sigma- Aldrich Corporation). After an additional 17 h, the reaction was concentrated under reduced pressure. The crude material was purified via column chromatography on silica gel column using a gradient of 0-80% of a 3:1 EtOAc:EtOH mixture (containing 2% triethylamine) in heptane to provide Ar-(tetrahydro-2H -pyran-2-yl)-(26S)-18-chloro-4- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1.3.5.14.15.32-hexaazahexacyclo[24.4.1.1~6,10~.0~2.7~.0~l l,19~.0~12.16~]dotriaconta- 2.4.6,8,10(32),ll,13,16,18-nonaen-24-one. m / z' (ESI): 722.2 (M+H)+.

[0335] The material was then dissolved in DCM (5 mL) and hydrogen chloride (4.0 M in 1,4- dioxanc, 0.9 mL, 3.60 mmol, Sigma-Aldrich Corporation) was added. After 1.5 h, the reaction was concentrated under reduced pressure and purified by prep-HPLC on a Phenomenex Gemini 5 micron, C18, 100 A, 150 x 30 mm column eluting with a gradient of 10-90% acetonitrile (0.1% TFA) in water (0.1% formic acid). The combined fractions were lyophilized to provide (26S)-18-chloro-4- (((2R,7aS)-2-fluorotetrahydro-lFf-pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-23,25,28-trioxa-1.3.5.14.15.32-hexaazahexacyclo[24.4.1.1~6,10~.0~2.7~.0~l l,19~.0~12.16~]dotriaconta- 2.4,6,8,10(32),ll,13,16,18-nonaen-24-one bis(2,2,2-trifluoroacetate) (Example 1.005, 18 mg, 0.02 mmol, 6% yield), m.'z (ESI): 638.0 (M+H)+.]H NMR (400 MHz, MeOD-d^ 5 ppm 8.82 (d, J=8.4 Hz, 1 H), 7.80 - 7.88 (m. 2 H), 7.64 (d, J=8.4 Hz, 1 H), 5.51 - 5.71 (m, 1 H), 5.40 (br d, J=16.5 Hz. 1 H), 4.88 (br s. 1 H), 4.66 - 4.76 (m. 3 H), 4.30 - 4.40 (m, 1 H), 3.87 - 4.13 (m, 6 H). 3.73 (dd, J=6.6, 3.4 Hz. 2 H), 3.59 - 3.69 (m. 1 H), 3.52 (br d. J=6.1 Hz, 2 H), 3.01 - 3.13 (m, 1 H), 2.86 - 2.97 (m. 1 H), 2.55 - 2.83 (m, 2 H). 2.31 - 2.51 (m, 3 H). 2.10 - 2.25 (m, 1 H). 1.76 - 1.90 (m, 1 H), 1.64 - 1.77 (m, 1 H).19F NMR (376 MHz. MeOD-d4) 5 ppm -77.35 (s, 1 F). -174.28 (s. 1 F).

[0336] (11R,l3R,19R)-9-Cliloio-26-(((2R,7a.S)-2-fliioroteti ahy(lio-l / / -pyrrolo| L2- |pyi rol- 7a(5H)-yl)methoxy)-19-metliyl-16-oxa-5,6,18,23,25,27,32- heptaazaheptacyclo[26.3.1.1~19,23~.0~2,10~.0~3,7~.0~ll,13~.0~24,29~]tritriaconta- l(32),2,4,7,9,24,26,28,30-nonaen-17-one (Example 1.006) and (l l.S.13.S.19R)-9-chloro-26- (((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2-«]pyrrol-7a(5H)-yl)methoxy)-19-methyl-16-oxa-5,6,18,23,25,27,32- heptaazaheptacyclo[26.3.1.1~19,23~.0~2,10~.0~3,7~.0~ll,13~.0~24,29~]tritriaconta- l(32),2,4,7,9,24,26,28,30-nonaen-17-one (Example 1.007).11005-W001-SEC

[0337] Step 1. tert- Butyl (3R)-3-(((2-((1R*,2R*)-2-(4-bromo-6-chloro-l-(tetrahydro-2H -pyran- 2-yl)-1H-indazoI-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methyIpiperidine-l- carboxylate. To a stirred mixture of tert-butyl (3r)-3-amino-3-methyl-piperidine-l-carboxylate (0.50 mL. 2.33 mmol, Pharmablock, Inc.) and MAZ-diisopropylethylamine (0.44 mL, 2.57 mmol, TCI America) in acetonitrile (4.7 mL) at room temperature, was added 4-nitrophenyl chloroformate (0.52 g, 2.57 mmol, Acros Organics) and the resulting mixture was stirred at room temperature. After 10 min, / 't7-2-(( L / ?,27?)-2-(4-bromo-6-chloro- 1 -(tetrahy dro-2H -pyran-2-y 1)- 1 rt-indazol-5 - yl)cyclopropyl)ethan-l-ol (Intermediate L, 1.40 g, 3.50 mmol) and A.,V-diisopropylcthylaminc (1.4 mL, 8.17 mmol) were added before the reaction mixture was heated to 80 °C. After stirring 19 h, the reaction mixture was concentrated under reduced pressure and purified via column chromatography using a C18 column using a gradient of 10-100% MeCN (containing 0.1% formic acid) in water (containing 0.1% formic acid) to provide tert-butyl (37?)-3-(((2-((ll?*,27?*)-2-(4-bromo-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3- methylpiperidine-1 -carboxylate (1.11 g, 1.73 mmol, 74% yield). wz (ESI): 661.0 (M+Na)+.

[0338] Step 2. tert-Butyl (3R)-3-(((2-((1RA,2RA)-2-(6-chloro-l-(tetrahydro-2H -pyran-2-yl)-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate. A reaction vessel was charged with cesium carbonate (0.84 g, 2.58 mmol, Combi-Blocks Inc.), bis(pinacalato)diboron (0.5211005-W001-SEC g, 2.06 mmol, Combi-Blocks Inc ), palladium(II) acetate (19 mg, 0.086 mmol, AK Scientific, Inc.), tris(4-mctlio.xyphcnyl)pbospliinc (61 mg, 0.17 mmol, Combi-Blocks Inc.), and tert-butyl (37?) -3 -(((2- ((17?*, 27?*)-2-(4-bromo-6-chloro-l -(tetr ahy dro-2 / / -pyran-2-yl)- 1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-metliylpiperidine-l-carboxylate (1.10 g, 1.72 mmol) before being suspended in EtOAc (3.4 mL), sparged with nitrogen for 5 min, and stirred at 80 °C. After stirring for 3.5 h, the reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude material was then purified via column chromatography on silica gel using a gradient of 0-40% EtOAc in heptane to provide tert-butyl (37?)-3-(((2-((17?*.27?*)-2-(6-chloro- l-(tetrahydro-27f-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate (0.91 g, 1.33 mmol. 77% yield), m / z (ESI): 687.2 (M+H)+.

[0339] Step 3. tert- Butyl (3R)-3-(((2-((1R%2R*)-2-(4-(4-(tert-butoxy)-2-(((2R ,7aS )-2- fluorotetrahydro-1H-pyrrolizin-7a(517)-yl)methoxy)pyrido[2,3-d |pyrimidin-7-yl)-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3- methylpiperidine-1 -carboxylate. A reaction vessel was charged with methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-l,T-biphenyl-2-yl)palladium(II) (65 mg, 0.09 mmol, Ambeed, Inc.), potassium phosphate (0.38 g, 1.79 mmol), tert-butyl (37?)-3-(((2- ((17?*,27?*)-2-(6-chloro-l-(tetrahydro-2H -pyran-2-yl)-4-(4,4.5.5-tetramethyl-l,3,2-dioxaborolan-2- yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate (0.49 g, 0.71 mmol), and 4-(tert-butoxy)-7-chloro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-d |pyrimidine (0.24 g, 0.59 mmol). The vial was purged with nitrogen and then the reactants were suspended in degassed 2-Me-THF (5.4 mL) and water (0.54 mL). The reaction was then sealed and heated to 80 °C. After stirring for 2 h, the reaction was concentrated under reduced pressure and purified via column chromatography on silica gel using a gradient of 0-80% of a 3:1 EtOAc:EtOH mixture (containing 2% triethylamine) in heptane to provide tert-butyl (37?)-3-(((2- ((17?*.27?*)-2-(4-(4-(tert-butoxy)-2-(((27?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-< |pyrimidin-7-yl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate (0.46 g, 0.51 mmol, 85% yield). m,'z (ESI): 919.4 (M+H)+.

[0340] Step 4. 2-((1RA,2RA)-2-(6-Chloro-4-(2-(((2R ,7aS )-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-hydroxypyrido[2,3-« / ]pyrimidin-7-yl)-1H-indazol-5-yl)cyclopropyl)ethyl ((R)-3-methylpiperidin-3-yl)carbamate trihydrochloride. To a stirred mixture of tert-butyl (37?)-3- (((2-((17?*.27?*)-2-(4-(4-(tert-butoxy)-2-(((2R,7aS)-2 -fluorotetr ahy dro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-< |pyrimidin-7-yl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-l-carboxylate (0.26 g, 0.28 mmol) in dichloromethane (3.5 mL) at room temperature, was added hydrogen chloride (4.0 M in 1,4-dioxane,11005-W001-SEC0.71 mL, 2.84 mmol) and the resulting mixture was stirred at room temperature. After stirring for 3 h, die reaction was dissolved with methanol (~3 mL) and then concentrated under reduced pressure to afford crude 2-((lR*,2R*)-2-(6-chloro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-hydroxypyrido[2,3-t / ]pyrimidin-7-yl)-1H-indazol-5-yl)cyclopropyl)ethyl ((R)-3- methylpiperidin-3-yl)carbamate trihydrochloride assuming quantitive yield and used wiUiout further purification in the subsequent step. m,'z (ESI): 679.2 (M+H)+.

[0341] Step 5. (11R,131?,19R)-9-Chloro-26-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolo[l ,2- a] pyrroI-7a(5H)-yl)methoxy)-l 9-methyl-l 6-oxa-5,6,l 8,23,25,27,32- heptaazahcptacyclo[26.3.1.1~19,23~.0~2,10~.0~3,7~.0~ll,13~.0~24,29~]tritriaconta- l(32),2,4,7,9,24,26,28,30-nonaen-17-one and (l l.S’,13X,19R)-9-chloro-26-(((2R,7a )-2- fluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-19-methyl-16-oxa- 5,6,18,23,25,27,32- heptaazaheptacyclo[26.3.1.1~19,23~.0~2,10~.0~3,7~.0~ll,13~.0~24,29~]tritriaconta- l(32),2,4,7,9,24,26,28,30-nonaen-17-one. To a stirred mixture of bromotris(dimethylamino)phosphonium hexafluorophosphate (0.44 g, 1.13 mmol. Oakwood Products, Inc.)) and A.A-diisopropylcthylaniinc (0.5 mL, 2.87 mmol. TCI America) in acetonitrile (50 mL) at room temperature, was added 2-((lR*,2R*)-2-(6-chloro-4-(2-(((2R,7aS)-2-fhiorotetrahydro-1H- pyrrolizin-7a(5F / )-yl)methoxy)-4-hydroxypyrido[2,3-t / |pyrimidin-7-yl)-1H-indazol-5- yl)cyclopropyl)ethyl ((R)-3-methylpiperidin-3-yl)carbamate trihydrochloride (0.22 g, 0.28 mmol) in dimethyl sulfoxide (7.0 mL) over 1.5 h via syringe pump and the resulting mixture was stirred at room temperature. After 2 d. the volatiles were removed under reduced pressure, and the resultant oil was then diluted with EtOAc (50 mL) and water (50 mL). The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by prep-HPLC on a Phenomenex Gemini 5 micron, C18. 100 A, 150 x 30 mm column with a gradient of 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA). The combined fractions were lyophilized to provide (1 lR,13R,19R)-9-chloro-26-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2- «]pyrrol-7a(5H)-yl)methoxy)-19-methyl-16-oxa-5.6.18,23,25,27,32- heptaazaheptacyclo[26.3.1.1~19,23~.0~2,10~.0~3.7~.0~l l,13~.0~24,29~]tritriaconta- l(32),2,4,7,9,24,26,28,30-nonaen-17-one bis(2,2,2-trifluoroacetate) (Example 1.006, 51 mg. 0.06 mmol, 20% yield), m / z (ESI): 661.2 (M+H)+. ’H NMR (400 MHz, MeOD-d) 5 ppm 8.89 (br d. J=8.4 Hz, 1 H), 8.27 (s, 1 H), 8.17 (d, J=8.6 Hz, 1 H), 7.85 (s, 1 H), 5.53 - 5.74 (m, 2 H), 5.26 (br d, 1=12.5 Hz, 1 H), 4.82 (d, 1=5.2 Hz, 2 H). 4.08 (br d, J=9.0 Hz, 1 H), 3.84 - 4.01 (m, 4 H), 3.78 (d, J=13.6 Hz, 1 H), 3.37 - 3.53 (m, 2 H), 2.61 - 2.84 (m, 3 H), 2.44 - 2.57 (m, 1 H), 2.34 - 2.42 (m, 2H ), 2.15 - 2.29 (m, 1 H), 1.97 - 2.07 (in, 1 H), 1.86 - 1.95 (in, 2 H), 1.75 - 1.84 (m, 1 H), 1.45 (s, 4 H), 0.81 (br d, J=9.8 Hz, 2 H), 0.53 - 0.63 (in, 1 H), 0.05 - 0.16 (in, 1 H).19F NMR (376 MHz, MeOD-d) 5 ppm - 77.21 (s, 1 F), -174.20 (s, 1 F)) and (llS',13S',19R)-9-chloro-26-(((2R ,7aS)-2-fluorotetrahydro-1H-11005-W001-SEC pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-19-metliyl-16-oxa-5,6,18,23,25,27,32- heptaazaheptacyclo[26.3.1.1~19,23~.0~2,10~.0~3,7~.0~l l,13~.0~24,29~]tritriaconta- l(32),2,4,7,9,24,26,28,30-nonaen-17-one bis(2,2,2-trifluoroacetate) (Example 1.007, 56 mg, 0.06 mmol, 22% yield), m / z (ESI): 661.2 (M+H)+.1H NMR (400 MHz, MeOD-dl) 5 ppm 8.89 (br d, J=8.4 Hz, 1 H), 8.27 (s, 1 H), 8.17 (d. J=8.6 Hz, 1 H), 7.85 (s, 1 H), 5.53 - 5.74 (m, 2 H), 5.26 (br d, J=12.5 Hz, 1 H), 4.82 (d, 1=5.2 Hz, 2 H), 4.08 (br d, J=9.0 Hz, 1 H), 3.84 - 4.01 (m, 4 H). 3.78 (d, J=13.6 Hz, 1 H), 3.37 - 3.53 (m. 2 H), 2.61 - 2.84 (in. 3 H), 2.44 - 2.57 (m. 1 H), 2.34 - 2.42 (m, 2H ), 2.15 - 2.29 (m, 1 H), 1.97 - 2.07 (m, 1 H), 1.86 - 1.95 (m, 2 H), 1.75 - 1.84 (m. 1 H), 1.45 (s, 4 H), 0.81 (br d, J=9.8 Hz, 2 H), 0.53 - 0.63 (m, 1 H), 0.05 - 0.16 (m. 1 H).19F NMR (376 MHz. MeOD-dl) 5 ppm - 77.21 (s, 1 F). -174.20 (s, 1 F).

[0342] (lA',3R)-ll-Chloro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2-«]pyrrol-7a(5H)- yl)methoxy)-34-oxa-5,14,15,24,26,28,33- heptaazaoctacyclo[26.3.1.1~l,3~.l~4,7~.l~19,23~.0~l 0,18~.0-13,17~.0~22,27~] pentatriaconta- 4,6,10,12,15,17,19(33),20,22,24,26-undecaen-3-ol (Example 1.008)

[0343] Step 1. tert- Butyl (2S',4R)-2-(5-(2-(4-(4-(tert-butoxy)-2-(((2R ,7aS )-2-fluorotetrahydro- 1H-pyiTolizin-7a(5H)-yl)methoxy)pyrido[2,3-r / ]pyrimidin-7-yl)-6-chloro-l -(tetrahydro-2H - pyran-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6- carboxylate. A reaction vessel was charged with methanesulfonato(diadamanty 1-n-butylphosphino)-11005-W001-SEC2'-amino-l,T-biphenyl-2-yl)palladimn(II) (70 mg, 0.096 mmol, Ambeed, Inc.), potassium phosphate (0.40 g, 1.90 mmol), tert-butyl (2s,4r)-2-(5-(2-(6-chloro-l-(tetrahydro-2H -pyran-2-yl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6- azaspiro[3.5]nonane-6-carboxylate (Intermediate J, 0.56 g, 0.76 mmol), and 4-(tert-butoxy)-7- chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(52f)-yl)methoxy)pyrido[2,3-d|pyrimidine (Intermediate C, 0.25 g, 0.63 mmol). The vial was purged with nitrogen and then the reactants were suspended in degassed 2-Me-THF (5.8 mL) and water (0.58 mL). The reaction was then sealed and heated to 80 °C. After stirring for 3 h, the reaction was concentrated under reduced pressure and purified via column chromatography on silica gel using a gradient of 0-60% of a 3: 1 EtOAc:EtOH mixture (containing 2% triethylamine) in heptane to provide tert-butyl (2>S',4R)-2-(5-(2-(4-(4-( / ert- butoxy )-2-(((2A.7a5)-2 -fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-tZ|pyrimidin-7- yl)-6-chloro-l-(tetrahydro-2 / / -pyran-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)- 6-azaspiro[3.5]nonane-6-carboxylate (0.43 g, 0.45 mmol, 70% yield), m / z (ESI): 973.4 (M+H)+.

[0344] Step 2. 7-(6-Chloro-5-(2-(2-((25,4R)-2-hydroxy-6-azaspiro[3.5]nonan-2-yl)oxazol-5- yl)cthvl)-1H-indazol-4-yl)-2-(((2R,7aA)-2-f'luorotetrahvdro-1H-])vrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-rf|pyrimidin-4-ol trihydrochloride. To a stirred mixture of tert-butyl (2S.4I?)-2-(5-(2-(4-(4-(tert-butoxy)-2-(((2A.7a5)-2-fluorotetrahydro-lEf-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-d ]pyrimidin-7-yl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5- yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate (0.43 g, 0.45 mmol) in dichloromethane (6 mL) at room temperature, was added hydrogen chloride (4 M in 1,4-dioxane, 1.1 mL. 4.40 mmol) and the resulting mixture was stirred at room temperature. After stirring for 5 h. the reaction was dissolved with methanol (~5 mL) and then concentrated under reduced pressure to afford crude 7-(6-chloro-5-(2-(2-((2S,4A)-2-hydroxy-6-azaspiro[3.5]nonan-2-yl)oxazol-5-yl)ethyl)- 1H-indazol-4-yl)-2-(((27L7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3- <7|pynmidin-4-ol trihydrochloride assuming quantitative yield and used in the subsequent step without further purification.

[0345] Step 3. (15',3R)-ll-Chloro-25-(((2R ,7aS )-2-fluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol- 7a(5 / f)-yl)methoxy)-34-oxa-5,l 4,15,24,26,28,33- heptaazaoctacyclo[26.3.1.1~l,3~.l~4,7~.l~19,23~.0~10,18~.0~13,17~.0~22,27~]pentatriaconta- 4,6,10,12,15,17,19(33),20,22,24,26-undecaen-3-ol. To a stirred mixture of bromotris(dimethylamino)phosphonium hexafluorophosphate (0.69 g. 1.78 mmol, Oakwood Products, Inc.) and AJV-diisopropylethylamine (0.8 mL, 4.59 mmol, TCI America) in acetonitrile (78 mL) at room temperature, was added 7-(6-chloro-5-(2-(2-((2S.47?)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)oxazol-5-yl)ethyl)-l / 7-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5f / )- yl)methoxy)pyrido[2,3-d |pyrimidin-4-ol trihydrochloride (0.36 g. 0.45 mmol) in dimethyl sulfoxide (11 mL) over 45 min via syringe pump and the resulting mixture was stirred at room temperature.11005-W001-SECAfter 16 h, the volatiles were removed under reduced pressure, and the resultant oil was then diluted with EtOAc (100 inL) and water (100 niL). The mixture was shaken before the layers were separated, and the organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified via reversed phase column chromatography using a gradient of 10-100% MeCN (containing 0.1% formic acid) in water (containing 0.1% formic acid) to provide (lS',3R)-l l-chloro- 25-(((2R,7aS)-2-fhiorotetrahydro-1H-pyrrolo[ l,2-a]pyrrol-7a(5F / )-yl)methoxy)-34-oxa- 5.14,15.24,26.28,33- heptaazaoctacyclo[26.3.1.1~l,3~. l~4,7~. l~19,23~.0~10,18~.0~13,17~.0~22.27~]pentatriaconta- 4.6.10, 12.15, 17, 19(33), 20, 22, 24, 26-undecaen-3-ol hexafluorophosphate(V) salt (Example 1.008, 80 mg. 0.098 mmol, 22% yield), m / z (ESI): 671.0 (M+H)1. *H NMR (400 MHz, MeOD-cL) 8 ppm 8.49 (dd. J=8.3, 2.8 Hz. 1 H), 7.87 (s, 1 H), 7.84 (d, J=3.1 Hz. 1 H). 7.54 (d, J=8.4 Hz, 1 H), 6.59 (d, J=3.8 Hz. 1 H), 5.43 - 5.71 (m. 1 H), 4.54 - 4.79 (in. 3 H), 3.86 - 4.04 (m. 3 H). 3.74 (br d. J=13.2H z, 1 H), 3.41 - 3.57 (m, 1 H). 3.13 - 3.28 (m, 2 H). 2.99 - 3.11 (m, 1 H). 2.55 - 2.82 (m, 5 H), 2.27 - 2.52 (m, 3 H), 2.13 - 2.24 (m. 1 H), 1.94 - 2.12 (m, 3 H), 1.75 - 1.92 (m, 4 H), 1.70 (br d, J=12.5 Hz, 1 H).19F NMR (376 MHz. MeOD-d4) 8 ppm -76.14 - -73.29 (m, 1 F), -174.38 (d. J=21.7 Hz, 1 F).

[0346] (l R.3R.7R.9.S)-l 1.20-I)icliloro-25-(((2R,7aS)-2-flu(irotetrahy(lro-1H |)M n)lo| 1.2- a] pyrroI-7a(5H)-yl)methoxy)-5-oxa-l 4,15,24,26,28,33- hexaazaoctacyclo[26.3.1.1~l,3~.l~19,23~.0~7,9~.0~10,18~.0~13,17~.0~22,27~]tetratriaconta- 10,12,15,17, 19(33), 20, 22, 24, 26-nonacn-3-ol and (l.S.3R.7.S.9R)-11.20-(lichloro-25-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-5-oxa-14,15,24,26,28,33- hexaazaoctacyclo[26.3.1.1~l,3~.l~19,23~.0~7,9~.0~10,18~.0~13,17~.0~22,27~]tetratriaconta- 10,12,15,17, 19(33), 20, 22, 24, 26-nonaen-3-ol (Examples 1.009 and 1.010).11005-W001-SEC

[0347] Step 1. tert- Butyl (2S,4R)-2-((((l R,2S)-2-(4-((5)-4-(tert-butoxy)-6-chloro-2-(((2R ,7aS )-2- t'luorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d |pyrimidin-7-yl)-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methoxy)methyl)-2-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate. To a stirred solution of tert-butyl (21S’,47?)-2-((((17?.2>S)-2-(6- chloro-l-(tetrahydro-2H -pyran-2-yl)-4-(4.4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (Intermediate G, 0.88 g, 1.28 mmol), 4-(tert-butoxy)-6.7-dichloro-2-(((2R,7aS’)-2-fluorotetrahydro-lJ7-pyrrolizin- 7a(5E / )-yl)methoxy)pyrido[2,3-d ]pyrimidine (Intermediate D, 0.50 g, 1.17 mmol) in 2- methyltetrahydrofuran (10 mL) and water (1 mL) was added K3PO4 (1.24 g, 5.82 mmol) and CataCXium A Pd G3 (0.17 g, 0.23 mmol). The resulting mixture was purged with nitrogen and stirred at 80 °C for 1 h. A total of 7 batches were combined for workup and purification. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 5 / 1 to 0 / 1 petroleum ether in EtOAc. The product was further purified by reversed phase MPLC on a 800 g Luna column with a flow rate of 130 mL / min, eluting with 70-100% MeCN (0.1% TFA) in water (0.1% TFA), to afford tert-butyl (2S.4R)-2-((((lA,25)-2-(4-((S)-4-(tert-butoxy)-6-chloro-2-(((27?.7a5)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5E / )-yl)methoxy)pyrido[2,3-d ]pyrimidin-7-yl)-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methoxy)methyl)-2-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (1.75 g, 1.84 mmol, 27% yield), m / z (ESI): 952.5 (M+H)+.

[0348] Step 2. (R)-6-Chloro-7-(6-chloro-5-((15,R,2R5)-2-((((25'R,47«)-2-hydroxy-6- azaspiro[3.5]nonan-2-yl)methoxy)methyl)cyclopropyl)-1H-indazol-4-yl)-2-(((2 / £S',7a5R)-2-11005-W001-SECHuorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d |pyrimidiii-4-ol. To a solution of tert-butyl (2S,47?)-2-(((( lR,2S)-2-(4-((S)-4-(tert-butoxy)-6-chloro-2-(((2.R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2.3-ty|pyrimidin-7-yl)-6-chloro-l -(tctraliydro-2 / / -pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.35 g, 0.37 mmol) in dichloromethane (3.5 mL) at 0 °C was added TFA (1.75 inL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was adjusted to pH 8 using aq. solution of ammonium hydroxide. The residue was purified by prep-HPLC on a Waters Xbridge BEH 10 micron, C18, 250 mm x 70 mm column, eluting with a gradient of 15-45% MeCN in water (0.5% NH4OH + 10 mM NH4HCO3) to afford (R)- 6-chloro-7-(6-chloro-5-((lSR,27dS)-2-((((2SA,47?S)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)methoxy)methyl)cyclopropyl)-1H-indazol-4-yl)-2-(((2RS.7a5R)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-y l)mcthoxy)pyrido|2.3-<: / |pyrimidin-4-ol (53 mg. 0.070 mmol, 20% yield), m / z (ESI): 712.3 (M+H)+.!H NMR (400 MHz, DMSO-d6) 5 ppm 13.26 (s, 1H), 8.26 (s, 1H). 7.79 (s, 1H). 7.65 (s. 1H), 5.20 - 5.34 (m. 1H), 4.83 (s, 1H), 3.94 - 3.96 (m. 2H ), 3.61 - 3.72 (m,lH), 3.02 - 3.15 (m, 5H), 2.73 - 2.92 (m. 6H), 2.12 - 2.32(m, 3H), 1.75 - 2.05 (m. 3H), 1.39 - 1.82 (m. 12H ). 0.60 (s, 1 H), 0.17 (s. 1H).19F NMR (376 MHz, DMSO-cR) 8 ppm -171.68 (s. IF).

[0349] Step 3. ( lR.3R.7R.9.S)-1 1.20-I)ichloro-25-(((2R,7aS)-2-f liiorotetrahy(lro-1H- pyiTolo[l,2-«|pyiTOI-7a(5H)-yl)methoxy)-5-oxa-14,15,24,26,28,33- hcxaazaoctacyclo[26.3.1.1~l,3~.l~19,23~.0~7,9~.0~10,18-.0~13,17~.0~22,27~|tetratriaconta- 10,12,15,17, 19(33), 20, 22, 24, 26-nonaen-3-ol and (l.S.3R.7.S.9R)-l l ,2O-dicliloro-25-(((2R,7aS)-2- tluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-5-oxa-14,15,24,26,28,33- hexaazaoctacyclo[26.3.1.1~1 ,3~.1~19,23~.0~7,9~.0~l 0,18~.0~l 3,17~.0~22,27~] tetratriaconta- 10,12,15,17,19(33),20,22,24,26-nonaen-3-ol (Examples 1.009 and 1.010). To a mixture of (A)-6- chloro-7-(6-chloro-5-((lSK.2RS)-2-((((2SK,47?>S)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)methoxy)methyl)cyclopropyl)- 1H-indazol-4-yl)-2-(((2AS,7aSK)-2-fluorotetrahydro- IH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[2,3-d ]pyrimidin-4-ol (0.11 g, 0.15 mmol). AtyV-diisopropylethylamine (51 pL, 0.30 mmol) in acetonitrile (5.3 mL) and dimethyl sulfoxide (1 mL) at room temperature under nitrogen was added BrOP (0.11 g, 0.30 mmol). The resulting mixture was stirred at room temperature for 2 h. A total of 8 batches were combined for the workup and purification. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC on a Waters Xbridge BEH 10 micro, C18, 250 mm x 50 mm column, eluting with a gradient of 25-65% MeCN in H2O (10 mM NH4HCO3). The product was further purified by SFC on a Daicel Chiralcel OD 10 micron, 250 mm x 30 mm column eluting with 50% COzin methanol (0.1% NH4OH). Peak 1: ( 1 R,3R,7R,9S)- 11, 20-dichloro-25-(((2R,7aS)-2 -fluoro tetrahydro- 1H-pyrrolo| 1 ,2-a]pyrrol-7a(5H)- yl)methoxy)-5-oxa-14,15,24,26,28,33- hexaazaoctacyclo[26.3.1.1-1, 3~.1-19,23-.0—7, 9- 0-10,18- 0-13,17— .0~22,27~]tetratriaconta-11005-W001-SEC10,12,15,17,19(33),20,22,24,26-nonaen-3-ol (Example 1.009, 94 mg, 0.14 mmol, 30% yield), m'z (ESI): 694.2 (M+H)+.]H NMR (400 MHz, DMSO-d6) 5 ppm 13.35 (s, 1H), 8.72 (s, 1H), 7.84 (s, 2H ), 5.18 - 5.31(m, 1H), 4.98( s, 1H), 4.68 - 6.71(m,lH), 4.42 (d, J=13.2 Hz, 1H), 4.00 - 4.11 (m, 2H ), 2.99 - 3.07 (m, 5H), 2.75 - 2.83 (in, 4H), 2.01 - 2.08 (m, 4H), 1.54 - 1.76(m, 10H), 1.33 - 1.37(m, 3H), 0.67 (s, 1H), 0.43 (s, 1H).19F NMR (376 MHz, DMSO-d6) 3 ppm -171.94 (s, 1 F). Peak 2: (lS.3R,7S,9R)-ll,20-dichloro-25-(((2R.7aN)-2-fluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol-7a(5H)- yl)methoxy)-5-oxa-14.15,24,26,28,33- hexaazaoctacyclo[26.3.1.1~l,3~.l~19,23~.0~7,9~.0~10.18~.0~13,17~.0~22,27~]tetratriaconta- 10,12,15,17.19(33),20.22,24.26-nonaen-3-ol (Example 1.010, 97 mg, 0.14 mmol. 31% yield), nvz' (ESI): 694.2 (M+H)1. ’H NMR (400 MHz, DMSO-d6) 3 ppm 13.35 (s, 1H), 8.72 (s, 1H). 7.84 (s, 2H ), 5.21- 5.35 (m. 1H), 4.97 (s, 1H), 4.69 (d, J=11.2 Hz. 1H), 4.42 (d, J=13.6 Hz. 1H), 4.00 - 4.11 (m, 2H ), 3.02 - 3.09 (m, 5H), 2.75- 2.83 (m, 4H), 2.01 - 2.16 (m. 4H), 1.70 - 1.95 (m, 10H), 1.33 - 1.58 (m. 3H), 0.67 (s. 1H), 0.43 (s, 1H).19F NMR (376 MHz. DMSO-d6) 8 ppm -171.96 (s. 1 F).

[0350] (265)-9,18-Dichloro-4-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2-«]pyrrol-7a(57 / )- yl)methoxy)-26-methyl-23,25,28-trioxa-l,3,5,14,15,32- hexaazahexacyclo [24.4.1.1~6,10~.0~2,7~.0~11 ,19~.0~12,16~] dotriaconta- 2,4,6(32),7,9,ll,13,16,18-nonaen-24-one (Example 1.011).11005-W001-SEC

[0351] Step 1. (S)-6-Methyl-4-(2,6,7-trichloropyrido[2,3-rf|pyrimidin-4-yl)-l,4-oxazepan-6-ol. To a solution of 2.4.6.7-tctrachloropyrido|2.3-<: / |pyrimidinc (Intermediate M, 14.0 g, 52.1 mmol) and N,N-diisopropylcthylaminc (27.3 mL, 156 mmol) in acetonitrile (98 inL) at 0 °C was added (S)-6- methyl-l,4-oxazepan-6-ol hydrochloride (8.73 g, 52.1 mmol). The resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched by addition of water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The crude material was purified by trituration with petroleum ether at room temperature for 15 min to afford (S)-6-methyl-4-(2,6.7-trichloropyrido[2,3-r / |pyrimidin- 4-yl)-l,4-oxazepan-6-ol (15 g, 41.3 mmol, 79% yield), m / z (ESI): 363.0 (M+H)+. *H NMR (400 MHz, CDCl3) 5 ppm 8.98 (s, 1H), 4.53 - 4.72 (m, 1H). 4.36 (d. J= 14.4 Hz. 1H), 3.86 - 4.19 (m, 3H), 3.55 - 3.73 (m, 4H), 1.35 (s, 3H).

[0352] Step 2. (5)-4-(6,7-Dichloro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)- yl)rnethoxy)pyrido|2,3-d |pyrirnidin-4-vl)-6-methyl-l ,4-oxazepan-6-ol, To a solution of (S)-6- methyl-4-(2,6.7-trichloropyrido[2,3-<7]pyrimidin-4-yl)-L4-oxazepan-6-ol (2.00 g, 5.50 mmol) in 1,4- dioxane (40 mL) at room temperature under nitrogen was added A.A-diisopropy Icthy lam inc (3.8 mL, 22.0 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.31 g, 8.25 mmol). The resulting mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0 to 100% EtOAc in petroleum ether, to afford (S)-4-(6,7-dichloro-2-(((27?,7a )-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-r / |pyrimidin-4-yl)-6-methyl-L4-oxazepan-6-ol (1.67 g, 3.43 mmol, 47% yield), m / z (ESI): 486.2 (M+H)+. ‘HNMR (400 MHz, CDCl3) 5 ppm 8.59 (s. 1H), 5.15 - 5.43 (m, 2H ), 4.45 (dt. J= 13.9, 3.81 Hz, 1H). 4.37 (d. J= 10.6 Hz. 1H), 4.20 - 4.29 (m. 2H ), 3.78 - 3.96 (m, 2H ). 3.62 - 3.75 (m. 2H ), 3.45 - 3.57 (m, 2H ). 3.14 - 3.34 (m, 3H). 2.89 - 3.07 (m, 1H), 2.09 - 2.29 (m. 2H ), 1.85 - 2.06 (m. 4H), 1.32 (s, 3H).19F NMR (376 MHz, CDCl3) S ppm -172.592 (s, 1 F).

[0353] Step 3. (65')-4-(7-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro- 2H -pyran-2-yl)-1H-indazol-4-yl)-6-chloro-2-(2-((2R,7aR)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)ethyl)pyrido[2,3-d]pyrimidin-4-yl)-6-methyl-l ,4-oxazepan-6-ol. To a solution of (.S)-4- (6,7-dichloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3- |pynmidin-4-yl)-6-mcthyl-1.4-oxazcpan-6-ol (2.40 g, 4.93 mmol) in 1,4-dioxane (24 mL) and water (2.4 mL) at room temperature under nitrogen was added K3PO4 (5.24 g, 24.7 mmol), 5-(3-((fert- butyldimethy lsilyl)oxy )propyl)-6-chloro- 1 -(tctrahy dro-2F / -py ran-2-y l)-4-(4.4,5 ,5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)- 1H-indazole (2.64 g. 4.93 mmol) and CataCXium A Pd G3 (0.36 g, 0.49 mmol). The mixture was stirred at 110 °C for 1 h then the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed xvith brine, dried over sodium11005-W001-SEC sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% EtOAc in petroleum ether, to afford (6S)-4-(7-(5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-l-(tetrahydro-2H -pyran-2-yl)-1H- indazol-4-y l)-6-chloro-2-(((2A’.7a,S)-2 -fluorotetr ahydro-l W-pyrrolizin-7a(5H)-yl)mctho\v)pyrido|2.3- <7|pyrimidin-4-yl)-6-methyl-l,4-oxazepan-6-ol (2.40 g, 2.79 mmol, 48% yield), m'z (ESI): 858.4 (M+H)+.

[0354] Step 4. ( 16^)-26,36-Dichloro-22-(((2R ,7aS)-2-fluorotetrahydro-l 7T-pyrrolizin-7a(57 / )- yl)methoxy)-16-methyl-31-(tetrahydro-2Z7-pyran-2-yl)-31 / 7-7,9-dioxa-l(4,6)-oxazepana-2(4,7)- pyrido[2,3-d |pvrimidina-3(4,5)-indazolacyclononaphan-8-onc. To solution of (6>S)-4-(7-(5-(3- ((tert-buty Idimethy lsilyl)oxy)propyl)-6-chloro- 1 -(tetrahydro-2H -pyran-2-y 1)- 1H-indazol-4-yl)-6- cliloro-2-(((27?,7a5)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-£ / ]pyrimidin-4- yl)-6-methyl-l,4-oxazepan-6-ol (0.70 g, 0.82 mmol) in tetrahydrofuran (3.5 mL) at room temperature under nitrogen was added CDI (0.53 g, 3.26 mmol). The reaction mixture was stirred at 80 °C for 4 h. To the resulting solution was added THF (70 mL) and TBAF (1.0 M in THF, 1.10 mL, 1.10 mmol) at room temperature under nitrogen and stirred at 60 °C for 1 h. A total of 6 batches were combined for the workup and purification. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 10 / 1 to 1 / 1 petroleum ether in EtOAc, to afford (l6S)-26,36-dichloro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5 / f)-yl)methoxy)-16-methyl-31-(tetrahydro-2H -pyran-2-yl)-31 / 7- 7.9-dioxa-l (4.6)-oxazcpana-2(4.7)-p\ rido[2.3-c / |pyrimidina-3(4.5)-mdazolacyclononaphan-8-onc (3.16 g, 4.10 mmol, 84% yield), m / z (ESI): 770.3 (M+H)+. *H NMR (400 MHz, CDCl3) 5 ppm 8.44 (s, 1H), 7.74 - 7.85 (m, 1H), 7.68 (d, J = 3.46 Hz, 1H), 5.65 - 5.81 (m, 1H), 5.57 (d, J = 16.9 Hz. 1H), 5.15 - 5.40 (m. 1H), 4.64 (d, J= 13.2 Hz, 1H). 4.34 - 4.42 (m. 2H ), 4.25 (dd. J= 10.6, 2.0 Hz, 1H), 3.96 - 4.09 (m. 2H ), 3.75 - 3.89 (m, 2H ). 3.71 (d, J= 12.2 Hz, 2H ), 3.57 (d, J= 16.9 Hz, 1H). 3.34 - 3.46 (m. 1H), 3.15 - 3.32 (in, 4H). 2.95 - 3.03 (m, 1H), 2.81 - 2.90 (m, 1H), 2.65 - 2.75 (m. 1H), 2.43 - 2.59 (m. 1H), 2.00 - 2.23 (in, 6H), 1.84 - 1.96 (m, 5H), 1.64 - 1.73 (m, 2H ), 1.57 (s, 3H).|00355] Step 5. (265)-9,18-Dichloro-4-(((2R ,7aS )-2-fluorotetrahydro-1H-pyrrolo[ l,2-a|pyrrol- 7a(5H)-yl)methoxy)-26-methyl-23,25,28-trioxa-l,3,5,14,15,32- hexaazahexacyclo [24.4.1.1 ~6,10~.0~2,7~.0~l 1 ,19~.0~l 2 , 16~] dotriaconta- 2,4,6(32),7,9,ll,13,16,18-nonaen-24-one (Example 1.011). To solution of (l6S)-26,36-dichloro-22- (((21?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-16-methyl-31-(tetrahydro-2H -pyran- 2-yl)-31H-7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2.3-r / |pyrimidina-3(4,5)-indazolacyclononaphan- 8-one (0.93 g, 1 .20 mmol) in dichloromethane (18.5 mL) at 0 °C under nitrogen was added TFA (9.25 mL). The resulting mixture was stirred at room temperature for 1 h. A total of 6 batches were combined for the workup and purification. The reaction mixture was concentrated under reduced11005-W001-SEC pressure and the residue was adjusted to pH 9 by aq. solution of NH4OH. The resulting mixture was concentrated under reduced pressure. The crude material was purified by prep-HPLC on a Waters Xbridge BEH 10 micron, 250 mm x 70 mm, C18 column, eluting with a gradient of 30-60% MeCN in water (10 mM NH4HCO3), to afford (265)-9,18-dichloro-4-(((2R ,7aS)-2-fluorotetrahydro-1H- pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-26-methyl-23,25,28-trioxa-1.3,5,14,15,32- hexaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11.19~.0~12,16~]dotriaconta-2,4,6(32),7,9,l l,13,16,18- nonaen-24-one (Example 1.011, 81 g, 1.18 mmol. 20% yield). m / z (ESI): 686.2 (M+H)+. 'HNMR (400 MHz, CDCl38 ppm 10.20 - 11.23 (m, 1H), 8.46 (s, 1H), 7.72 (s, 1H), 7.64 (s, 1H). 5.57 (br d, J = 16.8 Hz, 1H), 5.16 - 5.40 (in. 1H), 4.58 - 4.69 (m, 1H), 4.20 - 4.44 (m, 3H). 4.05 (dd, J= 12.4. 4.1 Hz. 1H), 3.79 - 3.91 (m, 1H). 3.67 - 3.76 (m, 2H ), 3.58 (d, J= 16.8 Hz. 1H), 3.15 - 3.46 (m, 5H). 2.93- 3.07 (m. 1H), 2.77 - 2.89 (m, 1H). 2.60 - 2.76 (m, 1H). 2.02 - 2.29 (m, 3H), 1.90 - 1.98 (m. 3H), 1.79- 1.87 (m. 2H ), 1.58 (s. 3H).19F NMR (376 MHz. CDC ) 3 ppm -172.41 (s, 1 F).

[0356] (165)-22-(((2R ,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-l 6,26,36- trimethyl-31H-7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3-d / |pyrimidina-3(4,5)- indazolacyclononaphan-8-one and (16S)-26-chloro-22-(((2R ,7aS)-2-fluorotetrahydro-1H- pyiTolizin-7a(5H)-yl)methoxy)-16,36-dimethyl-31H-7,9-dioxa-l(4,6)-oxazepana-2(4,7)- pyrido[2,3-rf]pyrimidina-3(4,5)-indazolacyclononaphan-8-one (Examples 1.012 and 1.013).

[0357] A stirred mixture of (16S)-26.36-dichloro-22-(((27?.7a5)-2-fluorotetrahydro-1H-pyrrolizin- 7a(52 / )-yl)methoxy)-16-methyl-31H-7, 9-dioxa-l(4, 6)-oxazepana-2(4.7)-pyrido[2, 3-<7|pyrimidina- 3(4,5)-indazolacyclononaphan-8-one (Example 1.011, 70 mg, 0.10 mmol) and methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-methylamino-l,r-biphenyl-2- yl)palladium(II) (18 mg, 0.02 mmol, Strem Chemicals. Inc.) in THF (2 mL) at room temperature under nitrogen, was sparged with nitrogen for 10 min. To the degassed mixture was added 1,4- diazabicyclo[2.2.2]octane bis(trimethylalumane) (0.11 g. 0.44 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was filtered through celite, and the filtrate concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3) (2% EtiN) in heptane. The resulting mixture was further purified by prep-HPLC on a Phenomenex Gemini 511005-W001-SEC micron, Cl 8, 100 A, 150 x 30 mm column eluting at 40 mL / min with a gradient of 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA). The combined fractions containing the product were frozen at -78 °C, and lyophilized. Peak 1: (16S)-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-16,26,36-trimethyl-31H-7,9-dioxa-l(4,6)-oxazepana-2(4,7)-pyrido[2,3- <7|pyrimidina-3(4,5)-indazolacyclononaphan-8-one bis(2,2,2-trifluoroacetate) (Example 1.012, 15 mg, 1.7 umol, 17% yield), m / z (ESI): 646.3 (M+H)+. ' H NMR (400 MHz, MeOD-d) 5 ppm 8.96 - 8.76 (m, 1H), 7.67 - 7.60 (m, 1H), 7.60 - 7.53 (m, 1H), 5.79 - 5.69 (m, 1H), 5.68 - 5.47 (m, 1H). 4.82 - 4.70 (m, 3H), 4.36 - 4.20 (m, 1H), 4.16 - 4.04 (m. 1H), 4.00 - 3.78 (m. 6H), 3.77 - 3.61 (m. 2H ), 3.53 - 3.38 (m, 2H ), 2.82 - 2.49 (m, 8H), 2.48 - 2.30 (m, 3H), 2.29 - 2.24 (m, 3H), 2.24 - 2.10 (m, 1H), 1.82 - 1.62 (m. 2H ), 1.60 - 1.54 (m, 3H).,9F NMR (376 MHz, MeOD-d4) 5 ppm -77.28 - -77.36 (m, IF). -174.14 - -174.53 (m, IF). Peak 2: (16S)-26-chloro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-16.36-dimethyl-31H-7,9-dioxa-l(4,6)-oxazepana-2(4.7)-pyrido[2,3- <7|pynmidina-3(4.5)-indazolacyclononaphan-8-onc bis(2,2,2-trifluoroacetate) (Example 1.013, 10 mg. 1.0 umol, 11% yield), m / z (ESI): 666.3 (M+H)+. ‘H NMR (400 MHz, MeOD-d) 5 ppm 9.01 - 8.93 (m, 1H). 7.69 - 7.64 (m, 1H). 7.58 - 7.53 (m, 1H). 5.68 - 5.46 (m, 2H ), 4.73 - 4.64 (m, 3H), 4.36 - 4.24 (m. 1H), 4.13 - 4.05 (m, 1H), 4.05 - 3.87 (m, 4H), 3.84 - 3.77 (m, 2H ). 3.72 - 3.59 (m, 2H ). 3.52 - 3.43 (m, 1H), 2.84 - 2.50 (m. 8H), 2.50 - 2.31 (m. 3H), 2.24 - 2.09 (m. 1H), 1.83 - 1.69 (m. 2H ). 1.61 - 1.52 (m, 3H).19F NMR (376 MHz, MeOD-di) 5 ppm -77.39 (s, IF), -174.34 (s. IF).

[0358] (15',3R)-ll-Chloro-20-fluoro-25-(((2«,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2- a]pyrrol-7a(5H)-yl)methoxy)-34-oxa-5,1 ,15,24,26,28,33- heptaazaoctacyclo[26.3.1.1~l,3~.l~4,7~.l~19,23~.0~10,18~.0~13,17~.0~22,27~]pentatriaconta- 4,6,10,12,15,17,19(33),20,22,24,26-undecaen-3-ol hexafluorophosphate(V) salt (Example 1.014).11005-W001-SEC

[0359] Step 1. tert- Butyl (2S',4R)-2-(5-(2-(6-chloro-4-(6-fluoro-2-(methylthio)-4-(2- (trimethylsilyl)ethoxy)pyrido[2,3-d ]pyrimidin-7-yl)-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5- yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate. A mixture of methanesulfonato(diadamantyl-M-butylphosphino)-2'-amino-l,l'-biphenyl-2-yl)palladium(II) (55 mg, 7.6 umol, Ambeed, Inc.). K3PO4 (0.32 g, 1.52 mmol), tert-butyl (2S,47?)-2-(5-(2-(6-chloro-l- (tetrahy dro-2H -py ran-2-y l)-4-(4,4, 5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1H-indazol-5 - yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate (Intermediate J, 0.41 g, 0.56 mmol), and 7-chloro-6-fluoro-2-(methylthio)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3- i / | pyrimidine (Intermediate E. 0.18 g, 0.51 mmol) in 2-Me-THF (4.6 mL) and water (0.46 mL) under nitrogen was stirred as 80 °C for 1.5 h. The reaction mixture was then concentrated under reduced pressure. The crude material was then purified via column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc in heptane to provide tert-butyl (2S,4 )-2-(5-(2-(6-chloro-4-(6-fluoro-2- (methylthio)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3-d|pyrimidin-7-yl)-l-(tetrahydro-2H -pyran-2-yl)- 1 H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxy methoxy )-6-azaspiro[3.5 ]nonane-6-carboxy late (0.56 g, 0.60 mmol, quantitative yield), m / z (ESI): 924.4 ( +H) .

[0360] Step 2. tert- Butyl (2,S’,4R)-2-(5-(2-(6-chloro-4-(6-fluoro-2-(methylsulfinyl)-4-(2-(trimethylsilyl)ethoxy)pyrido|2,3-d|pyrimidin-7-yl)-l -(tetrahydro- 2H -pyran-2-yl)-1H-indazol-5-11005-W001-SEC yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of tert-butyl (2S,47?)-2-(5-(2-(6-chloro-4-(6-fluoro-2-(metliylthio)-4-(2- (trimethylsilyl)ethoxy)pyrido[2,3-<7|pyrimidin-7-yl)-l-(tetrahydro-27f-pyran-2-yl)-1H-indazol-5- yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate (0.56 g, 0.49 mmol) and anhydrous magnesium sulfate (1.00 g, 8.31 mmol) in dichloromethane (4.9 mL) at 0 °C, was added 3 -chloroperoxy benzoic acid (0.22 g, 77 wt%, 0.98 mmol, Sigma-Aldrich Corporation) and the resulting mixture was stirred at 0 °C for 5 min. The reaction mixture was diluted with 10 wt% aq. solution of sodium thiosulfate (5 mL) and dichloromethane (5 mL). The aqueous layer was extracted with dichloromethane. The combined organic layers were then dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl (2>S'.47?)-2-(5-(2-(6-chloro-4-(6-fluoro-2- (methylsulfmyl)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3-i / ]pyrimidin-7-yl)-l-(tetrahydro-2H -pyran-2- yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate. m / z (ESI): 940.2 (M+H)+.

[0361] Step 3. tert- Butyl (2.S.4R)-2-(5-(2-(6-chloro-4-(6-fluoi()-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(517)-yl)methoxy)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3- rf]pyrimidin-7-yl)-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2- (methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of tert-butyl (2.s,4r)- 2-(5-(2-(6-chloro-4-(6-fhioro-2-(methylsulfinyl)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3-d ]pyrimidin- 7-yl)-l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6- azaspiro[3.5]nonane-6-carboxylate (0.46 g, 0.49 mmol). ((2R, 7aS)-2 -fluorotetrahydro- Irt-pyrrolizin- 7a(5H)-yl)methanol hydrchloride (0.19 g. 0.98 mmol, Pharmablock, Inc.), and magnesium sulfate (1.00 g, 8.31 mmol, Sigma-Aldrich Corporation) in acetonitrile (2.0 mL) at room temperature was added. ALA-diisopropylethylamine (0.43 mL. 2.46 mmol). The reaction mixture was stirred for 1.5 h, then heated to 80 °C for an additional 3.75 h. The resulting mixture was filtered, and the filtrate concentrated under reduced pressure. The crude material was then purified via column chromatography on silica gel. eluting with a gradient of 0-80% EtOAc:EtOH (3:1. with 2% Et3N) in heptane, to provide tert-butyl (2S.47?)-2-(5-(2-(6-chloro-4-(6-fluoro-2-(((27?.7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5f / )-yl)methoxy)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3-<7]pyrimidin-7-yl)-l - (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6- azaspiro[3.5]nonane-6-carboxylate (0.21 g, 0.21 mmol, 42% yield), m / z (ESI): 1035.4 (M+H)+.

[0362] Step 4. 7-(6-Chloro-5-(2-(2-((25,4R)-2-hydroxy-6-azaspiro[3.5]nonan-2-yl)oxazol-5- yl)ethyl)-1H-indazol-4-yl)-6-fluoro-2-(((2R ,7aS )-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)mcthoxy)pyrido[2,3-( / |pyrimidin-4-ol trihydrochloride. To a stirred mixture of Zert-butyl (21S,47?)-2-(5-(2-(6-chloro-4-(6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3-<7|pyrimidin-7-yl)-l-(tetrahydro-2H -pyran-2-yl)- 1 H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxy methoxy )-6-azaspiro[3.5 ]nonane-6-carboxy late (0.2111005-W001-SEC g, 0.20 mmol) in dichloromethane (2.7 mL) at room temperature, was added HC1 (4.0 M in 1,4- dioxane, 0.51 mL, 2.04 mmol, Sigma-Aldrich Corporation) and the resulting mixture was stirred at room temperature for 0.5 h. Methanol (0.5 mL) was added and the reaction was allowed to stir at room temperature for 20 min. Additional HC1 (4.0 M in 1,4-dioxane, 0.25 mL, 1.00 mmol) was added and the reaction was allowed to stir at room temperature for 10 min. The reaction mixture was then concentrated under reduced pressure to afford crude 7-(6-chloro-5-(2-(2-((2S,4R)-2-hydroxy-6- azaspiro[3.5]nonan-2-yl)oxazol-5-yl)ethyl)-1H-indazol-4-yl)-6-fluoro-2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin-7a(5F / )-yl)methoxy)pyrido[2,3-t / ]pyrimidin-4-ol trihydrochloride (0.17 g, 0.20 mmol, quantitative yield), m z (ESI): 707.4 (M+H)+.

[0363] Step 5. (lA\3R)-l l-Chloro-20-fluoro-25-(((2R,7aA)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-34-oxa-5,14,15,24,26,28,33- heptaazaoctacyclo[26.3.1.1~l,3~.l~4,7~.l~19,23~.0~10,18~.0~13,17~.0~22,27~]pentatriaconta- 4,6,10,12,15,17,19(33),20,22,24,26-undecaen-3-ol (Example 1.014). To a stirred mixture of bromotris(dimethylamino)phosphonium hexafluorophosphate (0.32 g, 0.81 mmol. Oakwood Products, Inc.) and A V-diisopropylcthylaminc (0.35 mL, 2.01 mmol) in acetonitrile (36 mL) at room temperature was added 7-(6-chloro-5-(2-(2-((2S,4R)-2-hydroxy-6-azaspiro[3.5]nonan-2-yl)oxazol-5- yl)ethyl)-1H-indazol-4-yl)-6-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[2,3-d ]pyrimidin-4-ol trihydrochloride (0.17 g, 0.20 mmol) in dimethyl sulfoxide (5.1 mL) over 1 h via syringe pump and the resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The crude material was purified via column chromatography on a C18 column, eluting with a gradient of 10-100% MeCN (0.1% formic acid) in water (0.1% formic acid), to provide (lS,3R)-ll-chloro-20-fluoro-25-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol-7<7(5 / T)-yl)methoxy)-34-oxa-5, 14, 15, 24,26,28.33- heptaazaoctacyclo[26.3.1.1~l,3~.l~4.7~.l~19,23~.0~10.18~.0~13.17~.0~22,27~]pentatriaconta- 4,6,10,12,15.17,19(33).20,22.24,26-undecaen-3-ol. hexafluorophosphate(V) salt (Example 1.014, 14.3 mg. 1.7 umol. 8% yield), m / z (ESI): 689.2 (M+H)+. *H NMR (400 MHz, MeOD-di) 5 ppm 8.27 (d, >8.6 Hz, 1 H), 7.90 (s, 1 H), 7.83 (d, J=4.2 Hz, 1 H). 6.61 (s, 1 H), 5.30 - 5.52 (m, 1 H), 4.78 (br s, 1 H), 4.54 (br d, >13.6 Hz, 1 H), 4.41 (dd, >8.5, 6.0 Hz, 2 H). 3.66 (br d, >13.2 Hz, 1 H), 3.39 - 3.60 (m. 3 H), 3.13 - 3.25 (m. 3 H), 2.99 - 3.11 (m, 1 H), 2.69 - 2.80 (m, 1 H), 2.60 - 2.66 (m, 2H ), 2.31 - 2.54 (m. 2 H), 2.19 - 2.31 (m, 1 H), 2.08 - 2.18 (m, 2 H), 2.05 (br d, J=13.2 Hz, 1 H), 1.97 (br d, >9.8 Hz, 2 H), 1.78 - 1.91 (in, 3 H), 1.69 - 1.76 (in, 1 H), 1.61 (br d, >12.5 Hz, 1 H).19FNMR (376 MHz, MeOD-d) 5 ppm -76.41 - -73.76 (m, 1 F), -126.95 (br d, >10.4 Hz, 1 F), -173.91 (br d, >17.3 Hz, 1 F).

[0364] (1R,3R,7R,95)-17-Fluoro-22-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2-tf]pyrrol- 7a(5H)-yl)methoxy)-l 1 -methyl-5-oxa-21 ,23,25,30-11005-W001-SEC tetraaz aheptacyclo[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.S.3R.7.S.9R)-17-fluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol-7a(5H)-yl)methoxy)-ll-methyl-5-oxa-21,23,25,30- 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 (Examples 1.015 and 1.016).Example 1.015 Example 1.016

[0365] Step 1. n'rt-Buty 1 (25,4R)-2-((((lR5,25R)-2-(2-(6-fluoro-2-(methylthio)-4-(2- (trimethylsilyl)ethoxy)pyrido|2,3-d|pyrimidin-7-yl)-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate.To a stirred mixture of 7-chloro-6-fluoro-2-(methylthio)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3- <7|pvnmidine (Intermediate E, 0.16 g, 0.47 mmol), tert-butyl (2>S',47?)-2-hydroxy-2-((((17?S,2S7?)-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 (Intermediate N, 0.28 g, 0.47 mmol) and KJPO-I (0.31 g, 1.44 mmol) in 2-Me-THF (4.0 mL) and water (0.40 mL) at room temperature under nitrogen, was added CataCXium A Pd G4 (36 mg, 0.05 mmol, Sigma- Aldrich Corporation). The resulting mixture was purged with nitrogen and stirred at 80 °C for 7 h. The reaction mixture was fdtered through celite, and the filtrate concentrated under reduced pressure. The11005-W001-SEC crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-60% ethyl acetate in heptane, to afford tert-butyl (2S,4R)-2-((((lRS,2SR)-2-(2-(6-fluoro-2-(methylthio)-4- (2-(trimethylsilyl)ethoxy)pyrido[2,3-<7|pyrimidin-7-yl)-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.21 g, 0.27 mmol, 57% yield), m / z (ESI): 785.2 (M+H)+. ’H NMR (400 MHz, CDCl3) 5 ppm 8.14 - 7.80 (m, 1H), 7.13 - 6.92 (m, 2H ), 5.26 - 5.04 (m, 2H ), 4.77 - 4.66 (m, 2H ), 3.51 - 3.43 (m, 3H), 3.34 - 3.05 (m, 7H), 2.93 - 2.76 (m, 2H ), 2.75 - 2.66 (m, 3H), 2.51 - 2.43 (m, 3H), 2.28 - 2.10 (m, 4H). 1.92 - 1.78 (m, 2H ), 1.74 - 1.58 (m, 4H), 1.50 - 1.39 (m. 11H), 0.94 - 0.76 (m, 1H). 0.75 - 0.54 (m, 1H). 0.16 - 0.10 (m, 9H).19F NMR (376 MHz. CDCl3) 5 ppm -120.31 (br s, IF).

[0366] Step 2. tert-Butyl (2.S.4R)-2-((((1R S,2SR)-2-(2-(6-flii()ro-2-(nieth) lsulfinyl)-4-(2- (trimethvlsilyl)ethoxv)pvrido|2,3-d |pvrimidin-7-yl)-4-(mcthoxvmethoxy)-6- methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate.To a stirred mixture of tert-butyl (2S,4R)-2-((((lR>S',2SR)-2-(2-(6-fluoro-2-(methylthio)-4-(2- (trimethylsilyl)ethoxy)pyrido[2,3-<7|pyrimidin-7-yl)-4-(methoxymethoxy)-6- methylphenyl)cyclopropyl)methoxy)methyl)-2 -hydroxy -6-azaspiro[3.5]nonane-6-carboxylate (0.21 g, 0.27 mmol) in dichloromethane (2 mL) at 0 °C under ambient atmosphere, was added m- chloroperbenzoic acid (89 mg, 77 wt%, 0.40 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was diluted with 10 wt% aq. solution of sodium thiosulfate at 0 °C and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford tert-butyl (2S,4R)-2- ((((lRS’.2S7?)-2-(2-(6-fluoro-2-(methylsulfinyl)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3-d |pyrimidin-7- yl)-4-(methoxymethoxy)-6-methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (0.21 g, 0.27 mmol, quantitative yield), n z (ESI): 801.4 (M+H)+.

[0367] Step 3. tert- Butyl (2.S.4R)-2-((((lR.S.2.SR)-2-(2-(6-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H -pyrrolizin-7a(5H)-yl)methoxy)-4-(2-(trimethylsilyl)cthoxy)pvrido[2,3- < / ]pyrimidin-7-yl)-4-(methoxymethoxy)-6-methylphenyl)cyclopropyl)methoxy)methyl)-2- hydroxy-6-azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of tert-butyl (2S,4R)-2- ((((lRS.2SR)-2-(2-(6-fluoro-2-(methylsulfinyl)-4-(2-(trimethylsilyl)ethoxy)pyrido|2,3-rf|pyrimidin-7- yl)-4-(methoxymethoxy)-6-methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6- azaspiro[3.5]nonane-6-carboxylate (0.21 g, 0.27 mmol) and magnesium sulfate (0.50 g, 4.15 mmol) in acetonitrile (2.0 mL) at room temperature under nitrogen, was added ((2R ,7aS)-2-fhiorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methanol hydrochloride (0.12 g. 0.61 mmol. Pharmablock, Inc.) and NJ - diisopropylethylamine (0.25 mL, 1.43 mmol). The resulting mixture was stirred at 80 °C for 22 h. The reaction mixture was filtered, 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% ethanol / ethyl acetate (1:3, 2% Et3N) in heptane to give tert-butyl (2S,47?)-2-((((17?S.2S7?)-2-(2-(6-fluoro-2-11005-W001-SEC(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2- (trimethylsilyl)ethoxy)pyrido[2,3-<f|pyrimidin-7-yl)-4-(niethoxymethoxy)-6- methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane-6-carboxylate (0.12 g, 0.13 mmol, 48% yield), m / z (ESI): 896.4 (M+H)+.]H NMR (400 MHz, CDCl3) 5 ppm 8.14 - 7.83 (m, 1H), 7.12 - 6.94 (m, 2H ), 5.44 - 5.22 (m, 2H ), 5.19 - 5.10 (m, 1H), 4.79 - 4.67 (m, 2H ), 4.46 - 4.30 (m, 2H ), 3.51 - 3.45 (m, 3H), 3.38 - 3.13 (m, 9H), 3.05 - 2.96 (m, 1H), 2.92 - 2.61 (m, 2H ). 2.54 - 2.46 (m, 3H), 2.26 - 2.08 (m, 3H), 2.01 - 1.79 (m. 6H), 1.73 - 1.61 (m. 4H), 1.51 - 1.38 (m. 12H ). 1.31 - 1.24 (m, 3H), 1.11 - 0.98 (m, 1H), 0.76 - 0.52 (m, 1H), 0.18 - 0.12 (m, 9H).19F NMR (376 MHz. CDCls) 5 ppm -122.67 (br s, IF), -172.45 - -172.89 (m, IF)).

[0368] Step 4. 6-Fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (5-hydroxy-2-((17tS',2S'R)-2-((((25,4S)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)methoxy)methyl)cyclopropyl)-3-methylphenyl)pyrido[2,3-rf]pyrimidin-4-ol. To a stirred mixture of tert-butyl (2S,4R)-2-((((lR5,2SK)-2-(2-(6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lF7- pyrrolizin-7a(5H)-yl)methoxy)-4-(2-(trimethylsilyl)ethoxy)pyrido[2,3-<7]pyrimidiii-7-yl)-4- (methoxymethoxy)-6-methylphenyl)cyclopropyl)methoxy)methyl)-2-hydroxy-6-azaspiro[3.5]nonane- 6-carboxylate (0.12 g, 0.13 mmol) in dichloromethane (3.0 mL) at room temperature under ambient atmosphere, was added HC1 (4.0 M in 1,4-dioxane, 0.5 mL, 2.00 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to afford 6-fluoro-2-(((2R,7a6)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(5-hydroxy-2- ((lRS',2SR)-2-((((2S.45)-2-hydroxy-6-azaspiro[3.5]nonan-2-yl)methoxy)methyl)cyclopropyl)-3- methylphenyl)pyrido[2,3-r / |pyrimidin-4-ol (84 mg, 0.13 mmol, quantitative yield), m / z (ESI): 652.2 (M+H)+.

[0369] Step 5. ( lR.3R.7R.9.S)-l 7-Fluoro-22-(((2R ,7aS )-2-fluorotetrahydro-1H-pyrrolo[l,2- «|pyrrol-7a(5H)-yl)methoxy)-l l-niethyl-5-oxa-21,23,25,30- tetraazaheptacyclo[23.3.1.1~l,3~.l~16,20~.0~7,9~.Q~10,15~.0~19,24~]Iientriaconta- 10,12,14,16(30),17,19,21,23-octaene-3,13-diol and (l.S.3R.7.S.9R)-17-fluoro-22-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolo|l ,2-«|pyiTol-7a(5H)-yl)methoxy)-l l-methyl-5-oxa-21,23,25,30- 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 (Examples 1.015 and 1.016). To a stirred mixture of N,N-diisopropylcthylaminc (0.25 mL, 1.43 mmol) and bromotris(dimethylamino)phosphonium hexafluorophosphate (0.11 g, 0.27 mmol, Oakwood Products. Inc.) in acetonitrile (27 mL) at room temperature under nitrogen, was slowly added 6-fhioro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5F / )-yl)methoxy)-7-(5-hydroxy-2-((1RS ,2SR )-2-((((2s,4S)-2-hydroxy-6- azaspiro[3.5]nonan-2-yl)methoxy)methyl)cyclopropyl)-3-methylphenyl)pyrido[2,3-d|pyrimidin-4-ol (84 mg, 0.13 mmol) as a solution in dimethyl sulfoxide (4.5 mL). The resulting mixture was stirred at room temperature for 1 h. Additional bromotris(dimethylamino)phosphonium hexafluorophosphate11005-W001-SEC(50 mg, 0.13 mmol, Oakwood Products, Inc.) was then added. The reaction was allowed to stir for an additional 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with sat. aq. solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethanol / ethyl acetate (1:3, 2% Et3N) in heptane. The ixture was further purified by prep-HPLC on a Phenomenex Gemini 5 micron, Cl 8, 100 A, 1 0 x 30 mm column eluting at 45 mL / min with a gradient of 10-90% acetonitrile (0.1% TFA) in water (0.1% TFA). The combined fractions containing the product were frozen at -78 °C and lyophilized. The resulting product was then purified by SFC using a (S,S) Whelk- 0 5 micron, 2 x 25 cm column with a mobile phase of 45% MeOH with 0.2% DEA using a flowrate of 80 mL / min. Peak 1: (lR.3R,7R,9S)-17-fluoro-22-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2- a|pyrrol-7a(5H)-yl)methoxy)-l l-methyl-5-oxa-21,23,25,30- tetraazaheptacyclo[23.3.1.1-1.3~.1~16.20- 0~7,9~.0~10,15~.0~19,24~]hentriaconta- 10, 12, 14,16(30), 17, 19,21, 23-octaene-3,13-diol (Example 1.015, 6.3 mg, 9.94 pmol, 8% yield), m / z (ESI): 634.0 (M+H)+. ’H NMR (400 MHz, MeOD-d) 5 ppm 8.32 - 8.13 (m. 1H), 7.31 - 7.19 (m. 1H). 6.88 - 6.84 (m, 1H). 5.54 - 5.16 (m, 1H). 4.79 - 4.62 (m, 1H). 4.54 - 4.42 (m, 1H). 4.38 - 4.24 (m, 2H ). 3.60 - 3.53 (m, 1H). 3.30 - 3.21 (m, 2H ). 3.17 - 3.01 (m, 3H), 2.64 - 2.54 (m, 1H), 2.52 - 2.45 (m. 3H), 2.44 - 2.15 (m, 4H), 2.10 - 1.71 (m, 8H), 1.71 - 1.44 (m, 4H), 1.44 - 1.27 (m, 5H), 1.04 - 0.81 (m, 1H), 0.23 - -0.01 (m, 1H).19FNMR (376 MHz, MeOD-d4) 5 ppm -124.96 (br s, IF), - 173.62 (s, IF). Peak 2: (1S,3R,7S.9R)-17-fluoro-22-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2- «]pyrrol-7a(5H)-yl)methoxy)-l l-methyl-5-oxa-21,23,25.30- 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 1.016, 6.0 mg, 9.47 μmol. 7% yield). m,z (ESI): 634.2 (M+H)+.]H NMR (400 MHz, MeOD-d) 5 ppm 8.30 - 8.14 (m, 1H), 7.26 - 7.20 (m, 1H), 6.89 - 6.85 (in, 1H), 5.51 - 5.18 (m, 1H), 4.75 - 4.65 (m, 1H), 4.52 - 4.41 (m, 1H), 4.40 - 4.25 (m, 2H ), 3.60 - 3.52 (m, 1H), 3.30 - 3.23 (m, 2H ), 3.15 - 3.03 (m, 3H), 2.61 - 2.53 (m, 1H), 2.48 - 2.45 (m, 3H), 2.34 - 2.13 (m, 4H), 2.09 - 1.94 (m, 5H), 1.89 - 1.71 (m, 3H), 1.68 - 1.59 (m, 3H), 1.55 - 1.23 (m, 7H), 0.15 - 0.04 (m, 1H).19F NMR (376 MHz, MeOD-d) 5 ppm -124.94 (br s, IF), - 173.64 (s, IF).

[0370] (15,3R)-ll,20-Dichloro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[l,2-a]pyrrol- 7a(5H)-yl)methoxy)-34-oxa-5,l 4,15,24,26,28,33- heptaazaoctacyclo[26.3.1.1~l,3~.l~4,7~.l~19,23~.0~10,18~.0~13,17~.0~22,27~]pentatriaconta- 4,6,10,12,15,17,19(33),20,22,24,26-undecaen-3-ol hexafluorophosphate(V) salt (Example 1.017).11005-W001-SEC

[0371] Step 1. tert-Butyl (2S',4R)-2-(5-(2-(4-(4-(tert-butoxy)-6-chloro-2-(((2R ,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d ]pyrimidin-7-yl)-6-chloro-l- (tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6- azaspiro[3.5]nonane-6-carboxylate. To a stirred mixture of / e / 7-butyl (2S,4R)-2-(5-(2-(6-chloro-l- (tetrahydro-2H -pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)ethyl)oxazol-2-yl)-2-(methoxymethoxy)-6-azaspiro[3.5]nonane-6-carboxylate (Intermediate J, 0.17 g, 0.23 mmol) and 4-(Zert-butoxy)-6,7-dichloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)mcthoxy)pyrido|2.3-<: / |pyrimidinc (Intermediate D. 0.10 g, 0.23 mmol) in 2-Me-THF (2.1 mL) and water (0.21 mL) at room temperature under nitrogen, was added CataCxium A Pd G3 (25 mg. 0.04 mmol, Combi-Blocks Inc.) and potassium phosphate tribasic (0.15 g, 0.70 mmol). The resulting mixture was sparged with nitrogen for 2 min and stirred at 80 °C for 7 h. The reaction was then concentrated under reduced pressure to afford a crude product. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-80% ethanol / ethyl acetate (1:3) with 2% triethylamine in heptane to afford / ert-butyl (2S,4R)-2-(5-(2-(4-(4-(Zert-butoxy)-6-chloro-2- (((2A,7a5)-2-fhiorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[2,3-d|pyrimidin-7-yl)-6- chloro- l-(tetrahydro-2H -pyran-2-yl)-1H-indazol-5-yl)ethyl)oxazol-2-yl)-2-(methoxy methoxy )-6- azaspiro[3.5]nonane-6-carboxylate (72 mg, 0.07 mmol. 31 % yield), m / z (ESI): 1007.4 (M+H)+.!H NMR (400 MHz. MeOD-d4) 5 ppm 8.68 (d, J= 2.7 Hz. 1H), 8.02 (s, 1H), 7.62 (s, 1H). 6.76 - 6.66 (m, 1H). 5.92 - 5.81 (m, 1H). 5.43 - 5.21 (m, 1H). 4.46 - 4.39 (m, 2H ), 4.39 - 4.23 (m, 3H), 4.04 - 3.94 (m. 1H), 3.74 (br d, J = 9.0 Hz. 1H), 3.22 - 3.10 (m. 6H), 3.09 - 3.05 (m. 4H), 3.04 - 2.72 (m. 5H), 2.50 - 2.31 (in, 4H), 2.23 - 2.06 (m, 7H). 2.01 - 1.89 (m, 4H). 1.90 - 1.80 (m, 13H), 1.77 - 1.62 (m, 7H). 1.55 - 1.44 (m, 4H).19F NMR (376 MHz, MeOD-dl) 5 ppm -173.27 - -174.57 (m, IF).11005-W001-SEC

[0372] Step 2. 6-Chloro-7-(6-chloro-5-(2-(2-((25',4R)-2-hydroxy-6-azaspiro[3.5]nonan-2- yl)oxazol-5-yl)ethyl)-1H-indazol-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-l f-pyrrolizin-7a(5Z / )- yl)methoxy)pyr...

Claims

11005-W001-SECWhat is claimed is:

1. A compound of Formula (I) :or a pharmaceutically acceptable salt of said compound, wherein;Z is C-R7or N;Q is CH, C-halogen, C-C1-4alkyl, C-C1-4haloalkyl or N;B is a 4-15 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O. S and N; p is 0, 1. 2 or 3; q is 0.

1. 2 or 3; each Rxis independently hydroxyl, halogen, oxo, cyano, -N(RZ)2. C1-4alkyl. C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl. C1-4haloalkoxy. C1-4hydroxyalkyl, 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, -C1-4alkydene-C(O)-Ci.4alkyl. -C1-4alkylene- C(O)N(RZ)2. C1-4alkylene-S(O)2-Ci.4alkyl, or -S-Ci.4alkyd;L is a bond. C1-4alkylene, -O-C1-4alkylene, -S-C1-6alkylene, NRZ, O or S. wherein each C1-4alkylene. -O-C1-4alkylene and -S-C1-4alkylene chain is substituted with 0-2 occurrences of R2;-S(O)-L2, C1-4alkylene-C(O)-L2, C1-4alkylene-C(O)O-L2, -C1-4alkylene-OC(O)O-L2, -C1-4alkylene- OC(O)-L2. -C1-4alkylene-O-L2, -C1-4alkylene-S(O)2-L2, -C1-4alkylene-S-L2, -C1-4alkylene-S(O)-L2, - 0-5-6 membered heteroaryl-L2. -C1-4alkylene-5-6 membered heteroaryl-L2, -C1-4hydroxyalkylene-5- 6-membered heteroaryl-L2or a 5-6 membered heteroaryl-L2;L2is C1-4alkylene, C1-4alkylene-O-, C1-4alkylene-O-C1-6alkylene, C1-4alkenylene, C1-4alkynylene, C3-7 cycloalk lene. C1-4alkylene-Cj ? cycloalkylene, C1-4haloalkylene-C,.- cycloalkylene, C3.7 cycloalky lene-Ci.4alkydene, C1-4hydroxyalkydene or C1-4haloalkylene;R1is hydrogen, hydroxyl, Ce-io ary l, 5-10 membered hctcroaryl, C3-8 cycloalky l or 4-15 membered heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl or heterocycloalky l is substituted with 0-3 occurrences of R5;R2is halogen, hy droxyl, C1-4alkyl or two R2on the same or adjacent carbon atoms can be taken together to form a C3-7 cycloalkyl;11005-W001-SECA is Ce-io aryl or 5-10 membered hctcroarvl and is substituted with q occurrences of R6; each R5independently is halogen, cyano, oxo, -T-Ry, hydroxyl. -N(RZ)2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy or -O-C2-4 alkynyl; each R6independently is halogen, hydroxyl, cyano, -N(RZ)2, -C(O)RZ, -C(O)ORZ, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4 alkynyl or C3-6 cycloalkyl or two R6taken together on adjacent carbon atoms form a C3-7 cycloalkyl;R7is hydrogen, halogen, cyano, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy or C3-7 cycloalkyl;T is C1-4alkylene, -S(O)2-, -C(O)-, -C1-4alkylene-C(O)-, C1-4alky lene-S (0)2- or -S-;Ryis halogen, oxo. C1-4alkyl. C1-4haloalkyl, hydroxyl, cyano or -N(RZ)2; and each Rzis hydrogen or C1-4alkyl.

2. The compound or salt of claim 1, wherein Z is N and Q is CH; Z is CH and Q is CH; Z is C-F and Q is CH; or Z is C-Cl and Q is CH.

3. The compound or salt of claim 1 or 2, wherein L is -O-methylene, -O-ethylene or -O-n- propylene substituted with 0-2 occurrences of R2.

4. The compound or salt of claim 3, wherein L is -O-methylene substituted w ith 0 occurrences of R2.

5. The compound or salt of claim 1 or 2, wherein -The compound or salt of claim 5, w herein11005-W001-SECThe compound or salt of claim 7, whereinThe compound or salt of claim 8, wherein10. The compound or salt of claim 1 or 2. wherein L is -S-alkylene substituted with 0-2 occurrences of R2.

11. The compound or salt of claim 10, wherein R1is hydrogen.

12. The compound or salt of claim 1 or 2, wherein -L-R1is11005-W001-SEC13. The compound or salt of any of claims 1-12, wherein B is a 6-10 membered heterocycloalkyl having 0-3 additional ring heteroatoms independently selected from O, S and N.

14. The compound or salt of claim 13, wherein15. The compound or salt of claim 14, whereinThe compound or salt of claim 14, wherein17. The compound or salt of claim 14, wherein18. The compound or salt of claim 14, wherein B-L1is11005-W001-SECThe compound or salt of claim 14, wherein20. The compound or salt of claim 14, wherein21. The compound or salt of any one of claims 1-20, wherein A is Ce-io aryl (e.g., phenyl or naphthyl).

22. The compound or salt of claim 21, wherein A is phenyl or naphthyl.The compound or salt of claim 21, wherein24. The compound or salt of claim 23, wherein11005-W001-SECThe compound or salt of claim 24. whereinThe compound or salt of claim 24, wherein1. The compound or salt of claim 24, wherein28. The compound or salt of any of claims 1-20. wherein A is 5-10 membered heteroaryl.

29. The compound or salt of claim 28, wherein A is 4-indazolyl.

30. The compound or salt of claim 28, wherein11005-W001-SEC31. The compound or salt of claim 30. wherein32. The compound or salt of claim 30, wherein33. The compound or salt of any one of claims 1-32. wherein -L'-L2- is -O-C(O)-O-L2.

34. The compound or salt of claim 33, wherein L2is ethylene, n-propylene, 2-methyl-n- propylene. cis-2-propenylene, trans-2 -propenylene or -CHz-cyclopropylene.0The compound or salt of claim 35, wherein -L'-L2- isOThe compound or salt of claim 36, wherein -L'-L2- is38. The compound or salt of any one of claims 1-32, wherein -L'-L2- is -C1-4 alkylene-O-L2.

39. The compound or salt of claim 38, wherein -L'-L2- is -methylene-O-L2.

40. The compound or salt of claim 39. wherein L2is w-buty lene, 2,2-difluoro-w-butylene. trans-2- butenylene, cis-2-butenylene. 3-methyl-M-butylene, -methylene-cyclopropylene-, -ethylene- cyclopropylene- or ethylene-O-methylene.

41. The compound or salt of claim 40, wherein -L'-L2- is42. The compound or salt of claim 41, wherein -L'-L2- isThe compound or salt of claim 42, wherein -L'-L2- isThe compound or salt of claim 42, wherein -L'-L2- isThe compound or salt of claim 42, wherein -L'-L2- is11005-W001-SEC46. The compound or salt of any one of claims 1-32. wherein -L'-L2- is -NRZ-C(O)-O-L2.

47. The compound or salt of claim 46, wherein Rzis hydrogen or methyl.

48. The compound or salt of claim 46 or 47, wherein L2is n-propylcnc. ethylene, -ethylene- cyclopropylene or -methylene-cyclopropylene.

49. The compound or salt of claim 48, wherein -L'-L2- is50. The compound or salt of claim 49. wherein -L'-L2- is51. The compound or salt of claim 50. wherein -L'-L2- is11005-W001-SEC52. The compound or salt of claim 50. wherein -L'-L2- isO53. The compound or salt of claim 50, wherein -L'-L2- is HO54. The compound or salt of claim 50, wherein -L'-L2- is55. The compound or salt of any one of claims 1-32, wherein -L'-L2- is a 5-6 membered heteroaryl.The compound or salt of claim 55, wherein -L'-L2- is11005-W001-SEC58. The compound or salt of claim 57. wherein -L'-L2- is59. The compound or salt of claim 1. wherein the compound is:11005-W001-SEC11005-W001-SEC60. The compound or salt of claim 59, wherein the compound is:

61. The compound or salt of claim 1, wherein die compound is:11005-W001-SEC11005-W001-SEC11005-W001-SEC62. The compound or salt of claim 61, wherein the compound is:11005-W001-SEC63. A pharmaceutical composition comprising the compound or salt according to any one of claims 1-62 and a pharmaceutically acceptable excipient.

64. A compound or salt according to any one of claims 1-62 or the pharmaceutical composition according to claim 63 for use as a medicament.

65. A compound or salt according to any one of claims 1-62 or the pharmaceutical composition according to claim 63 for use in treating cancer.

66. A compound or salt according to any one of claims 1-62 or the pharmaceutical composition according to claim 63 for use in treating cancer, wherein one or more cells of the cancer express a KRAS G12D mutant protein.

67. The compound, salt or pharmaceutical composition for use of claim 65 or 66, 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.

68. A use of the compound or salt according to any one of claims 1-62 or the pharmaceutical composition according to claim 63 in the preparation of a medicament for treating cancer.

69. A use of the compound or salt according to any one of claims 1-62 or the pharmaceutical composition according to claim 63 in the preparation of a medicament for treating cancer, wherein one or more cells of the cancer express a KRAS G12D mutant protein.

70. The use according to claim 68 or 69, 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.11005-W001-SEC71. A method of treating cancer in a subject in need thereof, the method comprising administering to die subject a therapeutically effective amount of the compound or salt according to any one of claims 1-62 or a pharmaceutical composition according to claim 63.

72. A meUiod 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 1-62 or a pharmaceutical composition according to claim 63, wherein one or more cells of the cancer express a KRAS G12D mutant protein.

73. The method according to claim 71 or 72, 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.

74. The method according to claim 71 or 72. 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.

75. The method according to claim 74, wherein the cancer is non-small cell lung cancer.

76. The method according to claim 74, wherein the cancer is colorectal cancer.

77. The method according to claim 74, wherein the cancer is pancreatic cancer.

78. The method according to any one of claims 71-77, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D mutant protein prior to administration of the compound, salt or composition.

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