Macrocyclic compounds as modulators of KRAS and uses thereof

Abstract

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

Description

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

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 565,479, filed March 14, 2024, and U.S. Provisional Patent Application No.63 / 645,701, filed, May 10, 2024, each of which is incorporated by referenced in its entirety. FIELD

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

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

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

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

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

[0007] One aspect of the disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein; X is -CH2- or -O- Z is C-H, C-halogen, C-CN, C-C1-4alkyl, C-C1-4haloalkyl, C-C1-4alkoxy, C-C1-4haloalkoxy, C-C3-7cycloalkyl or N; Q is CH, C-halogen, C-C1-4alkyl, C-C1-4haloalkyl or N; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4alkyl, C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkylene, C2-4alkenyl, 5-7 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2N(Rz)2, -C(O)Rz, -C(O)ORz, -C(O)N(Rz)2, -C1-4alkylene-C(O)-C1-4alkyl, -C1-4alkylene-C(O)N(Rz)2, C1-4alkylene-S(O)2-C1-4alkyl, or -S-C1-4alkyl; L2is a bond, C1-6alkylene, -O-C1-6alkylene, -S-C1-6alkylene, NRz, O or S, wherein each C1-6alkylene, -O-C1-6alkylene and -S-C1-6alkylene chain is substituted with 0-2 occurrences of R2;; R1is hydrogen, hydroxyl, C6-10aryl, 5-10 membered heteroaryl, C3-8cycloalkyl or 4-15 membered heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R5; each R2independently is halogen, deuterium, hydroxyl or C1-4alkyl, wherein two geminal groups, together with the atom to which they are attached, form a spiro-C3-7cycloalkyl groupsubstituted with 0-2 occurrences of Rw; or wherein two adjacent R2groups, together with the atoms to which they are attached form a fused-C3-7cycloalkyl group substituted with 0-2 occurrences of Rw; R4is hydrogen, hydroxyl, halogen, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl or cyano; each R5independently is halogen, cyano, oxo, -T-Ry, hydroxyl, -N(Rz)2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, =C(Rw)2or -O-C2-4alkynyl; each R6a,R6band R6cindependently is hydrogen, halogen, hydroxyl, cyano, -N(Rz)2, -C(O)Rz, - C(O)ORz, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4alkynyl or C3-6cycloalkyl or R6aand R6b, together with the atom to which they are attached form a fused C3-7cycloalkyl; R6dis hydrogen, -C(O)-C1-8alkyl or -C(O)-OC1-8alkyl; T is C1-4 alkylene, -S(O)2-, -C(O)-, -C1-4 alkylene-C(O)-, C1-4 alkylene-S(O)2- or -S-; each Rwindependently is C1-4alkyl, C1-4alkoxy, halogen, hydroxyl or C1-4haloalkyl; Ryis C1-4alkyl, C1-4haloalkyl, hydroxyl, cyano or -N(Rz)2; and each Rzindependently is hydrogen or C1-4alkyl.

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

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

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

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

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

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

[0014] The following definitions are provided to assist in understanding the scope of this disclosure. Unless defined otherwise, all technical and scientific terms used herein have the 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 C1-6alkyl includes alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges)). A “C1-4alkyl” includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Nonlimiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl.

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

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

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

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

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

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

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

[0023] The term “alkylene” refers to a divalent saturated, straight or branched hydrocarbon chain diradical containing the indicated number of carbon atoms. For example, C3alkylene means the alkylene group has 3 carbon atoms. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, C1-6alkylene means an alkylene group having a 1, 2, 3, 4, 5, or 6 carbon atoms, or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbon atoms, or any combination of the foregoing). When the number of carbon atoms in analkylene group is indicated as “C0,” then the alkylene group is not present and the recited substituent is directly attached to the rest of the compound. For example, the term C0-6alkylene-OH indicates that the OH group can be directly attached to the compound or through a C1-6alkylene linker. Examples of alkylene groups include methylene (—CH2—), ethylene (—CH2CH2—), n-propylene (— CH2CH2CH2—), isopropylene (—CH(CH3)CH2—), 1-butylene (—CH2CH2CH2CH2—), 1- methylbutylene (—CH(CH3)CH2CH2—), 2-methylbutylene (—CH2CH(CH3)CH2—), and 3- methylbutylene (—CH2CH2CH(CH3)—).

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

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

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

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

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

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

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

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

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

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

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

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

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

[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 RRgroups on a chain and ring can be depicted as:, .

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

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

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

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

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

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

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

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

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

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

[0050] For clarity and avoidance of doubt, the divalent structural elements of L1as provided herein are to be inserted into Formula (I) such that the left hand side is attached to the nitrogen-containing heterocycloalkyl and the right hand side is attached to the aryl ring. For example, if L1is

[0051] For clarity and avoidance of doubt, the divalent structural elements of L2as provided herein are to be inserted into Formula (I) such that the left hand side in the markush definition (e.g., -O-C1-4alkylene) is attached to the nitrogen-containing heterocycloalkyl and the right hand side is attached to the R1moiety. For example, if L2is -O-methylene or -O-CH2-, then the compound of Formula (I) isCOMPOUNDS OF FORMULA (I)

[0052] Provided herein as Embodiment 1 is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein; X is -CH2- or -O- Z is C-H, C-halogen, C-CN, C-C1-4alkyl, C-C1-4haloalkyl, C-C1-4alkoxy, C-C1-4haloalkoxy, C-C3-7cycloalkyl or N; Q is CH, C-halogen, C-C1-4alkyl, C-C1-4haloalkyl or N; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4alkyl, C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkylene, C2-4alkenyl, 5-7 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2N(Rz)2, -C(O)Rz, -C(O)ORz, -C(O)N(Rz)2, -C1-4alkylene-C(O)-C1-4alkyl, -C1-4alkylene-C(O)N(Rz)2, C1-4alkylene-S(O)2-C1-4alkyl, or -S-C1-4alkyl; L2is a bond, C1-6alkylene, -O-C1-6alkylene, -S-C1-6alkylene, NRz, O or S, wherein each C1-6alkylene, -O-C1-6alkylene and -S-C1-6alkylene chain is substituted with 0-2 occurrences of R2;,R1is hydrogen, hydroxyl, C6-10aryl, 5-10 membered heteroaryl, C3-8cycloalkyl or 4-15 membered heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R5; each R2independently is halogen, deuterium, hydroxyl or C1-4alkyl, wherein two geminal groups, together with the atom to which they are attached, form a spiro-C3-7cycloalkyl group substituted with 0-2 occurrences of Rw; or wherein two adjacent R2groups, together with the atoms to which they are attached form a fused-C3-7cycloalkyl group substituted with 0-2 occurrences of Rw; R4is hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7cycloalkyl or cyano; each R5independently is halogen, cyano, oxo, -T-Ry, hydroxyl, -N(Rz)2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, =C(Rw)2or -O-C2-4alkynyl; each R6a,R6band R6cindependently is hydrogen, halogen, hydroxyl, cyano, -N(Rz)2, -C(O)Rz, - C(O)ORz, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4alkynyl or C3-6cycloalkyl or R6aand R6b, together with the atom to which they are attached form a fused C3-7cycloalkyl; R6dis hydrogen, -C(O)-C1-8 alkyl or -C(O)-OC1-8 alkyl; T is C1-4alkylene, -S(O)2-, -C(O)-, -C1-4alkylene-C(O)-, C1-4alkylene-S(O)2- or -S-; each Rwindependently is C1-4alkyl, C1-4alkoxy, halogen, hydroxyl or C1-4haloalkyl;Ryis C1-4alkyl, C1-4haloalkyl, hydroxyl, cyano or -N(Rz)2; and each Rzindependently is hydrogen or C1-4alkyl.

[0053] Provided herein as Embodiment 2 is the compound or salt of Embodiment 1, wherein the compound or salt is a compound of Formula (I-B):or a pharmaceutically acceptable salt thereof, wherein; X is -CH2- or -O- Z is C-H, C-halogen, C-CN, C-C1-4alkyl, C-C1-4haloalkyl, C-C1-4alkoxy, C-C1-4haloalkoxy, C-C3-7cycloalkyl or N; Q is CH, C-halogen, C-C1-4alkyl, C-C1-4haloalkyl or N; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4alkyl, C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkylene, C2-4alkenyl, 5-7 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2N(Rz)2, -C(O)Rz, -C(O)ORz, -C(O)N(Rz)2, -C1-4alkylene-C(O)-C1-4alkyl, -C1-4alkylene-C(O)N(Rz)2, C1-4alkylene-S(O)2-C1-4alkyl, or -S-C1-4alkyl; L2is a bond, C1-6alkylene, -O-C1-6alkylene, -S-C1-6alkylene, NRz, O or S, wherein each C1-6alkylene, -O-C1-6alkylene and -S-C1-6alkylene chain is substituted with 0-2 occurrences of R2;, , ,,R1is hydrogen, hydroxyl, C6-10aryl, 5-10 membered heteroaryl, C3-8cycloalkyl or 4-15 membered heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl or heterocycloalkyl is substituted with 0-3 occurrences of R5; each R2independently is halogen, deuterium, hydroxyl or C1-4alkyl, wherein two geminal groups, together with the atom to which they are attached, form a spiro-C3-7cycloalkyl group substituted with 0-2 occurrences of Rw; or wherein two adjacent R2groups, together with the atoms to which they are attached form a fused-C3-7cycloalkyl group substituted with 0-2 occurrences of Rw; R4is hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7cycloalkyl or cyano; each R5independently is halogen, cyano, oxo, -T-Ry, hydroxyl, -N(Rz)2, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, =C(Rw)2or -O-C2-4alkynyl; each R6a,R6band R6cindependently is hydrogen, halogen, hydroxyl, cyano, -N(Rz)2, -C(O)Rz, - C(O)ORz, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4alkynyl or C3-6cycloalkyl or R6aand R6b, together with the atom to which they are attached form a fused C3-7cycloalkyl; T is C1-4 alkylene, -S(O)2-, -C(O)-, -C1-4 alkylene-C(O)-, C1-4 alkylene-S(O)2- or -S-; each Rwindependently is C1-4alkyl, C1-4alkoxy, halogen, hydroxyl or C1-4haloalkyl; Ryis C1-4alkyl, C1-4haloalkyl, hydroxyl, cyano or -N(Rz)2; andeach Rzindependently is hydrogen or C1-4alkyl.

[0054] Provided herein as Embodiment 3 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, Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, R6d, Rw, T, Ryand Rzare as defined above for Formula (I).

[0055] Provided herein as Embodiment 4 is the compound or salt of Embodiment 1 or 2, wherein the compound is a compound of Formula (II-B):or a pharmaceutically acceptable salt of said compound, wherein X, Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, Rw, T, Ryand Rzare as defined above for Formula (I).

[0056] Provided herein as Embodiment 5 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, Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, R6d, Rw, T, Ryand Rzare as defined above for Formula (I).

[0057] Provided herein as Embodiment 6 is the compound or salt of Embodiment 1 or 2, wherein the compound is a compound of Formula (III-B):or a pharmaceutically acceptable salt of said compound, wherein X, Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, Rw, T, Ryand Rzare as defined above for Formula (I).

[0058] Provided herein as Embodiment 7 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (IV):or a pharmaceutically acceptable salt of said compound, wherein X, Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, R6d, Rw, T, Ryand Rzare as defined above for Formula (I).

[0059] Provided herein as Embodiment 8 is the compound or salt of Embodiment 1 or 2, wherein the compound is a compound of Formula (IV-B):or a pharmaceutically acceptable salt of said compound, wherein X, 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 9 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, Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, R6d, Rw, T, Ryand Rzare as defined above for Formula (I).

[0061] Provided herein as Embodiment 10 is the compound or salt of Embodiment 1 or 2, wherein the compound is a compound of Formula (V-B):or a pharmaceutically acceptable salt of said compound, wherein X, Z, p, Rx, L2, L1, R1, R2, R4, R5, R6a, R6b, R6c, Rw, T, Ryand Rzare as defined above for Formula (I).

[0062] Provided herein as Embodiment 11 is the compound or salt of any of Embodiments 1-10, wherein Z is C-H, C-F, C-CN, C-CH3, C-CF3, C-OMe, C-Cl or N. Provided herein as Embodiment 12 is compound or salt of claim 11, wherein Z is N. Provided herein as Embodiment 13 is the compound or salt of Embodiment 11, wherein Z is CH. Provided herein as Embodiment 14 is the compound or salt of Embodiment 11, wherein Z is CF.

[0063] Provided herein as Embodiment 15 is the compound or salt of any of Embodiments 1-14, wherein Q is CH or N. Provided herein as Embodiment 16 is the compound or salt of Embodiment 15, wherein Q is CH. Provided herein as Embodiment 17 is the compound or salt of Embodiment 15, wherein Q is N.

[0064] Provided herein as Embodiment 18 is the compound or salt of any of Embodiments 1-10, wherein Z is N and Q is CH.

[0065] Provided herein as Embodiment 19 is the compound or salt of any of Embodiments 1-2, wherein Z is N and Q is N.

[0066] Provided herein as Embodiment 20 is the compound or salt of any of Embodiments 1-19, wherein L2is -O-. Provided herein as Embodiment 21 is the compound or salt of Embodiment 20, wherein R1is heterocycloalkyl substituted with 0-3 occurrences of R5. Provided herein as Embodiment 22 is the compound or salt of Embodiment 21, wherein R1is 4-tetrahydro-2H-pyranyl substituted with 0-3 occurrences of R5. Provided herein as Embodiment 23 is the compound or salt of Embodiment 22, wherein R1is 4-tetrahydro-2H-pyranyl substituted with 0 occurrences of R5.

[0067] Provided herein as Embodiment 24 is the compound or salt of any of Embodiments 20-23, wherein -L2-R

[0068] Provided herein as Embodiment 25 is the compound or salt of any of Embodiments 1-19, wherein L2is -O-methylene, -O-ethylene or -O-n-propylene substituted with 0-2 occurrences of R2. Provided herein as Embodiment 26 is the compound or salt of Embodiment 25, wherein L2is -O- methylene substituted with 0 occurrences of R2.

[0069] Provided herein as Embodiment 27 is the compound or salt of Embodiment 26, wherein wherein R1is heterocycloalkyl substituted with 0-3 occurrences of R5. Provided herein as Embodiment 28 is the compound or salt of Embodiment 27, wherein R1is 7a-(hexahydro-1H- pyrrolizinyl), 5-(1-azabicyclo[3.2.0]heptanyl), 2-azetidinyl, 6-(hexahydro-1H-pyrrolo[2,1- c][1,4]oxazinyl) or 2-pyrrolidinyl substituted with 0-3 occurrences of R5. Provided herein as Embodiment 29 is the compound or salt of Embodiment 28, wherein R1is unsubstituted 7a- (hexahydro-1H-pyrrolizinyl), unsubstituted 2-azetidinyl or unsubstituted 2-pyrrolidinyl substituted with 0 occurrences of R5.

[0070] Provided herein as Embodiment 30 is the compound or salt of Embodiment 28, wherein R1is 6-(hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl) substituted with 0 occurrences of R5.

[0071] Provided herein as Embodiment 31 is the compound or salt of Embodiment 28, wherein R1is 7a-(hexahydro-1H-pyrrolizinyl), 2-azetidinyl or 2-pyrrolidinyl substituted with one occurrence of R5. Provided herein as Embodiment 32 is the compound or salt of Embodiment 31, wherein R1is 7a- (hexahydro-1H-pyrrolizinyl) substituted with one occurrence of R5.

[0072] Provided herein as Embodiment 33 is the compound or salt of Embodiment 32, wherein R5is halogen, -O-C2-4alkynyl, =C(Rw)2or C1-4alkyl. Provided herein as Embodiment 34 is the compound or salt of Embodiment 33, wherein R5is -O-C2-4alkynyl. Provided herein as Embodiment 35 is the compound or salt of Embodiment 33, wherein R5is -O-2-propynyl. Provided herein as Embodiment 36 is the compound or salt of Embodiment 33, wherein R5is fluorine. Provided herein as Embodiment 37 is the compound or salt of Embodiment 33, wherein R5is methyl. Provided herein as Embodiment 38 is the compound or salt of Embodiment 33, wherein R5is =CH2. Provided herein as Embodiment 39 is the compound or salt of Embodiment 33, wherein R5is =C(H)(F).

[0073] Provided herein as Embodiment 40 is the compound or salt of Embodiment 31, wherein R1is 2-azetidinyl substituted with one occurrence of R5. Provided herein as Embodiment 41 is the compound or salt of Embodiment 40, wherein R5is C1-4alkyl (e.g., methyl).

[0074] Provided herein as Embodiment 42 is the compound or salt of Embodiment 31, wherein R1is 2-pyrrolidinyl substituted with one occurrence of R5. Provided herein as Embodiment 43 is the compound or salt of Embodiment 42, wherein R5is C1-4alkyl (e.g., methyl).

[0075] Provided herein as Embodiment 44 is the compound or salt of Embodiment 28, wherein R1is 5-(1-azabicyclo[3.2.0]heptanyl) or 2-pyrrolidinyl substituted with two occurrences of R5. Provided herein as Embodiment 45 is the compound or salt of Embodiment 44, wherein R1is 2-pyrrolidinyl substituted with two occurrences of R5. Provided herein as Embodiment 46 is the compound or salt of Embodiment 45, wherein one R5is methyl and the other R5is fluorine. Provided herein as Embodiment 47 is the compound or salt of Embodiment 45, wherein both R5are C1-4alkyl (e.g., methyl).

[0076] Provided herein as Embodiment 48 is the compound or salt of Embodiment 44, wherein R1is 5-(1-azabicyclo[3.2.0]heptanyl) substituted with two occurrences of R5. Provided herein as Embodiment 49 is the compound or salt of Embodiment 48, wherein both R5are halogen (e.g., fluorine).

[0077] Provided herein as Embodiment 50 is the compound or salt of Embodiment 25, wherein L2is -O-methylene substituted with 2 occurrences of R2. Provided herein as Embodiment 51 is the compound or salt of Embodiment 50, wherein both R2are deuterium. Provided herein as Embodiment 52 is the compound or salt of Embodiment 51, wherein R1is 7a-(hexahydro-1H- pyrrolizinyl) substituted with one occurrence of R5. Provided herein as Embodiment 53 is the compound or salt of Embodiment 52, wherein R5is halogen (e.g., fluorine).

[0078] Provided herein as Embodiment 54 is the compound or salt of Embodiment 25, wherein L2is -O-n-propylene substituted with two occurrences of R2. Provided herein as Embodiment 55 is the compound or salt of Embodiment 54, wherein two geminal R2groups, together with the atom to which they are attached, form a spiro-C3-7cycloalkyl group further substituted with 0-2 occurrences of Rw. Provided herein as Embodiment 56 is the compound or salt of Embodiment 55, wherein two geminal R2groups, together with the atom to which they are attached, form a spiro-cyclopropyl group further substituted with two occurrences of Rw. Provided herein as Embodiment 57 is the compound or salt of Embodiment 56, wherein both Rware halogen (e.g., fluorine). Provided herein as Embodiment 58 is the compound or salt of Embodiment 57, wherein R1is -N(Rz)2and Rzare methyl.

[0079] Provided herein as Embodiment 59 is the compound or salt of any of Embodiments 25-58, wherein -L2-Rs , , , , ,

[0080] Provided herein as Embodiment 60 is the compound or salt of Embodiment 59, w.

[0081] Provided herein as Embodiment 61 is the compound or salt of Embodiment 60,Provided herein as Embodiment 63 is the compound or salt of Embodiment 62, wherein -L2-R1isvided herein as Embodiment 64 is the compound or salt of Embodiment 62, wherein -L2-R1is. herein as Embodiment 65 is the compound or salt of Embodiment 62, wherein -L2-R1is

[0082] Provided herein as Embodiment 66 is the compound or salt of any of Embodiments 1-65, wherein X is O. Provided herein as Embodiment 67 is the compound or salt of Embodiment 66, wherein n is 1 and m is 2. Provided herein as Embodiment 68 is the compound or salt of Embodiment 67, wherein p is 0. Provided herein as Embodiment 69 is the compound or salt of Embodiment 67, w or,

[0083] Provided herein as Embodiment 71 is the compound or salt of Embodiment 67, wherein p is 1. Provided herein as Embodiment 72 is the compound or salt of Embodiment 71, wherein Rxis C1-4alkyl (e.g., methyl). Provided herein as Embodiment 73 is the compound or salt of Embodiment 72, whereins . Prov e erein as Embodiment 74 is the compound or, .Embodiment 75 is the compound or salt of Embodiment 73, wherein

[0084] Provided herein as Embodiment 76 is the compound or salt of Embodiment 66, wherein n is 1 and m is 1. Provided herein as Embodiment 77 is the compound or salt of Embodiment 76, wherein p is 0. Provided herein as Embodiment 78 is the compound or salt of Embodiment 76, whereinerein as Embodiment 79 is the compound or salt of Embodiment 78, wherein. s Embodiment 80 is the compound or salt of Embodiment 78,.

[0085] Provided herein as Embodiment 81 is the compound or salt of any of Embodiments 1-65, wherein X is -CH2-. Provided herein as Embodiment 82 is the compound or salt of Embodiment 81, wherein n is 1 and m is 2. Provided herein as Embodiment 83 is the compound or salt of Embodiment 82, wherein p is 0. Provided herein as Embodiment 84 is the compound or salt of Embodiment 83, w. erein as Embodiment 85 is the compound or salt of Embodiment 84, whereins . rov e ere n as Embodiment 86 is the compound or salt of Embodiment 84, whereins

[0086] Provided herein as Embodiment 87 is the compound or salt of Embodiment 82, wherein p is 1. Provided herein as Embodiment 88 is the compound or salt of Embodiment 87, wherein Rxis hydroxyl, halogen (e.g, fluorine), C1-4haloalkyl (e.g., fluoromethyl) or C1-4alkyl (e.g., methyl). Provided herein as Embodiment 89 is the compound or salt of Embodiment 88, wherein Rxis hydroxyl. Provided herein as Embodiment 90 is the compound or salt of Embodiment 88, wherein Rxis fluorine. Provided herein as Embodiment 91 is the compound or salt of Embodiment 88, wherein Rxis methyl. Provided herein as Embodiment 92 is the compound or salt of Embodiment 88, wherein Rxis fluoromethyl. Provided herein as Embodiment 93 is the compound or salt of Embodiment 88, whereinProvided herein as Embodiment 94 is the compound or salt of Embodiment 93, whereinherein as Embodiment 95 is the compound or salt of Embodiment 93, wherein. as Embodiment 96 is the compound or salt of Embodiment 93, wherein. here as Embodiment 97 is the compound or salt of Embodiment 93, wherein is. Provided herein as Embodiment 98 is the compound or salt of Embodiment 93, whereins .

[0087] Provided herein as Embodiment 99 is the compound or salt of Embodiment 81, wherein n is 1 and m is 1. Provided herein as Embodiment 100 is the compound or salt of Embodiment 99, wherein p is 0. Provided herein as Embodiment 101 is the compound or salt of Embodiment 100,ein as Embodiment 102 is the compound orsalt of Embodiment 101, whereinEmbodiment 103 is the compound or salt of Embodiment 101, wherein.

[0088] Provided herein as Embodiment 104 is the compound or salt of Embodiment 99, wherein p is 1. Provided herein as Embodiment 105 is the compound or salt of Embodiment 104, wherein Rxis hydroxyl, halogen (e.g, fluorine), C1-4alkoxy (e.g., methoxy) or C1-4alkyl (e.g., methyl). Provided herein as Embodiment 106 is the compound or salt of Embodiment 105, wherein Rxis hydroxyl. Provided herein as Embodiment 107 is the compound or salt of Embodiment 105, wherein Rxis fluorine. Provided herein as Embodiment 108 is the compound or salt of Embodiment 105, wherein Rxis methyl. Provided herein as Embodiment 109 is the compound or salt of Embodiment 105, wherein Rxis methoxy. Provided herein as Embodiment 110 is the compound or salt of Embodiment 10. o e e e as o e s e co pou o sa o o e , wherein is , , , , , , , , , or. Provided herein as Embodiment 112 is the compound or salt of Embodiment 111, win as Embodiment 113 is the compound or salt of Embodiment 111, whereinherein as Embodiment 114 is the compound or salt of Embodiment 111, whereinerein as Embodiment 115 is the compound or salt of Embodiment 111, wherein. s Embodiment 116 is, herein as Embodiment 117 is the compound or salt of Embodiment 111, wherein.

[0089] Provided herein as Embodiment 118 is the compound or salt of Embodiment 99, wherein p is 2. Provided herein as Embodiment 119 is the compound or salt of Embodiment 118, wherein one Rxis hydroxyl and the other Rxis C1-4alkyl (e.g., methyl). Provided herein as Embodiment 120 is the compound or salt of Embodiment 119, wherein one Rxis hydroxyl and the other Rxis methyl. Provided herein as Embodiment 121 is the compound or salt of Embodiment 120, wherein erein as Embodiment 122 is the compound orsalt of Embodiment 121, whereinEmbodiment 123 is the compound or salt of Embodiment 121, wherein.

[0090] Provided herein as Embodiment 124 is the compound or salt of Embodiment 81, wherein n is 0 and m is 1 or m is 0 and n is 1. Provided herein as Embodiment 125 is the compound or salt of Embodiment 124, wherein p is 0. Provided herein as Embodiment 126 is the compound or salt of Embodiment 125, wherein. as Embodiment 127 is the compound or salt of Embodiment 126, wherein. as Embodiment 128 is the compound or salt of Embodiment 126, wherein.

[0091] Provided herein as Embodiment 129 is the compound or salt of Embodiment 124, wherein p is 1. Provided herein as Embodiment 130 is the compound or salt of Embodiment 129, wherein Rxis hydroxyl, halogen (e.g., fluorine), C1-4alkyl (e.g., methyl), C1-4haloalkyl (e.g., fluoromethyl), C1-4alkoxy (e.g., methoxy) or C1-4hydroxyalkylene (e.g., hydroxymethylene). Provided herein as Embodiment 131 is the compound or salt of Embodiment 130, wherein Rxis hydroxyl. Provided herein as Embodiment 132 is the compound or salt of Embodiment 130, wherein Rxis fluorine. Provided herein as Embodiment 133 is the compound or salt of Embodiment 130, wherein Rxis methyl. Provided herein as Embodiment 134 is the compound or salt of Embodiment 130, wherein Rxis methoxy. Provided herein as Embodiment 135 is the compound or salt of Embodiment 130, wherein Rxis hydroxymethylene. Provided herein as Embodiment 136 is the compound or salt ofEmbodiment 130, wherein Rxis fluoromethyl. Provided herein as Embodiment 137 is the compound or salt of Embodiment 130, whereinherein as Embodiment 138 is the compound or salt of E w, , , , o . Provided herein as Embodiment 140 is the compound or salt of Embodiment 139, whereincompound or salt of Embodiment 139, whereinas Embodiment 142 is the compound or salt of Embodiment 139, wherein. rovided herein as Embodiment 143 is the compound or salt of Embodiment 139, wherein. erein as Embodiment 144 is the compound or salt of Embodiment 139, whereins . o e ee as Embodiment 145 is the compound or salt of Embodiment 139, whereins. Provided herein as Embodiment 146 is the compound or salt of Embodiment 139,s Embodiment 147 is the compound or salt of Embodiment 139, whereinherein as Embodiment 148 is the compound or salt of Embodiment 139, whereinherein as Embodiment 149 is the compound or salt of Embodiment 139, whereinas Embodiment 150 is the compound or salt of Embodiment 139, wherein. Provided herein as Embodiment 151 is the compound or salt of Embodiment 139, wherein. erein as Embodiment 152 is the compound or salt of Embodiment 139, wherein.

[0092] Provided herein as Embodiment 153 is the compound or salt of Embodiment 81, wherein n is 0 and m is 0. Provided herein as Embodiment 154 is the compound or salt of Embodiment 153, wherein p is 0. Provided herein as Embodiment 155 is the compound or salt of Embodiment 154, whereins . rov e herein as Embodiment 156 is the compound or saltp ,

[0093] Provided herein as Embodiment 158 is the compound or salt of any of Embodiments 1-157, w ,, .

[0094] Provided herein as Embodiment 159 is the compound or salt of Embodiment 158, wherein

[0095] Provided herein as Embodiment 160 is the compound or salt of Embodiment 158, wherein L1

[0096] Provided herein as Embodiment 161 is the compound or salt of Embodiment 158, wherein L1is. d herein as Embodiment 162 is the compound or salt of Embodiment 158, wherein L1is. as Embodiment 163 is the compound or salt of Embodiment 158, wherein L1is. as Embodiment 164 is the compound or salt of Embodiment 158, wherein L1is. ed herein as Embodiment 165 is the compound or salt of Embodiment 158, wherein L1is. as Embodiment 166 is the compound or salt of Embodiment 158, wherein L1is. o e e e as Embodiment 167 is the compound or salt of Embodiment 158, wherein L1is. rov ed herein as Embodiment 168 is the compound or salt of Embodiment 158, wherein L1is. as Embodiment 169 is the compound or salt of Embodiment 158, wherein L1is. Prov e ere n as Embodiment 170 is the compound or salt of Embodiment 158, wherein L1is. Provided herein as Embodiment 171 is the compound or salt of Embodiment 1158, wherein L is . Provided herein as Embodiment 172 is the compound or 1salt of Embodiment 158, wherein L is . Provided herein as Embodiment 173is the compound or salt of Embodiment 158, wherein L1isherein as Embodiment 174 is the compound or salt of Embodiment 158, wherein L1ised herein as Embodiment 175 is the compound or salt of Embodiment 158, wherein L1isas Embodiment 176 is the compound or salt of Embodiment 158, wherein L1is. as Embodiment 177 is the compound or salt of Embodiment 158, wherein L1is. ed herein as Embodiment 178 is the compound or salt of Embodiment 158, wherein L1is. as Embodiment 179 is the compound or salt of Embodiment 158, wherein L1is. o e e e as Embodiment 180 is the compound or salt of Embodiment 158, wherein L1is.

[0097] Provided herein as Embodiment 181 is the compound of salt of any of Embodiments 1-180, wherein R4is hydrogen, hydroxyl, halogen, C1-4alkyl or C1-4alkoxy. Provided herein as Embodiment 182 is the compound or salt of Embodiment 181, wherein R4is halogen or C1-4alkyl. Provided herein as Embodiment 183 is the compound or salt of Embodiment 182, wherein R4is fluorine.

[0098] Provided herein as Embodiment 184 is the compound or salt of any of Embodiments 1-183, wherein each of R6a,R6band R6cindependently is hydrogen, halogen, C1-4alkyl, C1-4alkoxy or C1-4haloalkyl. Provided herein as Embodiment 185 is the compound or salt of Embodiment 184, wherein each of R6a,R6band R6cis hydrogen. Provided herein as Embodiment 186 is the compound or salt of Embodiment 184, wherein each of R6band R6cis hydrogen and R6ais halogen (e.g., chlorine or fluorine). Provided herein as Embodiment 187 is the compound or salt of Embodiment 186, wherein each of R6band R6cis hydrogen and R6ais chlorine. Provided herein as Embodiment 188 is the compound or salt of Embodiment 186, wherein each of R6band R6cis hydrogen and R6ais fluorine. Provided herein as Embodiment 189 is the compound or salt of Embodiment 184, wherein each of R6band R6cis hydrogen and R6ais C1-4alkyl (e.g., methyl). Provided herein as Embodiment 190 is the compound or salt of Embodiment 189, wherein each of R6band R6cis hydrogen and R6ais methyl.

[0099] Provided herein as Embodiment 191 is the compound or salt of any of Embodiments 1-190, wherein R6dis hydrogen. Provided herein as Embodiment 192 is the compound or salt of any of Embodiments 1-190, wherein R6dis -C(O)-C1-8alkyl. Provided herein as Embodiment 193 is the compound or salt of Embodiment 192, wherein R6dis -C(O)Me

[0100] Provided herein as embodiment 194 is the compound or salt of Embodiment 1, wherein the compound is: Table 1

[0101] Provided herein as Embodiment 195 is the compound or salt of Embodiment 1, wherein the compound is:

[0102] Provided herein as Embodiment 196 is the compound or salt of Embodiment 1, wherein the compound is:

[0103] Provided herein as Embodiment 197 is the compound or salt of Embodiment 1, wherein the compound is:

[0104] Provided herein as Embodiment 198 is the compound or salt of Embodiment 194, wherein th066). Provided herein as Embodiment 199 is the compound or salt of Embodiment 194, wherein the compound iso pound 1.075). Provided herein as Embodiment 200 is the co, (Compound 1.019). Provided herein as Embodiment 201 is the compound or salt of Embodiment 194, wherein the compound isompoun . ). Provided herein as Embodiment 202 is the compound or salt of Embodiment 194, wherein the compound isund 1.027). Provided herein as Embodiment 203 is the1.007). Provided herein as Embodiment 204 is the compound or salt of Embodimentodiment 205 is the compound or salt of Embodiment 194, wherein the compound is(Compound 1.010). Provided herein as Embodiment 206 is thesalt of Embodiment 194, wherein the compound is1.006). Provided herein as Embodiment 207 is the compound or salt of Embodimentodiment 208 is the compound or salt of Embodiment 194, wherein the compound is(Compound 1.061). Provided herein as Embodiment 209 is the, 1.072). Provided herein as Embodiment 210 is the compound or salt of Embodimentherein as Embodiment 211 is the compound or salt of Embodiment 194, wherein the compound isp d 1.111). Provided herein as Embodiment 212 is the c(Compound 1.119). Provided herein as Embodiment 213 is the compound or salt of Embodiment 194, wherein the compound iso pou . ). Provided herein as Embodiment 214 is the compound or salt of Embodiment 194, wherein the compound iscompound or salt of Embodiment 194, wherein the compound is(Compound 1.123). Provided herein as Embodiment 216 is the compound or salt of Embodiment 194, wherein the compound isherein as Embodiment 217 is the compound or salt of Embodiment 194, wherein the compound is

[0105] In another aspect of the disclosure, Embodiment 218 provides a compound from the table below: Table 2

[0106] Provided herein as Embodiment 219 is the compound or salt of Embodiment 218, wherein th099). Provided herein as Embodiment 220 is the compound or salt of Embodiment 218, wherein the compound isp nd 1.035).

[0107] It is understood that selections of values of each variable are those that result in the formation of stable or chemically feasible compounds. Stereoisomers

[0108] The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropoisomers. Accordingly, the scope of the present disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.

[0109] 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. Forname (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.

[0110] 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.

[0111] This disclosure also encompasses the pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein. Further, this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGrawHill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). Tautomers

[0112] 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 onetautomeric form, it will be understood that for convenience, referral to a compound of a givenstructural formula includes other tautomers of said structural formula. For example, representsor example, the chemical name (4R,5R)-4- methoxy-5-methyl-4,5,6,7-tetrahydro-1H-indazole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7- tetrahydro-1H-indazole and (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-indazole. Accordingly, the scope of the present disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein. Isotopically-Labeled Compounds

[0113] 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 as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Certain isotopically-labeled compounds of the compounds disclosed herein, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium (2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances. As such, the term “deuterated” refers to the substitution of one or more hydrogen atoms with one or more deuterium atoms on a particular structure or functional group. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. Isotopically- labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying GENERAL SYNTHETIC PROCEDURES and EXAMPLES sections using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.BIOLOGICAL ACTIVITY

[0114] In some cases, the compounds or salts disclosed herein (such as compounds of Formula (I), Formula (I-B), Formula (II), Formula (II-B), Formula (III), Formula (III-B), Formula (IV), Formula (IV-B), Formula (V) or Formula (V-B), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-220, or a pharmaceutically acceptable salt of any of the foregoing), have an IC50value of less than 5 µM, or less than 4 µM, or less than 3 µM, or less than 2 µM, or less than 1 µM, or less than 0.9 µM, or less than 0.7 µM, or less than 0.6 µM, or less than 0.5 µM, or less than 0.4 µM, or less than 0.3 µM, or less than 0.2 µM, or less than 0.1 µM, or less than 0.09 µM, or less than 0.08 µM, or less than 0.07 µM, or less than 0.06 µM, or less than 0.05 µM, or less than 0.04 µM, or less than 0.03 µM, or less than 0.02 µM, or less than 0.01 µM in the G12D Coupled Exchange assay, AsPC-1 p-ERK assay, AsPC-1 CTG assay or the SW620 CTG assay, described in “SECTION 3: Biochemical and Cellular Assays.” In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50value of between 0.001 to 0.200 µM. FORMULATION AND ROUTE OF ADMINISTRATION

[0115] 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 (I-B), Formula (II), Formula (II-B), Formula (III), Formula (III-B), Formula (IV), Formula (IV-B), Formula (V) or Formula (V-B), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-220, or a pharmaceutically acceptable salt of any of the foregoing), in combination with one or more pharmaceutically acceptable excipients and, if desired, other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol.1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In some cases, the pharmaceutical composition described herein comprises a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0116] The compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended. The compounds and compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously,sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0117] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. In some cases, the pharmaceutical composition is made in the form of a dosage unit containing a particular amount of the active ingredient.

[0118] 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.

[0119] Provided herein as Embodiment 221 is pharmaceutical composition comprising the compound or salt of any one of Embodiments 1 to 220, and a pharmaceutically acceptable excipient. METHODS OF USE

[0120] The compounds described herein (such as compounds of Formula (I), Formula (I-B), Formula (II), Formula (II-B), Formula (III), Formula (III-B), Formula (IV), Formula (IV-B), Formula (V) or Formula (V-B), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-220, or a pharmaceutically acceptable salt of any of the foregoing) can competitively bind to KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C or a mutated KRAS comprising one or more mutations selected from G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R and G12C. In some cases, the compounds described herein can act as inhibitors of KRAS G12D. In some cases, the compounds described herein can act as inhibitors of KRAS G12V. In some cases, the compounds described herein can act as inhibitors of KRAS G12A. In some cases, the compounds described herein can act as inhibitors of KRAS G12S. In some cases, the compounds described herein can act as inhibitors of KRAS G13D. In some cases, the compounds described herein can act as inhibitors of KRAS Q61H. In some cases, the compounds described herein can act as inhibitors of KRAS Q61R. In some cases, the compounds described herein can act as inhibitors of KRAS Q61L. In some cases, the compounds described herein can act as inhibitors of KRAS G12R. In some cases, the compounds described herein can act as inhibitors of KRAS G12C. Without intending to be bound by any particular theory, the compounds of the disclosure can, in some cases, inhibit KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C, leading to an improvement in conditions or symptoms mediated by a KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutation (e.g., reduction in tumor size).

[0121] 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.

[0122] 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 (I-B), Formula (II), Formula (II-B), Formula (III), Formula (III-B), Formula (IV), Formula (IV-B), Formula (V) or Formula (V-B), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-220, or a pharmaceutically acceptable salt of any of the foregoing) to a patient.

[0123] 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.

[0124] Another aspect of the disclosure provides a compound or salt disclosed herein (such as compounds of Formula (I), Formula (I-B), Formula (II), Formula (II-B), Formula (III), Formula (III- B), Formula (IV), Formula (IV-B), Formula (V) or Formula (V-B), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-220, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein, for use in treating cancer.

[0125] 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.

[0126] A further aspect provided by the disclosure is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0127] 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 celllung cancer. In some cases, the cancer is colorectal cancer. In some cases, the cancer is pancreatic cancer.

[0128] Provided herein as Embodiment 222 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 220, or the composition of Embodiment 221.

[0129] Provided herein as Embodiment 223 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS G12D mutant protein.

[0130] Provided herein as Embodiment 224 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS G12V mutant protein.

[0131] Provided herein as Embodiment 225 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS G12A mutant protein.

[0132] Provided herein as Embodiment 226 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS G12S mutant protein.

[0133] Provided herein as Embodiment 227 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS G13D mutant protein.

[0134] Provided herein as Embodiment 228 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS Q61H mutant protein.

[0135] Provided herein as Embodiment 229 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS Q61L mutant protein.

[0136] Provided herein as Embodiment 230 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS Q61R mutant protein.

[0137] Provided herein as Embodiment 231 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS G12R mutant protein.

[0138] Provided herein as Embodiment 232 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 220, or the composition of Embodiment 221, wherein one or more cells express KRAS G12C mutant protein.

[0139] Provided herein as Embodiment 233 is the method according to any one of embodiments 222-232, 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.

[0140] Provided herein as Embodiment 234 is the method according to Embodiment 233, 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 235 is the method according to Embodiment 234, wherein the cancer is non-small cell lung cancer. Provided herein as Embodiment 236 is the method according to Embodiment 234, wherein the cancer is colorectal cancer. Provided herein as Embodiment 237 is the method according to Embodiment 234, wherein the cancer is pancreatic cancer.

[0141] Provided herein as Embodiment 238 is the compound or salt of any one of Embodiments 1 to 220, or the pharmaceutical composition of Embodiment 221 for use as a medicament.

[0142] Provided herein as Embodiment 239 is the compound or salt of any one of Embodiments 1 to 220, or the pharmaceutical composition of Embodiment 221 for use in the treatment of cancer.

[0143] Provided herein as Embodiment 240 is the use of the compound or salt of any one of Embodiments 1 to 220, or the pharmaceutical composition of Embodiment 221, for the manufacture of a medicament for the treatment of cancer.

[0144] Provided herein as Embodiment 241 is the use of the compound or salt of any one of Embodiments 238 to 240, 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.

[0145] Provided herein as Embodiment 242 is the method according to Embodiment 241, 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 243 is the method according to Embodiment 242, wherein the cancer is non-small cell lung cancer. Provided herein as Embodiment 244 is the method according to Embodiment 242, wherein the cancer is colorectal cancer. Provided herein as Embodiment 245 is the method according to Embodiment 242, wherein the cancer is pancreatic cancer. Combination Therapy

[0146] 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 (I-B), Formula (II), Formula (II-B), Formula (III), Formula (III- B), Formula (IV), Formula (IV-B), Formula (V) or Formula (V-B), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-220, or a pharmaceutically acceptable salt of any of the foregoing). In one aspect, such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect. See, e.g., 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.

[0147] 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, Rafkinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agent. In some cases, the second compound is administered as a pharmaceutically acceptable salt. In some cases, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0148] 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.

[0149] Exemplary Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2- fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2- methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H- pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8- dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2- chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13- yl]morpholine), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4- methylthiophen-2-yl)phthalazin-1-amine), MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H- pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4- (cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca- 2(7),3,5-trien-11-yl]-2-oxoethyl]acetamide), SNS-314 (1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2- d]pyrimidin-4-ylamino)ethyl]-1,3-thiazol-2-yl]urea), CYC116 (4-methyl-5-[2-(4-morpholin-4- ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607.

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

[0151] Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1- aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1- aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1- aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-, 2,10-diethyl ester), ONC201 (11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ 751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3- chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0152] 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.

[0153] 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.

[0154] Exemplary CDK 4 / 6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin- 7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfony1)- 4-piperidinyl]amino]).

[0155] 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: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). The term “ErbB family inhibitor” as used herein refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one member of the ErbB family. The modulation or inhibition of one or more ErbB tyrosine kinase may occur through modulating or inhibiting kinase enzymatic activity of one or more ErbB family member or by blocking homodimerization or heterodimerization of ErbB family members.

[0156] 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.

[0157] 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.

[0158] In yet another embodiment the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti- HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).

[0159] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody.

[0160] In one embodiment, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7- [3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide)), PF 6274484 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4- (dimethylamino)but-2-enamide).

[0161] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3- (trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3- methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3- fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate), and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2- methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

[0162] 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.

[0163] Exemplary ERK inhibitors for use in the methods provided herein include, but are not limited to, ulixertinib, ravoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6-dimethyl- 2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4- one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7- one), ASTX029, LTT462, and JSI-1187.

[0164] 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.

[0165] Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4- yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5- yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), VS-4718 (2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N- methylbenzamide), and APG-2449.

[0166] 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.

[0167] Exemplary FGFR inhibitors for use in the methods provided herein include, but are not limited to, futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5- dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5- dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), debio 1347 ([5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl- methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453, and HGS1036.

[0168] 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.

[0169] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0170] 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.

[0171] Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS-754807 ((2S)-1-[4- [(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2- methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2- [(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro- 2,3,24,33-tetramethyl-22H-9,4,8-(metheniminomethyno)-14,20:26,23-dimetheno-10H,20H- pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4- pyrimidinyl]methoxy]benzenepropanoic acid), and ABBV-467.

[0176] MEK Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is an MEK inhibitor.

[0177] Exemplary MEK inhibitors for use in the methods provided herein include, but are not limited to, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3- dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4- iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide), GDC-0623 (5-(2- fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4- difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2- yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)- 8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4- difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N- (cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodophenylamino)benzamide), PD98059 (2-(2-amino-3-methoxyphenyl)-4H- chromen-4-one), PD334581 (N-[5-[3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-1,3,4- oxadiazol-2-yl]-4-morpholineethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554.

[0178] 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.

[0179] Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, vistusertib, dactolisib, Torin-1 (1-(4-(4-propionylpiperazin-1-yl)-3- (trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea), and VS-5584 (SB2343, (5-(8-methyl-2-rnorpholin-4-yl-9-propan-2-ylpurin-6- yl)pyrimidin-2-amine).

[0180] 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.

[0181] Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR- 042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and the anti-PD-1 antibody as described in US 10,640,504 B2 (the “Anti-PD-1 Antibody A,” column 66, line 56 to column 67, line 24 and column 67, lines 54-57), which is incorporated herein by reference.

[0182] 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.

[0183] Exemplary PD-L1 inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR-1316, MSB2311, MDX- 1105, KN035, IMC-001, HLX20, FAZ053, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167.

[0184] 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.

[0185] Exemplary PI3K inhibitors for use in the methods provided herein include, but are not limited to, idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolisib, tenalisib, serabelisib, acalisib, CUDC-907 (N-hydroxy-2- [[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl- methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4- yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2- amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2- phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 ((2S)-2-[[(2S)-3- carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2- yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]- 3-hydroxypropanoate), XL147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4- methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3- thiazolidine-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H- purin-6-amine).

[0186] Raf Kinase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a Raf Kinase inhibitor. The term “RAF kinase” as used herein refers to a member of a mammalian serine / threonine kinases composed of three isoforms (C-Raf, B-Raf and A- Raf) and includes homodimers of each isoform as well as heterodimers between isoforms, e.g., C- Raf / B-Raf heterodimers. The term “Raf kinase inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Raf family kinases, or is capable of disrupting Raf homodimer or heterodimer formation to inhibit activity.

[0187] Exemplary Raf kinase inhibitors include, but is not limited to, encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a- dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1- sulfonamide), Raf-709 (N-(2-methyl-5,-morpholino-6’-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'- bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3- dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6- yl)phenyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3- (trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP- 32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2- yl)isoxazol-3-yl)urea), CCT196969 (1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3- oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea), and RO5126766 (N-[3-fluoro-4-[[4- methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl- sulfamide).

[0188] SHP2 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.

[0189] Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6- (2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TNO155, (3S,4S)-8-[6-amino-5-(2-amino-3- chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and vociprotafib (RMC-4630 - Revolution Medicine).

[0190] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3- dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3- hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7), and 6- [(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5- methyl-2-pyrazinemethanol (CAS 2172652-48-9).

[0191] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4- methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5- a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3- dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]- 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-57-2), 4-[(3S,4S)-4-amino-3-methyl-2- oxa-8-azaspiro[4.5]dec-8-yl]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8- azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2), and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0192] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5- hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3- dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decan-1-amine (CAS 2238840- 62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2- pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]- 8-azaspiro[4.5]decan-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2-[(2,3- dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2- [(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]- 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2- pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8- yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-amino-3-chloro- 4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2- pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)- 5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS 2238840-72-5), 5-[(2-amino-3-chloro-4- pyridinyl)thio]-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-3- pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8- yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 3-[(3S,4S)-4-amino- 3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8), and 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3- methyl-2-oxa-8- azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyridin-3-ol.

[0193] In one embodiment, the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1- amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5). In one embodiment, the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in US 10,590,090 B2, US 2020 / 017517 A1, US 2020 / 017511 A1, or WO 2019 / 075265 A1.

[0194] SOS1 Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a SOS1 inhibitor.

[0195] Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6- [(3S)-oxolan-3-yl]oxyquinazolin-4-amine), and BI 1701963.

[0196] Src Kinase Inhibitors. In some cases, the compounds of the disclosure can be administered simultaneously, separately, or sequentially with an effective amount of a second compound, wherein the second compound is a Src Kinase inhibitor. The term “Src kinase” as used herein refers to a member of a mammalian nonreceptor tyrosine kinase family including: Src, Yes, Fyn, and Fgr (SrcA subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily), and Frk subfamily. The term “Src kinase inhibitor” as used herein refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Src kinases.

[0197] Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7- tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4- methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide).

[0198] 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.

[0199] 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

[0200] 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.

[0201] 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.

[0202] In general, the compounds of Formula (I) can be synthesized according to Schemes I-IV as shown below: Scheme I

[0203] Compounds of Formula (I-A) can be prepared according to Scheme I. In step A, compound (I-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 (I-2). In step B, compound (I-2) undergoes borylation with a reagent such as bis(pinacolate)diboron under Pd catalyzed conditions to give compound (I-3). In step C, compound (I-3) is coupled with a pyridopyrimidine to give compound (I-4). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-Me THF and water, and a catalyst such as cataCXium A Pd G3 (CAS No. 1651823-59-4), with or without a base such as potassium phosphate. In step D, compound (I-4) is hydrolyzed to give compound (I-5) using a reagent such as HCl in dioxane or TFA. In step E, compound (I-5) is cyclized under conditions such as PyBrop or Brop and DIPEA in a solvent such as CH3CN and DMSO to give compounds of Formula (I-A). Scheme II

[0204] Compounds of Formula (II-A) can also be prepared according to Scheme II. In step A, compound (II-1) undergoes SNAr reaction with an optionally substituted cyclic amine bearing an alcohol or protected amine in a solvent such as acetonitrile and in the presence of a base such as Hunig’s base to give compound (II-2). In step B, compound (II-2) undergoes SNAr reaction with a nucleophile having the formula R1-L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig’s base to give compound (II-3). In step C, compound (II-3) is coupled with an organometallic reagent or a boronic acid (ester) attached to an aryl or heteroaryl bearing a terminal TBS protected alcohol to give compound (II-4). This coupling reaction proceeds in a solvent or mixture of solvents such as THF and water, and a catalyst such as cataCXium A Pd G3 (CAS 1651823-59-4), with 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 HCl in dioxane or TFA. In step E, compound (II-5) is reacted with CDI, followed by treated with a desilyating reagent such as TBAF in solvent such as THF to give compounds of Formula (II-A). Scheme III

[0205] Compounds of Formula (III-A) can also be prepared according to Scheme III. In step A, compound (III-1) undergoes SNAr reaction with an optionally substituted cyclic amine bearing an terminal alkene in a solvent such as acetonitrile and in the presence of a base such as Hunig’s base to give compound (III-2). In step B, compound (III-2) undergoes SNAr reaction with a nucleophile having the formula R1-L-H in a solvent such as acetonitrile, in the presence of a base such as Hunig’s base to give compound (III-3). In step C, compound (III-3) is coupled with an organometallic reagent or a boronic acid (ester) attached to an aryl or heteroaryl bearing an terminal alkene to give compound (III-4). This coupling reaction proceeds in a solvent or mixture of solvents such as THF and water, and a catalyst such as cataCXium A Pd G3 (CAS 1651823-59-4), with or without a base such as potassium phosphate. In step D, compound (III-4) undergoes ring closure metathesis to give compound (III-5). This reaction proceeds with Hoveyda-Grubbs 2ndgeneration catalyst in a solvent such as DCE and in the presence of an acid such as TsOH. In step E, compound (III-5) is hydrolyzed to give compound (III-A) using a reagent such as HCl in dioxane or TFA.

[0206] Scheme IV

[0207] Compounds of Formula (IV-A) can also be prepared according to Scheme IV. In step A, compound (I-A) undergoes an acylation reaction with an acyl chloride in a solvent such as DCM, THF or acetonitrile and in the presence of a base such as Hünig’s base or triethylamine to produce IV- A. Alternatively, compound (I-A) can undergo an acylation reaction upon treatment with an acid anhydride or a chloroformate in a solvent such DCM, THF or acetonitrile in the presence of a catalyst such as DMAP and a base such as Hünig’s base or triethylamine to produce IV-A.

[0208] 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.

[0209] 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.

[0210] 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

[0211] This section provides specific examples of compounds of Formula (I) and methods of making the same. List of Abbreviations

[0212] Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific examples provided herein.

[0213] 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.

[0214] Preparative HPLC Method: Where indicated, the compounds described herein were purified via reversed phase HPLC using Waters FractionLynx or Gilson semi-preparative HPLC-MS system using one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run through the instrument included: eluting at 45 mL / min with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) over 10 minutes. Conditions can be varied to achieve improved separations.

[0215] Proton NMR Spectra: Unless otherwise indicated, all1H NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz. All observed protons are reported as parts-per- million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as reference. Some1H signals may be missing due to exchange with D from MeOD, or due to signal suppression.

[0216] Fluorine NMR Spectra: Unless otherwise indicated, all19F NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz under1H-decoupled conditions. All observed fluorines are reported as parts-per-million (ppm).

[0217] 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.

[0218] Provided in this section is the synthesis of various intermediates used to prepare compounds of Formula (I). All starting materials are either commercially available from Sigma-Aldrich, Combi- Blocks, Enamine, PharmaCore, PharmaBlock, Synnovator, Chemscene, AA blocks, Oakwood or Ambeed, or similar vendors, unless otherwise noted, or known in the art and may be synthesized by employing known procedures using ordinary skill. SECTION 1: Synthesis of Intermediates Intermediate A: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine.

[0219] Step 1: 4-(tert-Butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 198 mmol) in tetrahydrofuran (1.5 L) was added t-BuOK (1 M in THF, 190 mL, 190 mmol) dropwise at -60 °C and the reaction mixture was stirred at -60 °C for 2 h. The mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with petroleum ether at room temperature for 1 h. The suspension was filtered, and the cake was concentrated under reduced pressure to give 4- (tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (30 g, 103 mmol, 54% yield).1H NMR (400 MHz, CDCl3) δ ppm 9.08 (s, 1 H), 1.74 (s, 9 H).

[0220] Step 2: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(tert-butoxy)-2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 172 mmol) and 4Å MS (10 g) in 1,4-dioxane (1 L) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (30.2 g, 190 mmol) and DIPEA (60.0 g, 431 mmol) in sequence. Then the mixture was stirred at 80 °C for 5 h.^After cooling to room temperature, the reaction mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE at room temperature for 1 h. The suspension was filtered, and the cake was concentrated under reduced pressure to give 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine (40 g, 97 mmol, 56% yield).^m / z^(ESI): 413.2 / 415.2 (M+H)+.

[0221] Intermediate B1: rac-((1R,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)methanol.

[0222] Step 1. rac-Ethyl (1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropane-1-carboxylate. A vial was charged with 4-bromo-6-chloro-5-iodo-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (0.75 g, 1.70 mmol, Lab Network), rac-ethyl (1R,2S)-2- (tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (0.49 mL, 2.04 mmol, Enamine), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.12 g, 0.17 mmol), potassium phosphate tribasic (1.26 g, 5.95 mmol) in toluene (5 mL) and water (1 mL). The reaction mixture was flushed with nitrogen and heated at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated and the residue purified by column chromatography on silica gel, eluting with a gradient of 0–60% EtOAc / heptane to provide rac-ethyl (1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1-carboxylate (0.24 g, 0.56 mmol, 33% yield). m / z (ESI): 448.8 (M+Na)+.

[0223] Step 2. rac-((1R,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)methanol. To a stirred solution of rac-ethyl (1R,2S)-2-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1-carboxylate (0.95 g, 2.23 mmol) in tetrahydrofuran (6 mL) at -78 °C was added diisobutylaluminum hydride solution (1.0 M in DCM, 5.6 mL, 5.6 mmol) slowly. The resulting mixture was allowed to warm to room temperature and stirred for another 30 min. The reaction mixture was poured slowly into Rochelle's salt aqueous solution in an ice bath and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–60% EtOAc / heptane to afford rac-((1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methanol (Intermediate B1, 0.69 g, 1.78 mmol, 80% yield). m / z (ESI): 384.8 (M+H)+. Intermediate B: rac-2-((1R,2R)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethan-1-ol.

[0224] Step 1. rac-(1R,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropane-1-carbaldehyde. To a solution of rac-((1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methanol (Intermediate B1, 5.00 g, 13.0 mmol) in dichloromethane (75 mL) was added Dess-Martin periodinane (11.00 g, 25.9 mmol) at 0 °C. Then the reaction mixture was stirred at 20 °C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% EtOAc in petroleum ether, to give rac-(1R,2S)-2-(4-bromo-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1-carbaldehyde (4.16 g, 10.9 mmol, 85% yield).

[0225] Step 2. rac-4-Bromo-6-chloro-5-((1S,2R)-2-((Z)-2-methoxyvinyl)cyclopropyl)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole. To the mixture of (methoxymethyl)triphenylphosphonium (24.0 g, 78 mmol) in tetrahydrofuran (200 mL) was added t-BuOK (1 M in THF, 78 mL, 78 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then the solution of rac- (1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1- carbaldehyde (10.0 g, 26.1 mmol) in tetrahydrofuran (200 mL) was added dropwise at 0 °C to the mixture. The reaction mixture was stirred at room temperature for 30 min, then was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% EtOAc in petroleum ether, to give rac-4-bromo-6-chloro-5-((1S,2R)-2-((Z)- 2-methoxyvinyl)cyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (9.62 g, 23 mmol, 90% yield).

[0226] Step 3. rac-2-((1S,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)acetaldehyde. To the mixture of rac-4-bromo-6-chloro-5-((1S,2R)-2-((Z)-2- methoxyvinyl)cyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (33 g, 80 mmol) in 1,4- dioxane (790 mL) and water (130 mL) was added pyridine 4-methylbenzenesulfonate (32.4 g, 128mmol). The reaction mixture was stirred at 70 °C for 12 h. After cooling to room temperature, the reaction mixture was quenched by addition of water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% EtOAc in petroleum ether, to give rac-2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)acetaldehyde (20.0 g, 50.3 mmol, 63% yield).

[0227] Step 4. rac-2-((1S,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethan-1-ol. To the mixture of rac-2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)acetaldehyde (20.0 g, 50.3 mmol) in ethanol (200 mL) was added NaBH4(3.23 g, 85 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, was then quenched by addition of saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 20–35% EtOAc in petroleum ether, to give rac-2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)cyclopropyl)ethan-1-ol (19.1 g, 48.0 mmol, 95% yield).1H NMR (400 MHz, DMSO- d6) δ ppm 8.06 (s, 1 H), 7.99 (s, 1 H), 5.87 (dd, J = 9.6, 2.4 Hz, 1 H), 4.29 - 4.33 (m, 1 H), 3.85 - 3.88 (m, 1 H), 3.76 - 3.77 (m, 1 H), 3.36 - 3.41(m, 2 H), 2.29 - 2.38 (m, 1 H), 1.97 – 2.03 (m, 3 H), 1.84 - 1.86 (m, 1 H), 1.69 - 1.73 (m, 1 H), 1.54 - 1.60 (m, 2 H), 1.38 - 1.48 (m, 1 H), 1.31 - 1.37 (m, 1 H), 0.80 - 0.92 (m, 1 H), 0.20 - 0.26 (m, 1 H). m / z (ESI): 401.0 / 399.0 (M+H)+. Intermediate C: 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine.

[0228] Step 1.2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 198 mmol, LabNetwork) in tetrahydrofuran (750 mL) cooled to -60oC was added 2,2,2-trifluoroethan-1-ol (18.82 g, 188 mmol), followed by t-BuOK (1 M in THF, 188 mL, 188 mmol) dropwise. The mixture was stirred at -60 °C for 2 h. The reaction mixture was quenched by addition of H2O (1-L) at 20 °C and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was washed with petroleum ether (50 mL), then filtered. The filter cake was concentrated underreduced pressure to give 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50.0 g, 158 mmol, 84% yield).1H NMR (400 MHz, CDCl3) δ ppm 9.18 (s, 1 H), 5.06 – 5.12 (m, 2 H).

[0229] Step 2.7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 2,7-dichloro-8- fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (28 g, 89 mmol) in 1,4-dioxane (280 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (16.9 g, 106 mmol) and DIPEA (46.4 mL, 266 mmol) in sequence. Then the mixture was stirred at 80 °C for 10 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–100% EtOAc in petroleum ether, to provide 7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine (28.0 g, 63.8 mmol, 72% yield). m / z^(ESI): 439.1 / 441.1 (M+H)+. Intermediate D: (Z)-4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3- en-1-ol.

[0230] Step 1.4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn- 1-ol. A mixture of 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (20.0 g, 45.3 mmol), TEA (63 mL, 453 mmol), but-3-yn-1-ol (4.13 g, 58.9 mmol), CuI (0.86 g, 4.50 mmol) and Pd(PPh3)2Cl2 (3.18 g, 4.53 mmol) in N,N-dimethylformamide (120 mL) was degassed and purged with nitrogen, the reaction mixture was 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 over Na2SO4, filtered, and concentrated. The crude product was purified by reversed phase MPLC, eluting with a gradient of 30–60% CH3CN in water, to give 4-(4-bromo-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (12.3 g, 32.2 mmol, 71% yield).

[0231] Step 2. (Z)-4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3- en-1-ol. To a suspension of PtO2(1.95 g) in tetrahydrofuran (220 mL) was added 4-(4-bromo-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-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, was then filteredthrough a pad of celite and the filtrate concentrated under reduced pressure. The residue was purified by reversed phase chromatography on a C18 column, eluting with a gradient of 35–67% of (CH3CN in water with 10 mM NH4HCO3 as an additive), to provide (Z)-4-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-ol (7.85 g, 20.4 mmol, 71% yield). m / z (ESI): 387.0 / 385.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 8.00 (s, 1 H), 7.69 (s, 1 H), 6.45 (d, J = 11.2 Hz, 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). Intermediate E: (S)-4-(tert-Butoxy)-7-chloro-8-fluoro-2-((1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidine.

[0232] Step 1: (S)-4-(tert-Butoxy)-7-chloro-8-fluoro-2-((1-methylpyrrolidin-2- yl)methoxy)pyrido[4,3-d]pyrimidine. To a mixture of 4-(tert-butoxy)-2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidine (Step 1 in Intermediate A, 14.0 g, 48.3 mmol) and 4Å MS (2.5 g) in 1,4-dioxane (280 mL) was added (S)-(1-methylpyrrolidin-2-yl)methanol (8.34 g, 72.4 mmol) and Cs2CO3(39.3 g, 121 mmol) in sequence. The reaction mixture was stirred at room temperature for 10 h, then was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was triturated with MTBE at room temperature for 2 h. The suspension was filtered, and the filter cake was washed with MTBE and concentrated under reduced pressure to give (S)-4-(tert-butoxy)-7-chloro-8-fluoro-2- ((1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidine (7.89 g, 21.4 mmol, 44% yield). m / z (ESI): 369.1 / 371.1.1H NMR (400 MHz, CDCl3) δ ppm 8.86 (s, 1 H), 4.58 (br d, J = 3.2 Hz, 1 H), 4.41 - 4.47 (m, 1 H), 3.07 - 3.28 (m, 1 H), 2.73 - 2.89 (m, 1 H), 2.55 (br s, 3 H), 2.28 - 2.45 (m, 1 H), 2.04 - 2.19 (m, 1 H), 1.78 - 1.93 (m, 3 H), 1.76 (s, 9 H).19F NMR (376 MHz, CDCl3) δ ppm -135.34 (s).

[0233] Intermediate F: 4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)butan-1-ol.

[0234] Step 1.4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal. To a solution of 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (25.0 g, 56.6 mmol, Lab Network) in N,N-dimethylformamide (300 mL) was added NaHCO3(11.9 g, 142 mmol) and TBACl (14.8 g, 56.6 mmol) under N2. The reaction mixture was stirred at room temperature for 15 min, then but-3-en-1-ol (8.17 g, 113 mmol) and Pd(OAc)2(1.27 g, 5.66 mmol) was added. The mixture was stirred at 80 °C for 12 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 over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% ethyl acetate in petroleum ether, to give 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal (15 g, 39 mmol, 70% yield). m / z (ESI): 385.1 / 387.1 (M+H)+.

[0235] Step 2.4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butan-1- ol. To a solution of 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal (15 g, 39 mmol) in EtOH (300 mL) was added NaBH4(4.41 g, 117 mmol) in portions at 0 °C. The mixture was stirred at room temperature for 2 h, was then quenched by addition of saturated NH4Cl and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% ethyl acetate in petroleum ether, to give 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butan-1-ol (11 g, 28 mmol, 73% yield). m / z (ESI): 387.0 / 389.0 (M+H)+.

[0236] Intermediate G: 4-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)butan-1-ol.

[0237] Step 1.4-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal 4- (4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal. To a solution of 4- bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.0 g, 23.5 mmol) in N,N- dimethylformamide (120 mL) was added NaHCO3 (4.94 g, 58.8 mmol) and TBACl (6.15 g, 23.5 mmol) under N2. Then but-3-en-1-ol (3.39 g, 47.1 mmol) and Pd(OAc)2(0.53 g, 2.4 mmol) was added. The reaction mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the residue was diluted with water and extracted with EtOAc. The combined organic layers were washedwith 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 10–20% ethyl acetate in petroleum ether, to give 4-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal (3.50 g, 9.50 mmol, 40% yield).

[0238] Step 2.4-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butan-1- ol. To a solution of 4-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butanal (3.50 g, 9.50 mmol) in EtOH (50 mL) was added NaBH4(1.08 g, 28.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h, was then quenched by addition of saturated NH4Cl solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–30% ethyl acetate in petroleum ether, to give 4-(4-bromo-6-fluoro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)butan-1-ol (3.30 g, 8.90 mmol, 94% yield). m / z (ESI): 371.1 / 373.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (s, 1 H), 7.69 (d, J = 10.0 Hz, 1 H), 5.79 - 5.82 (m, 1 H), 4.37 - 4.40 (m, 1 H), 3.76 - 3.85 (m, 1H), 3.41 - 3.43 (m, 1 H), 3.33 - 3.40 (m, 2 H), 2.80 - 2.84 (m, 2 H), 2.31 - 2.39 (m, 1 H), 1.97 - 1.99 (m, 2 H), 1.57 - 1.58 (m, 1 H), 1.49 - 1.55 (m, 4 H), 1.45 - 1.47 (m, 2 H).19F NMR (376 MHz, DMSO-d6) δ ppm -113.65 (s, 1 F).

[0239] Intermediate H: rac-2-((1S,2S)-2-(4-Bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl) cyclopropyl) ethan-1-ol.

[0240] The title compound was prepared in an analogous fashion to Intermediate B1 & B using 4- bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole in Step 1. m / z (ESI): 379.0 / 381.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.96 (s, 1 H), 7.33 (s, 1 H), 5.63 - 5.65 (m, 1 H), 4.01 - 4.12 (m, 1 H), 3.74 - 3.76 (m, 1 H), 3.63 - 3.66 (m, 2 H), 2.57 (s, 3 H), 2.49 - 2.52 (m, 1 H), 2.10 - 2.15 (m, 1 H), 2.03 - 2.07 (m, 3 H), 1.73 - 1.78 (m, 4 H), 1.37 -1.42 (m, 3 H), 0.44 - 0.49 (m, 1 H).

[0241] Intermediate I: 3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)propan-1-ol.

[0242] Step 1: 3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanal. To a 40-mL vial was charged with 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (3.00 g, 6.80 mmol, Lab Network), sodium bicarbonate (1.43 g, 17.0 mmol), TBACl (1.95 g, 6.82 mmol), and N,N-dimethylformamide (14 mL). The solution was degassed by nitrogen bubbling for 10 min. Then palladium(II) acetate (77 mg, 0.34 mmol) and allyl alcohol (0.7 mL, 10 mmol) were added at 50 °C. The reaction mixture was stirred at 50 °C for 18 h. After cooling to room temperature, the reaction was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–50% 3:1 EtOAc / EtOH in heptane, to provide 3-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)propanal (2.12 g, 5.70 mmol, 84% yield). m / z (ESI): 371.0 (M+H)+.

[0243] Step 2.3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1- ol. To a 100-mL round-bottom flask was added 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)propanal (1.06 g, 2.86 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL). The reaction mixture was cooled to 0 °C then sodium borohydride (0.11 g, 2.86 mmol) was slowly added in portion. The reaction mixture was stirred at 0 °C for 30 min, then was slowly quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to provide 3-(4-bromo-6-chloro- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1-ol (1.03 g, 2.76 mmol, 97% yield). m / z (ESI): 289.0 (M-THP+H)+.

[0244] Intermediate J: tert-Butyl 6-(2-(((rac-1R,2S)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)methoxy)ethyl)-1,4- oxazepane-4-carboxylate.

[0245] Step 1. tert-Butyl 6-(2-hydroxyethyl)-1,4-oxazepane-4-carboxylate. A 40-mL vial was charged with 2-{4[(tert-butoxy)carbonyl]-1,4-oxazepan-6-yl}acetic acid (1.01 g, 3.88 mmol, Enamine) in tetrahydrofuran (13 mL). To the mixture was added aluminium lithium hydride (2 M in toluene, 2.3 mL, 4.6 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then was allowed to warm to room temperature with stirring for 45 minutes. The reaction was cooled to 0 °C again and quenched carefully with sodium sulfate decahydrate. The crude mixture was filtered, the filtrate was passed through anhydrous sodium sulfate and concentrated to yield tert-butyl 6-(2-hydroxyethyl)-1,4-oxazepane-4-carboxylate (0.92 g, 3.80 mmol, 97% yield). m / z (ESI): 268.0 (M+Na)+.

[0246] Step 2. tert-Butyl 6-(2-((methylsulfonyl)oxy)ethyl)-1,4-oxazepane-4-carboxylate. To a vial was charged with tert-butyl 6-(2-hydroxyethyl)-1,4-oxazepane-4-carboxylate (0.10 g, 0.41 mmol), dichloromethane (4 mL), and triethylamine (0.11 mL, 0.82 mmol). To this was added methanesulfonyl chloride (0.04 mL, 0.49 mmol) and the reaction was stirred at room temperature for 30 minutes. Saturated aqueous sodium carbonate was added, and the DCM layer was decanted and concentrated. The crude material was purified by flash column chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in heptane, to give tert-butyl 6-(2-((methylsulfonyl)oxy)ethyl)-1,4- oxazepane-4-carboxylate (0.11 g, 0.34 mmol, 83% yield). m / z (ESI): 346.0 (M+Na)+.

[0247] Step 3. tert-Butyl 6-(2-(((rac-1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)methoxy)ethyl)-1,4-oxazepane-4-carboxylate. To a 40-mL vial was charged with rac-((1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)methanol (Intermediate B1, 0.92 g, 2.40 mmol), tetrahydrofuran (15 mL), and sodium hydride (60 wt% in mineral oil, 96 mg, 2.40 mmol). The reaction mixture was stirred at room temperature for 15 minutes. To this solution was then added tert-butyl 6-(2- ((methylsulfonyl)oxy)ethyl)-1,4-oxazepane-4-carboxylate (0.52 g, 1.60 mmol) and the reaction mixture was heated to 65 °C for 20 h. After cooling to room temperature, the reaction mixture wascarefully quenched with saturated aqueous ammonium chloride solution and concentrated. The residue was diluted with DMSO, filtered, and purified by reversed-phase column chromatography to yield tert-butyl 6-(2-(((cis-rac-1R,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)methoxy)ethyl)-1,4-oxazepane-4-carboxylate (0.57 g, 0.93 mmol, 58% yield). m / z (ESI): 633.8 (M+Na)+.

[0248] Step 4. tert-Butyl 6-(2-(((rac-1R,2S)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)methoxy)ethyl)-1,4- oxazepane-4-carboxylate. To a solution of tert-butyl 6-(2-(((rac-1R,2S)-2-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methoxy)ethyl)-1,4-oxazepane-4- carboxylate (0.51 g, 0.83 mmol) in THF (4 mL) cooled to -78 °C was added butyl lithium (2.5 M in hexanes, 0.43 mL, 1.10 mmol) dropwise. The reaction mixture was stirred at -78 °C for 5 minutes and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.25 mL, 1.30 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring for 1.5 h. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–60% EtOAc in heptane, to provide tert-butyl 6-(2-(((rac-1R,2S)-2-(6- chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)methoxy)ethyl)-1,4-oxazepane-4-carboxylate (0.48 g, 0.73 mmol, 88% yield). m / z (ESI): 660.2 (M+H)+.

[0249] Intermediate K: tert-Butyl (3R,5S)-3-amino-5-((tert-butyldiphenylsilyl)oxy)piperidine- 1-carboxylate.

[0250] A mixture of (3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 9.25 mmol, Aurum Pharmatech LLC), imidazole (2.52 g, 37.0 mmol), benzene, 1,1'-[chloro(1,1- dimethylethyl)silylene]bis- (4.8 mL, 18 mmol) in dichloromethane (45 mL) was stirred at room temperature for 16 h. The crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in heptane, to yield tert-butyl (3R,5S)-3-amino-5-((tert- butyldiphenylsilyl)oxy)piperidine-1-carboxylate (Intermediate K, 4.45 g, crude). m / z (ESI): 455.2 (M+H)+.

[0251] Intermediate L: (Z)-4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)but-3-en-1-ol.

[0252] Step 1.4-(4-Bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn- 1-ol. To a stirred mixture of TEA (10.8 mL, 77 mmol), 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole (3.25 g, 7.72 mmol), copper(I) iodide (0.15 g, 0.77 mmol), and trans- dichlorobis(triphenyl-phosphine)palladium (II) (0.54 g, 0.77 mmol) in N,N-dimethylformamide (19 mL) at room temperature, was added 3-butyn-1-ol (0.95 mL, 12.4 mmol). The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and saturated aqueous sodium chloride. The aqueous layer was extracted with EtOAc, and the combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–70% EtOAc in heptane, to provide 4-(4-bromo-6-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (2.13 g, 5.86 mmol, 76% yield). m / z (ESI): 363.0 (M+H)+.

[0253] Step 2. (Z)-4-(4-Bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3- en-1-ol. To a stirred mixture of bis(cyclopentadienyl)zirconium chloride hydride (10.75 g, 41.8 mmol) in tetrahydrofuran (20 mL) was added 4-(4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)but-3-yn-1-ol (3.80 g, 10.5 mmol) in tetrahydrofuran (20 mL). The resulting mixture was stirred at room temperature for 9 h, was then diluted with EtOAc and carefully quenched with water and filtered. The filtrate was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–70% EtOAc in heptane, to provide (Z)-4- (4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-ol (Intermediate L, 1.41 g, 3.86 mmol, 36% yield). m / z (ESI): 365.2 (M+H)+.

[0254] Intermediate M: 4-(Benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine.

[0255] Step 1.4-(Benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 198 mmol) in THF (1.5 L) was added benzylalcohol (20.4 g, 188 mmol) and KOtBu (1.0 M in THF, 188 mL, 188 mmol) dropwise at -60 °C, and the mixture was stirred at -60 °C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was triturated with pet. ether (500 mL) at 25 ℃ for 30 min to provide 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (322 g, 70% yield). m / z (ESI): 324.0 (M+H)+.

[0256] Step 2.4-(Benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidine (32 g, 99 mmol) in 1,4-dioxane (640 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (18.9 g, 118 mmol), followed by DIPEA (31.9 g, 247 mmol), and the mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was triturated with MBTE (100 mL) at 25 ℃ for 30 minutes to provide 4-(benzyloxy)-7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine (Intermediate M, 70 g, 79% yield). m / z (ESI): 447.1 (M+H)+.

[0257] Intermediate N: 4-(tert-Butoxy)-7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine.

[0258] Step 1.4-(tert-Butoxy)-2,7-dichloropyrido[4,3-d]pyrimidine. To a solution of 2,4,7- trichloropyrido[4,3-d]pyrimidine (2.07 g, 8.83 mmol, eNovation Chemicals LLC) in tetrahydrofuran (15 mL) cooled to -78oC was added sodium tert-butoxide (2 M in THF, 4.7 mL, 9.4 mmol) dropwise. The mixture was stirred at -78 °C for 1.5 h. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in heptanes, to provide 4-(tert-butoxy)-2,7-dichloropyrido[4,3-d]pyrimidine (1.47 g, 5.42 mmol, 61% yield).1H NMR (400 MHz, CDCl3) δ ppm 9.22 (s, 1H), 7.69 (s, 1H), 1.80 (s, 9H).

[0259] Step 2.4-(tert-Butoxy)-7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of ((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methanol (0.95 g, 5.9 mmol) in tetrahydrofuran (27 mL) cooled to 0oC wasadded LiHMDS (1 M in THF, 8.1 mL, 8.1 mmol) dropwise. The mixture was stirred at 0 °C for 10 minutes. A solution of 4-(tert-butoxy)-2,7-dichloropyrido[4,3-d]pyrimidine (1.47 g, 5.42 mmol) in tetrahydrofuran (2 mL) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched by addition of saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–65% 3:1 EtOAc / EtOH (with 2% TEA) in heptanes, to provide 4-(tert-butoxy)-7-chloro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (1.47 g, 3.72 mmol, 69% yield). m / z (ESI): 395.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.05 (s, 1H), 7.55 (s, 1H), 5.44 – 5.15 (m, 1H), 3.28 – 3.22 (m, 2H), 3.19 (s, 1H), 3.03 (td, J = 9.4, 5.7 Hz, 1H), 2.39 – 1.87 (m, 7H), 1.79 (s, 9H), 1.78 – 1.75 (m, 1H).

[0260] Intermediate O: 2-(4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-5-yl)ethan-1-ol.

[0261] Step 1.1-Allyl-7-bromo-5-fluoro-2,3-dihydro-1H-indene. To a solution of 7-bromo-5- fluoro-2,3-dihydro-1H-inden-1-one (6.00 g, 26.2 mmol, Enamine) in methanol (20 mL) at 0 °C was added sodium borohydride (1.19 g, 31.4 mmol) portionwise. The reaction mixture was stirred at room temperature for 4 h, then was diluted with slow addition of water. The mixture was concentrated, and the residue was treated with water and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to afford crude 7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-ol (6.00 g, 26.0 mmol, 99% yield). The crude material dissolved in dichloromethane (20 mL) was treated with iron(III) chloride hexahydrate (0.35 g, 1.30 mmol) and allyltrimethylsilane (7.4 mL, 65 mmol). The reaction mixture was stirred at room temperature for 12 h and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–60% 3:1 EtOAc / EtOH in heptane to afford 1-allyl-7-bromo-5-fluoro-2,3-dihydro-1H-indene (5.90 g, 23 mmol, 89% yield).1H NMR (400 MHz, CDCl3) δ ppm 7.07 (dd, J = 2.3, 8.6 Hz, 1H), 6.87 (dd, J = 0.8, 8.4 Hz, 1H), 5.87 – 5.76 (m, 1H), 5.13 – 5.03 (m, 2H), 3.35 – 3.27 (m, 1H), 3.12 – 3.00 (m, 1H), 2.93 – 2.84 (m, 1H), 2.59 –2.51 (m, 1H), 2.26 – 2.14 (m, 2H), 2.11 – 2.00 (m, 1H).19F NMR (376 MHz, CDCl3) δ ppm -115.07 (s).

[0262] Step 2.2-(7-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)acetaldehyde. To a solution of 1-allyl-7-bromo-5-fluoro-2,3-dihydro-1H-indene (4.00 g, 15.7 mmol) and potassium osmate (VI) dihydrate (0.58 g, 1.57 mmol) in acetone (20 mL) and water (4 mL) was added 4-methylmorpholine 4-oxide (6.43 g, 54.9 mmol). The reaction mixture was allowed to stir under nitrogen for 2 h, then was quenched with the addition of solid sodium sulfite and stirred at room temperature for 10 minutes. The contents were partially concentrated in vacuo and was diluted with EtOAc and brine solution. The aqueous layer was extracted with EtOAc, and the combined organics were dried (Na2SO4) and concentrated to afford crude 3-(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)propane-1,2-diol. The crude material dissolved in THF (80 mL) was treated with sodium metaperiodate (8.38 g, 39.2 mmol), followed by addition of water (15 mL). The resulting reaction mixture was allowed to stir under nitrogen for 4 h, then was diluted with a mixture of EtOAc / heptane (1:1). The mixture was filtered through a pad of celite, and the filtrate was treated with sat. aqueous NaHCO3and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–80% 3:1 EtOAc / EtOH in heptane, to afford 2-(7-bromo-5-fluoro-2,3-dihydro-1H- inden-1-yl)acetaldehyde (3.39 g, 13.2 mmol, 84% yield).1H NMR (500 MHz, CDCl3) δ ppm 9.85 (dd, J = 1.0, 2.3 Hz, 1H), 7.09 (dd, J = 2.2, 8.6 Hz, 1H), 6.90 (td, J = 1.0, 8.3 Hz, 1H), 3.78 – 3.72 (m, 1H), 3.13 – 3.03 (m, 1H), 2.99 – 2.92 (m, 2H), 2.58 (ddd, J = 2.3, 10.5, 17.2 Hz, 1H), 2.42 – 2.33 (m, 1H), 1.94 (tdd, J = 1.8, 8.0, 13.2 Hz, 1H).19F NMR (471 MHz, CDCl3) δ ppm -114.03 (s).

[0263] Step 3. (2-(7-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)ethoxy)(tert- butyl)dimethylsilane. To a solution of 2-(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)acetaldehyde (2.40 g, 9.33 mmol) in methanol (15 mL) at 0 °C was added sodium tetrahydroborate (0.42 g, 11.2 mmol) portionwise. The reaction mixture was stirred at room temperature for 2 h, was then diluted with slow addition of water and concentrated. The residue was partitioned between water and EtOAc. The organic was dried (Na2SO4) and concentrated to afford crude 2-(7-bromo-5-fluoro-2,3-dihydro- 1H-inden-1-yl)ethan-1-ol. The crude material dissolved in DMF (5 mL) at 0 °C was treated with 1H- imidazole (0.76 g, 11.2 mmol) and (1,1-dimethylethyl)dimethylsilyl chloride (1.41 g, 9.33 mmol). The reaction mixture was stirred at room temperature for 2 h, was then diluted with water and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated and the residue was purified by column chromatography on silica gel, eluting with a gradient of 0–40% EtOAc in heptane, to afford (2-(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-yl)ethoxy)(tert- butyl)dimethylsilane (3.12 g, 8.36 mmol, 90% yield).1H NMR (500 MHz, CDCl3) δ ppm 7.06 (dd, J = 2.3, 8.6 Hz, 1H), 6.87 (td, J = 1.1, 8.3 Hz, 1H), 3.79 – 3.72 (m, 2H), 3.34 – 3.27 (m, 1H), 3.14 –3.02 (m, 1H), 2.93 – 2.85 (m, 1H), 2.24 – 2.14 (m, 1H), 2.10 – 1.98 (m, 2H), 1.61 – 1.56 (m, 1H), 0.93 (s, 9H), 0.09 (d, J = 2.6 Hz, 6H).

[0264] Step 4.4-Bromo-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-2,3-dihydro-1H- indene-5-carbaldehyde. To a solution of (2-(7-bromo-5-fluoro-2,3-dihydro-1H-inden-1- yl)ethoxy)(tert-butyl)dimethylsilane (3.12 g, 8.36 mmol) in tetrahydrofuran (15 mL) at -78 °C was added LDA (1 M in tetrahydrofuran / hexanes, 11.6 mL, 11.6 mmol) dropwise. After stirring at -78 °C for 30 minutes, DMF (0.9 mL, 11.6 mmol) was added, and the resulting solution was stirred at -78 °C for another 30 minutes before being quenched with saturated NH4Cl solution and warmed to room temperature. The reaction mixture was extracted with EtOAc, and the combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in heptane, to afford 4-bromo-3-(2-((tert- butyldimethylsilyl)oxy)ethyl)-6-fluoro-2,3-dihydro-1H-indene-5-carbaldehyde (3.05 g, 7.6 mmol, 92% yield). m / z (ESI): 401.0 / 403.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 10.36 (s, 1H), 6.98 (d, J = 10.0 Hz, 1H), 3.83 – 3.73 (m, 2H), 3.45 (br t, J = 9.2 Hz, 1H), 3.21 – 3.09 (m, 1H), 3.03 – 2.90 (m, 1H), 2.29 – 2.11 (m, 2H), 2.05 – 1.95 (m, 1H), 1.61 - 1.52 (m, 1H), 0.94 (s, 9H), 0.10 (d, J = 2.3 Hz, 6H).19F NMR (376 MHz, CDCl3) δ ppm -117.11 (s, 1F).

[0265] Step 5.4-Bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(tetrahydro-2H-pyran-2- yl)-1,5,6,7-tetrahydrocyclopenta[f]indazole. A mixture of 4-bromo-3-(2-((tert- butyldimethylsilyl)oxy)ethyl)-6-fluoro-2,3-dihydro-1H-indene-5-carbaldehyde (1.00 g, 2.49 mmol) and hydrazine (0.24 mL, 7.5 mmol) in 1,2-dimethoxyethane (3 mL) was heated in microwave at 75 °C for 18 h. After cooling to room temperature, the reaction mixture was purified by column chromatography on silica gel, eluting with a gradient of 0–80% 3:1 EtOAc / EtOH in heptane to afford 4-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7-tetrahydrocyclopenta[f]indazole (0.43 g, 1.10 mmol, 44% yield). m / z (ESI): 395.0 / 397.0 (M+H)+.

[0266] A mixture of the 4-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7- tetrahydrocyclopenta[f]indazole (0.90 g, 2.28 mmol), 3,4-dihydro-2H-pyran (0.29 mL, 3.4 mmol), and 4-methylbenzenesulfonic acid hydrate (43 mg, 0.23 mmol) in dichloromethane (8 mL) was stirred at room temperature for 18 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated and the residue was purified by column chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in heptane to afford 4-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(tetrahydro-2H- pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazole (0.98 g, 2.00 mmol, 90% yield). m / z (ESI): 479.0 / 481.0 (M+H)+.

[0267] Step 6.2-(4-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7- tetrahydrocyclopenta[f]indazol-5-yl)ethan-1-ol. To the solution of 4-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazole (0.98 g, 2.0 mmol) in THF (5 mL) was added TBAF (1 M in THF, 3 mL, 3 mmol). The reaction mixture was stirred at room temperature for 1 h, was then concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 10–50% EtOAc in heptane, to afford 2-(4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1,5,6,7-tetrahydrocyclopenta[f]indazol-5-yl)ethan-1-ol (Intermediate O, 0.45 g, 1.20 mmol, 62% yield). m / z (ESI): 365.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.95 (s, 1 H), 7.35 (s, 1 H), 5.64 - 5.66 (m, 1 H), 4.01-4.04 (m, 1 H), 3.74 - 3.83 (m, 3 H), 3.46 - 3.51 (m, 1 H), 3.21 - 4.31 (m, 1 H), 3.01 - 3.03 (m, 1 H), 2.50 - 2.61 (m, 1 H), 2.11 - 2.20 (m, 1 H), 2.08 - 2.10 (m, 1 H), 2.07 - 2.08 (m, 1 H), 2.05 - 2.55 (m, 1 H), 1.74 - 1.78 (m, 4 H), 1.55 - 1.66 (m, 2 H).

[0268] Intermediate P: rac-((1R,2S)-2-(4-Bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl) methanol.

[0269] To a solution of 4-bromo-5-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (45 g, 107 mmol, Advanced ChemBlocks) in acetonitrile (1 L) and water (250 mL) was added potassium trifluoro ((1S,2R)-2-(hydroxymethyl)cyclopropyl) borate (38.0 g, 214 mmol, Lab Network), K3PO4(113 g, 534 mmol) and Pd(dppf)Cl2(15.64 g, 21.37 mmol) in sequence under nitrogen. The reaction mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 10–35% EtOAc in petroleum ether, to give rac-((1R,2S)-2- (4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl) methanol (Intermediate P, 12.9 g, 35.6 mmol, 33% yield). m / z (ESI): 365.0 / 367.0 (M+H)+.

[0270] Intermediate Q: rac-tert-Butyl (3R,5S)-3-(2-hydroxyethyl)-5- (methoxymethoxy)piperidine-1-carboxylate.

[0271] Step 1. tert-Butyl 3-oxo-2-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate. To a solution of sodium bicarbonate (2.00 g, 24.4 mmol) and tert-butyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (5.00 g, 22.2 mmol, Aurum Pharmatech LLC) in dichloromethane (220 mL) was added 3- chloroperoxybenzoic acid (4.60 g, 26.6 mmol). The reaction mixture was stirred at room temperature for 1 h, filtered over celite and the filtrate was quenched with saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate solutions. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford tert-butyl 3-oxo-2-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate (5.36 g, 22.2 mmol, 100% yield). m / z (ESI): 264.2 (M+Na)+.

[0272] Step 2. rac-tert-Butyl (3S,5S)-3-hydroxy-5-(2-methoxy-2-oxoethyl)piperidine-1- carboxylate. To a solution of tert-butyl 3-oxo-2-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate (5.36 g, 22.2 mmol) in methanol (84 mL) at room temperature was added a solution of sodium methoxide (0.5 M in MeOH, 13 mL, 6.5 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction was quenched with saturated NH4Cl solution, and the mixture was concentrated. The residue was extracted with DCM and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to provide rac-tert-butyl (3S,5S)-3-hydroxy-5-(2-methoxy-2- oxoethyl)piperidine-1-carboxylate (6.07 g, 22.2 mmol, 100% yield). m / z (ESI): 296.2 (M+Na)+.

[0273] Step 3. rac-tert-Butyl (3R,5R)-3-(2-methoxy-2-oxoethyl)-5- (methoxymethoxy)piperidine-1-carboxylate. To a solution of rac-tert-butyl (3S,5S)-3-hydroxy-5- (2-methoxy-2-oxoethyl)piperidine-1-carboxylate (6.07 g, 22.2 mmol) and DIPEA (11.6 mL, 66.6 mmol) in dichloromethane (44 mL) cooled at 0oC was added bromo(methoxy)methane (3.6 mL, 44.4 mmol) dropwise. The reaction was stirred at room temperature for 10 minutes and then heated to 45 oC for 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with DCM and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient 0–100% EtOAc in heptanes, to provide rac-tert-butyl (3R,5R)-3-(2-methoxy-2-oxoethyl)-5-(methoxymethoxy)piperidine-1-carboxylate (5.15 g, 16.2 mmol, 73% yield). m / z (ESI): 340.2 (M+Na)+.

[0274] Step 4. rac-tert-Butyl (3R,5S)-3-(2-hydroxyethyl)-5-(methoxymethoxy)piperidine-1- carboxylate. To a solution of rac-tert-butyl (3R,5R)-3-(2-methoxy-2-oxoethyl)-5- (methoxymethoxy)piperidine-1-carboxylate (5.15 g, 16.2 mmol) in methanol (3.5 mL) and tetrahydrofuran (50 mL) cooled to 0oC was added lithium borohydride (2.0 M in THF, 18 mL, 36 mmol) dropwise. The mixture was stirred and allowed to warm to room temperature for 2 h. A solution of 4-(tert-butoxy)-2,7-dichloropyrido[4,3-d]pyrimidine (1.47 g, 5.42 mmol) in tetrahydrofuran (2 mL) was added and then the mixture was stirred at room temperature for 20 h. The reaction mixture was quenched by addition of saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide rac-tert- butyl (3R,5S)-3-(2-hydroxyethyl)-5-(methoxymethoxy)piperidine-1-carboxylate (4.70 g, 16.2 mmol, 100% yield). m / z (ESI): 290.2 (M+H)+.

[0275] Intermediate R: (7R)-7-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-5-((1RS,2RS)-2- vinylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine.

[0276] Step 1. rac-4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-((1R,2R)-2- vinylcyclopropyl)-1H-indazole. To a 150-mL round-bottom flask was added methyltriphenylphosphonium bromide (3.35 g, 9.38 mmol) in THF (18 mL). The solution was cooled to 0 °C and potassium 2-methylpropan-2-olate (1 M in THF, 8.4 mL, 8.4 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min, then rac-(1R,2S)-2-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1-carbaldehyde (Step 1 in Intermediate B, 1.80 g, 4.69 mmol) in 3 mL THF was added. The reaction mixture was stirred at room temperaturefor 3 h, was then diluted with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with saturated NH4Cl and dried over MgSO4, filtered and concentrated. The crude material was purified by chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in hexane, to provide rac-4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-((1R,2R)-2-vinylcyclopropyl)-1H- indazole (1.60 g, 4.19 mmol, 89% yield). m / z (ESI): 402.8 / 404.8 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 8.00 (s, 1 H), 7.65 (s, 1 H), 5.64 (dt, J=9.2, 2.5 Hz, 1 H), 5.00 - 5.12 (m, 2 H), 4.78 - 4.86 (m, 1 H), 3.99 - 4.08 (m, 1 H), 3.71 - 3.81 (m, 1 H), 2.44 - 2.57 (m, 1 H), 2.38 (s, 1 H), 2.06 - 2.28 (m, 4 H), 1.60 - 1.82 (m, 4 H), 1.27 - 1.43 (m, 1 H).

[0277] Step 2. rac-6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-((1R,2R)-2-vinylcyclopropyl)-1H-indazole. To a round-bottom flask containing a solution of rac-4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-((1R,2R)-2- vinylcyclopropyl)-1H-indazole (1.6 g, 4.2 mmol) in THF (17 mL) cooled to -78 °C was added butyl lithium (2.5 M in hexanes, 2.2 mL, 5.5 mmol) dropwise. The reaction mixture was stirred at -78 °C for 5 min and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 mL, 6.3 mmol) was added. The reaction mixture was allowed to warm to room temperature with stirring for 1.5 h. The reaction mixture was diluted with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with saturated NaCl, dried over MgSO4, filtered and concentrated. The crude material was purified by chromatography on silica gel, eluting with a gradient of 0–60% 3:1 EtOAc / EtOH (with 1% TEA) in heptane, to provide rac-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-((1R,2R)-2-vinylcyclopropyl)-1H-indazole (1.4 g, 3.3 mmol, 78% yield). m / z (ESI): 429.0 (M+H)+.

[0278] Step 3. (7R)-7-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-5-((1RS,2RS)-2- vinylcyclopropyl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. A vial was charged with 7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (Intermediate C, 0.59 g, 1.33 mmol), potassium triphosphate (0.65 g, 3.1 mmol), cataCXium A Pd G3 (CAS 1651823-59-4) (75 mg, 0.10 mmol), rac- 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((1R,2R)-2- vinylcyclopropyl)-1H-indazole (0.44 g, 1.00 mmol), 2-methyltetrahydrofuran (4.5 mL) and water (0.45 mL) under nitrogen. The reaction mixture was heated to 80 °C for 3 h. After cooling to room temperature, the mixture was concentrated and the crude material was purified by chromatography on silica gel, eluting with a gradient of 0–60% 3:1 EtOAc / EtOH (with 1% TEA) in heptane, to provide (7R)-7-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-((1RS,2RS)-2-vinylcyclopropyl)-1H-indazol-4-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (Intermediate R, 0.50 g, 0.71 mmol, 69% yield). m / z (ESI): 704.8 (M+H)+.

[0279] Intermediate S: (R)-3-((Allyloxy)methyl)piperidine hydrochloride.

[0280] Step 1. tert-Butyl (R)-3-((allyloxy)methyl)piperidine-1-carboxylate. A 100-mL round- bottom flask was charged with (R)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (0.50 g, 2.30 mmol, Ambeed, Inc.) in THF (12 mL). The solution was cooled to 0oC and potassium tert-butoxide (1 M in THF, 3.3 mL, 3.3 mmol) was added. The reaction mixture was stirred for 10 min then allyl bromide (0.4 mL, 4.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, diluted with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with saturated NaCl and dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–60% 3:1 EtOAc / EtOH (with 1% TEA) in heptane, to provide tert-butyl (R)-3-((allyloxy)methyl)piperidine-1-carboxylate. m / z (ESI): 278.2 (M+Na)+.

[0281] Step 2. (R)-3-((Allyloxy)methyl)piperidine hydrochloride. tert-Butyl (R)-3- ((allyloxy)methyl)piperidine-1-carboxylate (crude, step 1) was dissolved in 10 mL of 1,4-dioxane. To the solution was added HCl (4 M in 1,4-dioxane, 5.8 mL, 23 mmol). The reaction mixture was stirred at room temperature for 2 h, was then fully concentrated to give (R)-3-((allyloxy)methyl)piperidine hydrochloride (0.41 g, 2.10 mmol, 92% yield). m / z (ESI): 156.2 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 5.81 – 6.06 (m, 1 H), 5.28 (dd, J=17.2, 1.7 Hz, 1 H), 5.18 (dd, J=10.5, 1.8 Hz, 1 H), 3.99 (dq, J=5.5, 1.3 Hz, 2 H), 3.34 – 3.50 (m, 1 H), 3.34 – 3.57 (m, 1 H), 3.34 – 3.49 (m, 4 H), 2.93 (d, J=3.3 Hz, 1 H), 2.72 – 2.83 (m, 1 H), 2.03 – 2.23 (m, 1 H), 1.92 – 2.02 (m, 1 H), 1.68 – 1.91 (m, 2 H), 1.23 – 1.53 (m, 1 H).

[0282] Intermediate T: (3S,5R)-5-((Allyloxy)methyl)piperidin-3-ol hydrochloride.

[0283] Step 1.1-(tert-Butyl) 3-methyl (3R,5S)-5-(methoxymethoxy)piperidine-1,3- dicarboxylate. A round-bottom flask was charged with 1-(tert-butyl) 3-methyl (3R,5S)-5-hydroxypiperidine-1,3-dicarboxylate (3.00 g, 11.6 mmol, PharmaBlock), N-ethyl-N-isopropylpropan- 2-amine (6.1 mL, 34.7 mmol) and dichloromethane (40 mL). Bromo(methoxy)methane (1.9 mL, 23 mmol) was added slowly, and the reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 5 h. The reaction was carefully quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with DCM and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with 0–100% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane, to provide 1-(tert-butyl) 3-methyl (3R,5S)-5-(methoxymethoxy)piperidine- 1,3-dicarboxylate (2.67 g, 8.80 mmol, 76% yield). m / z (ESI): 326.2 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 4.69 (s, 2 H) 3.99 - 4.44 (m, 2 H) 3.71 (s, 3 H) 3.46 - 3.62 (m, 1 H) 3.38 (s, 3 H) 2.67 - 2.84 (m, 1 H) 2.35 - 2.61 (m, 3 H) 1.51 - 1.64 (m, 1 H) 1.46 - 1.48 (m, 9 H).

[0284] Step 2. tert-Butyl (3R,5S)-3-(hydroxymethyl)-5-(methoxymethoxy)piperidine-1- carboxylate. A vial was charged with 1-(tert-butyl) 3-methyl (3R,5S)-5- (methoxymethoxy)piperidine-1,3-dicarboxylate (1.5 g, 4.9 mmol) and tetrahydrofuran (15 mL), then cooled to 0 °C. Lithium borohydride (2.0 M in THF, 5.4 mL, 10.8 mmol) was added dropwise and then the reaction mixture was allowed to slowly warm to room temperature with stirring for 30 minutes. The reaction mixture was carefully quenched with half-saturated aqueous ammonium chloride and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated aqueous bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide tert-butyl (3R,5S)-3-(hydroxymethyl)-5- (methoxymethoxy)piperidine-1-carboxylate (1.2 g, 4.4 mmol, 88% yield). m / z (ESI): 298.2 (M+Na)+.1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 - 4.66 (m, 3 H) 4.04 - 4.17 (m, 1 H) 3.91 - 4.01 (m, 1 H) 3.37 - 3.46 (m, 1 H) 3.21 - 3.34 (m, 6 H) 2.28 - 2.46 (m, 2 H) 1.99 (s, 1 H) 1.54 (br s, 1 H) 1.40 (s, 9 H).

[0285] Step 3. tert-Butyl (3R,5S)-3-((allyloxy)methyl)-5-(methoxymethoxy)piperidine-1- carboxylate. To a stirred mixture of tert-butyl (3R,5S)-3-(hydroxymethyl)-5- (methoxymethoxy)piperidine-1-carboxylate (1.7 g, 6.2 mmol) and allyl bromide (1.6 mL, 19 mmol) in tetrahydrofuran (25 mL) at 0 °C was added potassium tert-butoxide (1.0 M in THF, 12.5 mL, 12.5 mmol). The reaction mixture was stirred at 0 °C to room temperature for 2 h, was then diluted with saturated aqueous ammonium chloride solution 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 0–60% of EtOAc in heptane, to provide tert-butyl (3R,5S)-3-((allyloxy)methyl)-5-(methoxymethoxy)piperidine- 1-carboxylate (1.4 g, 4.4 mmol, 72% yield). m / z (ESI): 338.2 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 5.83 - 6.06 (m, 1 H), 5.20 (s, 2 H), 4.70 (s, 2 H), 4.05 - 4.35 (m, 2 H), 3.97 (br d, J=5.2 Hz, 2H), 3.53 - 3.65 (m, 1 H), 3.29 - 3.45 (m, 5 H), 2.36 - 2.70 (m, 2 H), 2.08 - 2.23 (m, 1 H), 1.69 - 1.97 (m, 1 H), 1.48 (s, 9 H), 1.10 - 1.28 (m, 1 H).

[0286] Step 4. (3S,5R)-5-((Allyloxy)methyl)piperidin-3-ol hydrochloride. To a stirred mixture of tert-butyl (3R,5S)-3-((allyloxy)methyl)-5-(methoxymethoxy)piperidine-1-carboxylate (1.4 g, 4.4 mmol,) in 1,4-dioxane (9 mL) at 0 °C was added hydrogen chloride (4.0 M in 1,4-dioxane, 22 mL, 88 mmol). The reaction mixture was stirred at room temperature for 2 h, was then fully concentrated. The residue was diluted with 1:1 EtOAc / heptane solution and the solid formed was collected by filtration to give (3S,5R)-5-((allyloxy)methyl)piperidin-3-ol hydrochloride (0.9 g, 4.3 mmol, 98% yield). m / z (ESI): 172.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.39 (br s, 2H), 5.98 – 5.76 (m, 1H), 5.40 – 5.08 (m, 2H), 4.01 – 3.54 (m, 3H), 3.43 – 3.06 (m, 4H), 2.47 – 2.36 (m, 2H), 2.22 – 2.02 (m, 1H), 2.00 – 1.82 (m, 1H), 1.13 (d, J = 11.7 Hz, 1H).

[0287] Intermediate U: (S,Z)-4-(tert-Butoxy)-7-chloro-8-fluoro-2-((2- (fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine.

[0288] To a solution of (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl) methanol hydrochloride (27.9 g, 134 mmol) in tetrahydrofuran (600 mL) was added NaHMDS (1 M in THF, 310 mL, 310 mmol) dropwise at 0 °C over 30 minutes under N2. The resulting mixture was stirred at 0 °C for 0.5 h. The solution of 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (Step 1 in Intermediate A, 30 g, 103 mmol) in tetrahydrofuran (600 mL) was added dropwise at -40 °C over 30 minutes. The reaction mixture was stirred at -40 °C for 0.5 h, was then poured into aqueous saturated NH4Cl in portions, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was triturated with DMSO (100 mL) at 20 ℃ for 20 minutes. The suspension was filtered, and the filter cake concentrated under reduced pressure to give (S,Z)-4-(tert-butoxy)-7-chloro-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (21 g, 49 mmol, 48% yield). m / z (ESI): 425.1 / 427.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 8.86 (s, 1H), 6.39-6.61 (m, 1H), 4.23-4.32 (m, 2H), 3.88 (d, 1H, J=15.2 Hz), 3.45 (d, 1H, J=15.1 Hz), 3.22-3.25 (m, 1H), 2.65-2.72 (m, 2H), 2.37 (d, 1H, J=15.4 Hz), 2.12-2.15 (m, 1H), 1.92-1.96 (m, 2H), 1.77-1.80 (m, 1H), 1.76 (s, 9H).19F NMR (400 MHz, CDCl3) δ ppm -135.25 (s, 1 F).

[0289] Intermediate V: 3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)propan-1-amine.

[0290] Step 1.3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propyl methanesulfonate. To a solution of 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)propan-1-ol (Intermediate I, 8.00 g, 21.41 mmol) in dichloromethane (80 mL) was added TEA (9.0 mL, 64 mmol) and Ms2O (5.59 g, 32.10 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h, was then diluted with H2O and extracted with ethyl acetate. 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 0–15% EtOAc in petroleum ether, to provide 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)propyl methanesulfonate (9.0 g, 20 mmol, 93% yield). m / z (ESI): 475.0 (M+Na)+.

[0291] Step 2.5-(3-Azidopropyl)-4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole. To a solution of 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propyl methanesulfonate (9.0 g, 20 mmol) in N,N-dimethylformamide (90 mL) was added NaN3(1.51 g, 23.2 mmol) in portions then the mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water and adjusted to pH 9 with 1 N NaOH solution, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product containing 5-(3-azidopropyl)-4-bromo-6-chloro- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8 g, 20 mmol) was used in the next step without further purification.

[0292] Step 3: 3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1- amine. To a solution containing 5-(3-azidopropyl)-4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole (8.0 g, 20 mmol) in tetrahydrofuran (80 mL) was added H2O (2.2 mL, 120 mmol) and PPh3(10.5 g, 40.1 mmol). The reaction mixture was stirred at 60 °C for 2 h, was then diluted with water and extracted with ethyl acetate. 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 0–100% EtOAc in petroleum ether, to provide 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1-amine (Intermediate V, 6.8 g, 18.2 mmol, 91% yield). m / z (ESI): 374.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.96 (s, 1 H), 7.64 (s, 1 H), 5.60 - 5.67 (m, 1 H), 3.94 - 4.06 (m, 1 H), 3.67 - 3.82 (m, 1 H), 3.09 (t, J=8.0 Hz, 2 H), 2.85 (t, J=7.2 Hz, 2 H), 2.38 - 2.57 (m, 1 H), 2.11 - 2.19 (m, 1 H), 2.05 - 2.11 (m, 1 H), 1.74 - 1.82 (m, 7 H).

[0293] Intermediate W: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidine.

[0294] Step 1. ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methan-d2-ol. To a solution of methyl (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (9.00 g, 48.1 mmol) in tetrahydrofuran (200 mL) was added LiAlD4(2.0 M in THF, 3.74 g, 89 mmol) slowly. Then the mixture was stirred at 0 °C for 1 h under N2atmosphere. Then sodium sulfate decahydrate (45 g) was added to quench the reaction and ethyl acetate was added. The reaction mixture was stirred at room temperature for 1 h, filtered and the filtrate was concentrated under reduced pressure. The residue was combined two other 9 g batches and purified by column chromatography on silica gel, eluting with a gradient of 50–100% EtOAc in petroleum ether to provide ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methan-d2-ol (22.0 g, 136 mmol, 88% yield).1H NMR (400 MHz, CDCl3) δ ppm 5.13 (d, J=3.2 Hz, 1 H), 2.99 - 3.26 (m, 4 H), 2.87 - 2.96 (m, 1 H), 2.00 - 2.16 (m, 2 H), 1.74 - 1.98 (m, 4 H).

[0295] Step 2.4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidine. To a solution of ((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methan-d2-ol (2.89 g, 17.9 mmol) in 1,4-dioxane (40 mL) was added 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (Step 1 in Intermediate A, 4.00 g, 13.8 mmol), DIPEA (7.2 mL, 41 mmol) and 4Å MS (4 g). The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE at 25 ℃ for 30 minutes to give 4-(tert- butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy- d2)pyrido[4,3-d]pyrimidine (3.0 g, 7.2 mmol, 52% yield). m / z (ESI): 415.1 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 8.86 (s, 1 H), 5.23 - 5.40 (m, 1 H), 3.28 - 3.38 (m, 1 H), 3.14 - 3.28 m, 2 H), 2.98 - 3.06 (m, 1 H), 2.29 (s, 1 H), 2.11 - 2.24 (m, 2 H), 1.90 - 2.02 (m, 3 H), 1.75 (s, 9 H).

[0296] Intermediates X & Y: (R)-7-Chloro-2-((1-((dimethylamino)methyl)-2,2- difluorocyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-ol & (S)-7-chloro-2-((1- ((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4- ol.

[0297] Step 1.2-Methylenepropane-1,3-diyl diacetate. To a solution of 3-chloro-2- (chloromethyl)prop-1-ene (60.0 g, 480 mmol) in triethylamine (146 g, 1.44 mol) was added acetic acid (72.1 g, 1.20 mol) dropwise. The resulting mixture was heated and stirred at 70 °C for 12 h under N2. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–100% EtOAc in petroleum ether, to provide 2-methylenepropane-1,3-diyl diacetate (56.4 g, 328 mmol, 67% yield).1H NMR (400 MHz, CDCl3) δ ppm 5.21 (s, 2 H), 4.54 (s, 4 H), 2.02 (s, 6 H).

[0298] Step 2. (2,2-Difluorocyclopropane-1,1-diyl)bis(methylene) diacetate. To a solution of 2- methylenepropane-1,3-diyl diacetate (80.0 g, 465 mmol) in diglyme (640 mL) was added the solution of ClCF2CO2Na (353 g, 2.32 mol) in diglyme (640 mL) dropwise at 180 °C under nitrogen over 5 h. The resulting mixture was stirred at 180 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted with petroleum ether. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude containing (2,2- difluorocyclopropane-1,1-diyl)bis(methylene) diacetate (80 g) which was used directly without further purification.

[0299] Step 3. (2,2-Difluorocyclopropane-1,1-diyl)dimethanol. To a solution of (2,2- difluorocyclopropane-1,1-diyl)bis(methylene) diacetate (100 g, 450 mmol) in methanol (1.25 L) was added potassium carbonate (124 g, 900 mmol). The resulting mixture was stirred at room temperaturefor 12 h under N2, was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–100% EtOAc in petroleum ether, to provide (2,2-difluorocyclopropane-1,1-diyl)dimethanol (43.0 g, 312 mmol, 69% yield).

[0300] Step 4. (1-((Benzyloxy)methyl)-2,2-difluorocyclopropyl)methanol. To a solution of (2,2- difluorocyclopropane-1,1-diyl)dimethanol (64.0 g, 463 mmol) in N,N-dimethylformamide (1.18 L) was added sodium hydride (60 wt% in mineral oil, 22.2 g, 927 mmol) in portions under N2at 0 °C. The mixture was stirred at 0 °C for 1 h. Then the solution of (bromomethyl)benzene (95.0 g, 556 mmol) in N,N-dimethylformamide (100 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h under N2, was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–100% EtOAc in petroleum ether, to provide (1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methanol (47.75 g, 209 mmol, 45% yield).

[0301] Step 5. (1-((Benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate. To a 3-L three-neck bottle was added the solution of (1-((benzyloxy)methyl)-2,2- difluorocyclopropyl)methanol (58.0 g, 254 mmol) in dichloromethane (1.20 L), TEA (142 mL, 1.02 mol) was added slowly at 0 °C, then methanesulfonyl chloride (57.7 g, 504 mmol) was added dropwise at 0 °C under N2. The resulting mixture was stirred at room temperature for 3 h, was then diluted with ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–100% EtOAc in petroleum ether, to provide (1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (70.0 g, 228 mmol, 90% yield).

[0302] Step 6.1-(1-((Benzyloxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylmethanamine. To a solution of (1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methyl methanesulfonate (40.0 g, 131 mmol) in tetrahydrofuran (400 mL) was added Me2NH in THF (326 mL, 653 mmol) and K2CO3(36.1 g, 261 mmol) in sequence. The resulting mixture was stirred at 50 °C for 24 h under N2, was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–100% EtOAc in petroleum ether, to provide 1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylmethanamine (24 g, 94 mmol, 72% yield).

[0303] Step 7. (1-((Dimethylamino)methyl)-2,2-difluorocyclopropyl)methanol. To a solution of 10% Pd / C (8 g) and 20% Pd(OH)2(8 g) in 2,2,2-trifluoroethan-1-ol (1.0 L) was added 1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylmethanamine (50 g, 196 mmol) under an Ar atmosphere. The suspension was degassed and purged with H2for 3 times. The reaction mixture was stirred under H2(15 psi) at room temperature for 12 h, was then filtered through a pad of celite and washed with methanol. To the combined filtrate was treated with HCl (3 M in MeOH, 100 mL, 300 mmol), then was concentrated under reduced pressure to give (1-((dimethylamino)methyl)-2,2- difluorocyclopropyl)methanol as its HCl salt (20.49 g, 102 mmol, 52% yield).

[0304] Step 8.1-(1-(((7-Chloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylmethanamine. To a solution of 2,7- dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (Step 1 in Intermediate C, 20.0 g, 63.3 mmol) in 1,4-dioxane (400 mL) was added (1-((dimethylamino)methyl)-2,2- difluorocyclopropyl) methanol hydrochloride (15.31 g, 76 mmol) and DIPEA (27.6 mL, 158 mmol) in sequence under N2at 0 °C. The reaction mixture was stirred at 25 °C for 3 h, was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 1-(1-(((7-chloro-8-fluoro-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)-N,N- dimethylmethanamine (12.3 g, 27 mmol, 44% yield).

[0305] Step 9.7-Chloro-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-4-ol. To a solution of 1-(1-(((7-chloro-8-fluoro-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-2,2-difluorocyclopropyl)-N,N- dimethylmethanamine (32.3 g, 72.6 mmol) in tetrahydrofuran (640 mL) and water (128 mL) was added LiOH.H2O (12.2 g, 290 mmol). The reaction mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the mixture was combined with another batch (10 g) and diluted with H2O and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–100% EtOAc in petroleum ether, to provide 7-chloro-2-((1-((dimethylamino)methyl)- 2,2-difluorocyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-ol (25.5 g, 70 mmol, 74% yield).

[0306] Step 10. (R)-7-Chloro-2-((1-((dimethylamino)methyl)-2,2- difluorocyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4-ol & (S)-7-chloro-2-((1- ((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-4- ol. 7-Chloro-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8-fluoropyrido[4,3- d]pyrimidin-4-ol (33 g, 91 mmol) was separated by SFC (Column: Chiralpak IG 250 x 50 mm x 10 um, Mobile phase: A for CO2and B for EtOH (0.1%NH3.H2O), Gradient: B%=60% isocratic, Flow rate: 200 g / min) to give two compounds (the structures were temporary assigned) as follows:

[0307] Peak 1: (R)-7-chloro-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-4-ol (13.8 g, 38.1 mmol, 42% yield). m / z (ESI): 363.1 / 365.0 (M+H)+.

[0308] 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.72 (s, 1 H), 4.48 - 4.59 (m, 2 H), 2.98 (d, J = 13.6 Hz, 1 H), 2.77 (d, J = 12.8 Hz, 1 H), 2.52 (s, 6 H), 1.76 – 1.79 (m, 1 H), 1.51 – 1.54 (m, 1 H).19F NMR (376 MHz, METHANOL-d4) δ ppm -136.99 – -137.42 (m, 1 F), -138.84 -139.55 (m, 2 F). SFC: ee % = 99.9%

[0309] Peak 2: (S)-7-chloro-2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-8- fluoropyrido[4,3-d]pyrimidin-4-ol (16.7 g, 47.7 mmol, 52% yield). m / z (ESI): 363.1 / 365.0 (M+H)+.

[0310] 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.74 (s, 1 H), 4.50 (s, 2 H), 2.86 (d, J = 16.4 Hz, 1 H), 2.40 (d, J = 14.4 Hz, 1 H), 2.26(s, 6 H), 1.64 – 1.65 (m, 1 H), 1.32 – 1.33 (m, 1 H).19F NMR (400 MHz, METHANOL-d4) δ ppm-137.31 – -137.73 (m, 1 F), -138.94 -139.70 (m, 2 F). SFC: ee% = 99.7%. Intermediate Z: rac-(3R,5R)-5-((Allyloxy)methyl)piperidin-3-ol hydrochloride.The title compound was prepared in an analogous fashion to Intermediate T using 1-tert-butyl 3- methyl (3S,5S)-rel-5-hydroxypiperidine-1,3-dicarboxylate (Pharmablock) in Step 1. m / z (ESI): 172.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δppm 6.05 – 5.73 (m, 1H), 5.37 – 5.08 (m, 2H), 4.26 – 4.12 (m, 1H), 4.05 – 3.93 (m, 2H), 3.68 (s, 2H), 3.50 – 3.34 (m, 3H), 3.27 – 3.18 (m, 1H), 3.10 – 2.98 (m, 1H), 2.88 – 2.71 (m, 1H), 2.61 – 2.40 (m, 1H), 1.96 – 1.79 (m, 1H), 1.58 (s, 1H). Intermediate AA: 4-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)butyl methanesulfonate.Step 1.4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)butan-1-ol. A vial was charged with tris(4- methoxyphenyl)phosphine (1.45 g, 4.13 mmol, Ambeed, Inc.), palladium acetate (0.46 g, 2.06 mmol, Combi-Blocks Inc.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.93 g, 15.5 mmol, Ambeed, Inc.), cesium carbonate (6.72 g, 20.6 mmol), 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butan-1-ol (4.00 g, 10.3 mmol) and ethyl acetate (10 mL), then sparged with nitrogen and heated to 80 °C for 12 h. The reaction mixture was cooled to room temperature then the crude material was filtered through a plug of celite and concentrated. The crude material was purified by chromatography on silica gel, eluting with a gradient of 0–20% 3:1 EtOAc / EtOH (with 2% TEA) in heptane, to provide 4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)butan-1-ol (3.05 g, 7.03 mmol, 68% yield). m / z (ESI): 435.1 (M+H)+.

[0311] Step 2.4-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)butyl methanesulfonate. A vial was charged with 4-(6-chloro- 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)butan- 1-ol (3.20 g, 7.36 mmol), triethylamine (1.24 mL, 8.83 mmol) and dichloromethane (36 mL), then cooled to 0 °C. Methanesulfonyl chloride (0.63 mL, 8.10 mmol) was added dropwise and upon completion, the mixture was allowed to warm to room temperature with stirring. The crude mixture was and purified by column chromatography on silica gel, eluting with a gradient of 0–50% (3:1 EtOAc / EtOH with 2% TEA) / heptane, to provide 4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)butyl methanesulfonate (3.25 g, 6.34 mmol, 86% yield). m / z (ESI): 513.0 (M+H)+. Intermediate BB: rac-2-((1R,2R)-2-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)ethan-1-ol.

[0312] Step 1. rac-((1R,2S)-2-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)methanol. To a solution of 4-bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole (25.0 g, 58.8 mmol) in 1,4-dioxane (100 mL) and water (25 mL) was added potassium trifluoro-rac-((1S,2R)-2-(hydroxymethyl)cyclopropyl)borate (20.9 g, 118 mmol, Lab Network), K3PO4(49.9 g, 235 mmol) and Pd(dppf)Cl2(10.76 g, 14.70 mmol) in sequence under nitrogen. Thereaction mixture was stirred at 100 °C for 12 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 over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a gradient of 20–35% EtOAc in petroleum ether, to give rac-((1R,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)methanol (9.0 g, 24.3 mmol, 41% yield).

[0313] Step 2. rac-(1R,2S)-2-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropane-1-carbaldehyde. To a stirred mixture of rac-((1R,2S)-2-(4-bromo-6-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)methanol (2.24 g, 6.06 mmol) and iodobenzene diacetate (2.34 g, 7.26 mmol) in dichloromethane (25 mL) was added TEMPO (95 mg, 0.61 mmol) and the resulting mixture was stirred at room temperature for 18 h. The reaction was then concentrated under reduced pressure and the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–40% EtOAc in heptane, to provide rac-(1R,2S)-2-(4-bromo- 6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane-1-carbaldehyde (2.23 g, 6.09 mmol, 100% yield). m / z (ESI): 367.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.04 - 9.13 (m, 1 H), 7.99 (s, 1 H), 7.28 (s, 1 H), 5.64 (dt, J=8.9, 2.8 Hz, 1 H), 3.94 - 4.09 (m, 1 H), 3.67 - 3.80 (m, 1 H), 2.41 - 2.56 (m, 3 H), 2.04 - 2.20 (m, 2 H), 1.65 - 1.97 (m, 5 H).

[0314] Step 3. rac-4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((1R,2R)-2- vinylcyclopropyl)-1H-indazole. To a stirred mixture of methyltriphenylphosphonium bromide (2.44 g, 6.84 mmol) in tetrahydrofuran (30 mL) at -78 °C under nitrogen, was added lithium bis(trimethylsilyl)amide solution (1.0 M in THF, 6.0 mL, 6.0 mmol). The resulting mixture was stirred at -78 °C for 15 minutes and then was allowed to warm to 0 °C for 30 min. The solution was cooled back to -78 °C and rac-(1R,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropane-1-carbaldehyde (2.01 g, 5.47 mmol) was added as a solution in tetrahydrofuran (6 mL). The reaction mixture was stirred at 0 °C for 0.5 h, was then diluted with sat. aq. sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–30% EtOAc in heptane, to provide rac-4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((1R,2R)-2-vinylcyclopropyl)-1H- indazole (1.81 g, 4.95 mmol, 90% yield). m / z (ESI): 365.0 (M+H)+.

[0315] Step 4. rac-2-((1R,2R)-2-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethan-1-ol. To a stirred mixture of rac-4-bromo-6-fluoro-1-(tetrahydro-2H-pyran- 2-yl)-5-((1R,2R)-2-vinylcyclopropyl)-1H-indazole (1.80 g, 4.93 mmol) in tetrahydrofuran (16 mL) at 0 °C under nitrogen, was added 9-borabicyclo[3.3.1]nonane solution (0.5 M in THF, 20 mL, 10 mmol). The resulting mixture was allowed to warm to room temperature with stirring for 1 h. The reaction was cooled again to 0 °C and sodium hydroxide solution (10 M, 3.2 mL, 32 mmol) andhydrogen peroxide solution (30% w / w, 3.6 mL, 32 mmol) was added dropwise. The solution was allowed to warm to room temperature with stirring for 10 minutes. The reaction mixture was diluted with 10 wt% aq. sodium thiosulfate solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–50% EtOAc in heptane, to provide rac-2-((1R,2R)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)ethan-1-ol (1.85 g, 4.83 mmol, 98% yield). m / z (ESI): 383.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 8.00 (s, 1 H), 7.24 (d, J=10.5 Hz, 1 H), 5.59 - 5.67 (m, 1 H), 4.02 (br d, J=11.3 Hz, 1 H), 3.60 - 3.81 (m, 3 H), 2.43 - 2.58 (m, 1 H), 2.06 - 2.23 (m, 2 H), 1.89 - 2.04 (m, 2 H), 1.65 - 1.86 (m, 3 H), 1.41 (br dd, J=4.2, 1.9 Hz, 1 H), 1.25 - 1.36 (m, 2 H), 0.97 (qd, J=5.7, 1.9 Hz, 1 H), 0.64 - 0.78 (m, 1 H). Intermediate CC: tert-Butyl (3R)-3-(((2-((1S,2S)-2-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate

[0316] Step 1: 2-((1S,2S)-2-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate. To a solution of Intermediate BB (2.0 g, 5.2 mmol) and TEA (3.6 mL, 26.1 mmol) in THF (20 mL) was added 4-nitrophenyl chloroformate (1.4 g, 6.8 mmol) at 0 °C. The mixture was sparged with nitrogen then stirred at 20 °C for 3 h. The reaction mixture was concentrated to provide 2-((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate (2.6 g, crude), which was used without further purification.

[0317] Step 2: tert-Butyl (3R)-3-(((2-((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-3-methylpiperidine-1-carboxylate. To a solution of 2-((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate (2.6 g, 4.7 mmol) and TEA (3.3 mL, 23.7 mmol) in THF (20 mL) was added tert-butyl (R)-3-amino-3-methylpiperidine-1-carboxylate (1.3 g, 6.2 mmol) at 20 °C. The mixture was sparged with nitrogen then stirred at 80 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography, eluting with a 15:1 to 6:1 gradient of pet. ether inEtOAc, to give tert-butyl (3R)-3-(((2-((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-3-methylpiperidine-1-carboxylate (2.0 g, 3.2 mmol, 68% yield).

[0318] Step 3: tert-Butyl (3R)-3-(((2-((1S,2S)-2-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-3-methylpiperidine-1-carboxylate, Intermediate CC.

[0319] A mixture of B2Pin2(3.05 g, 12 mmol), Cs2CO3(2.35 g, 7.2 mmol), tert-butyl (3R)-3-(((2- ((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (1.50 g, 2.4 mmol), and Pd(dppf)Cl2(0.35 g, 0.48 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was sparged with nitrogen then stirred at 100 °C for 1 h. The reaction mixture was filtered, diluted with H2O (60 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography, eluting with a gradient of 10:1 to 3:1 pet. ether in EtOAc, to provide Intermediate CC (1.71 g, 2.10 mmol, 89% yield). m / z (ESI): 671.5 [M+H]+.

[0320] Intermediates in Table 24 were prepared following the procedure described above for Intermediate CC, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 24: Additional Intermediates Prepared in an Analogous Manner to Intermediate CCTable 25: Additional Intermediates Prepared in an Analogous Manner to Intermediate CC.Intermediate DD: tert-Butyl (3R)-3-(((2-((1S,2S)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate.

[0321] Step 1.2-((1S,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethan-1-ol.

[0322] A mixture of 4-bromo-6-chloro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10.0 g, 22.6 mmol, Lab Network), potassium trifluoro((1S,2S)-2-(2-hydroxyethyl)cyclopropyl)borate (6.5 g, 34 mmol), K3PO4(16.8 g, 79 mmol) and Pd(dppf)Cl2(3.3 g, 4.5 mmol) in 1,4-dioxane (200 mL) and H2O (40 mL) was sparged with nitrogen then stirred at 110 °C for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography, eluting with a gradient of 1:0 to 3:1 pet. ether in EtOAc to provide 2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethan-1-ol (2.8 g, 7.0 mmol, 31% yield). m / z (ESI): 317.0 (M+H)+.

[0323] Step 2.2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate.

[0324] To a solution of 2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethan-1-ol (2.8 g, 7.0 mmol) in THF (28 mL) was added TEA (4.9 mL, 35 mmol) and 4-nitrophenyl chloroformate (2.3 g, 11.2 mmol) in sequence at 0 °C. Then the mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to provide 2-((1S,2S)- 2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate (4 g, crude) which was used in subsequent steps without further purification. m / z (ESI): 566.0 (M+H)+.

[0325] Step 3. tert-Butyl (3R)-3-(((2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate.

[0326] To a solution of 2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate (4.0 g, 7.1 mmol) in THF (20 mL) was added tert- butyl (R)-3-amino-3-methylpiperidine-1-carboxylate (1.9 g, 9.2 mmol). The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with H2O (80 mL), extracted with EtOAc (3 x 20 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography, eluting with a gradient of 50:1 to 0:1 of pet. ether in EtOAc, to provide tert- butyl (3R)-3-(((2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (2.4 g, 3.8 mmol, 54% yield). m / z (ESI): 541.2 [M-Boc+H]+.

[0327] Step 4. tert-Butyl (3R)-3-(((2-((1S,2S)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-3-methylpiperidine-1-carboxylate, Intermediate DD.

[0328] To a solution of tert-butyl (3R)-3-(((2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (2.4 g, 3.8 mmol) in 1,4-dioxane (49 mL) and water (4.9 mL) was added B2Pin2(4.9 g, 19.1 mmol), Cs2CO3(3.7 g, 11.5 mmol) and Pd(dppf)Cl2(0.3 g, 0.4 mmol), then the mixture was stirred at 100 °C for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 10 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography, eluting with a gradient of 50:1 to 2:1 of pet. ether in EtOAc, to provide Intermediate DD (2.24 g, 3.26 mmol, 85% yield). m / z (ESI): 587.4 [M-Boc+H]+. Intermediate EE: tert-Butyl (3R,5R)-3-(((2-((1S,2S)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-5-fluoropiperidine-1-carboxylate

[0329] Step 1: 2-((1S,2S)-2-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate. To a solution of 2-((1S,2S)-2-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (4.5 g, 11.3 mmol) and TEA (7.8 mL, 56.3 mmol) in THF (45 mL) was added 4-nitrophenyl chloroformate (3.6 g, 18 mmol) at 0 °C. The mixture was sparged with nitrogen then stirred at 20 °C for 3 h. The reaction mixture was concentrated to provide 2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate (5.8 g, 10.3 mmol, 91% yield) which was used without further purification.

[0330] Step 2: tert-Butyl (3R,5R)-3-(((2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-5-fluoropiperidine-1- carboxylate. To a solution of 2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate (5.8 g, 10.3 mmol) in THF (58 mL) was added tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (3.4 g, 15.4 mmol). The mixture was sparged with nitrogen and stirred at 80 °C for 6 h. The reaction mixture was concentrated, and the residue was diluted with H2O (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography, eluting with a gradient of 10:1 to 1:1 of pet. ether in EtOAc, to provide tert-butyl (3R,5R)-3-(((2-((1S,2S)-2-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-5- fluoropiperidine-1-carboxylate (5.42 g, 6.21 mmol, 82% yield). m / z (ESI): 645.2 [M+H]+.

[0331] Step 3: tert-Butyl (3R,5R)-3-(((2-((1S,2S)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-5-fluoropiperidine-1-carboxylate.

[0332] A mixture of B2Pin2(5.4 g, 21.3 mmol), cesium carbonate (4.2 g, 12.8 mmol), tert-butyl (3R,5R)-3-(((2-((1S,2S)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-5-fluoropiperidine-1-carboxylate (2.0 g, 4.3 mmol) and Pd(dppf)Cl2(0.2 g, 0.4 mmol) in 1,4-dioxane (27 mL) and water (2.7 mL) was sparged with nitrogen then stirred at 100 °C for 1 h. The reaction mixture was filtered and concentrated. The residue was diluted with H2O (200 mL) then extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated. The residue waspurified by column chromatography, eluting with a gradient of 10:1 to 3:1 of pet. ether in EtOAc, to provide Intermediate EE (4.0 g, 69% yield). Intermediate FF: tert-Butyl 3-((((4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3- methylpiperidine-1-carboxylate.

[0333] Step 1: (Z)-4-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3- en-1-yl (4-nitrophenyl) carbonate. To a solution of Intermediate D (0.38 g, 1.0 mmol) in THF (3.8 mL) was added TEA (0.72 mL, 5.2 mmol) and 4-nitrophenyl chloroformate (0.36 g, 1.8 mmol) at 0 °C, the mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated to provide (Z)-4- (4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-yl (4-nitrophenyl) carbonate (2.18 g, crude), which was used without further purification.

[0334] Step 2: tert-Butyl (Z)-3-((((4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate. To a solution of (Z)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-yl (4- nitrophenyl) carbonate (0.55 g, 1.0 mmol) in THF (5.5 mL) was added tert-butyl 3-amino-3- methylpiperidine-1-carboxylate (0.28 g, 1.3 mmol). The mixture was sparged with nitrogen, and stirred at 80 °C for 12 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by reversed phase medium pressure LC, eluting with a gradient of 60-90% ACN in H2O, to obtain tert-butyl (Z)-3-((((4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (2.0 g, 3.1 mmol, 79% yield). m / z (ESI): 647.2 [M+Na]+.

[0335] Step 3: tert-Butyl 3-((((4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3- methylpiperidine-1-carboxylate, Intermediate FF. To a solution of tert-butyl (Z)-3-((((4-(4-bromo- 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3- methylpiperidine-1-carboxylate (0.4 g, 0.6 mmol) in 1,4-dioxane (7.3 mL) and H2O (0.7 mL) wasadded B2Pin2(0.7 g, 3 mmol), Cs2CO3(0.6 g, 1.7 mmol) and Pd(dppf)Cl2(0.04 g, 0.06 mmol). The mixture was sparged with nitrogen and stirred at 100 °C for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 20 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by reversed phase medium pressure LC, eluting with a gradient of 55-85% ACN in H2O, to obtain Intermediate FF (1.53 g, 2.30 mmol, 73% yield). m / z (ESI): 673.4 [M+H]+. Intermediate GG: tert-Butyl (R)-3-(((2-((1RS,2RS)-2-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpyrrolidine-1- carboxylate

[0336] Step 1: rac-2-((1R,2R)-2-(2-Bromo-6-chlorophenyl)cyclopropyl)ethan-1-ol. A mixture of 1-bromo-3-chloro-2-iodobenzene (1.0 g, 3.2 mmol), potassium trifluoro((1S,2S)-2-(2- hydroxyethyl)cyclopropyl)borate (1.21 g, 6.30 mmol), K3PO4(2.0 g, 9.5 mmol) and Pd(dppf)Cl2- CH2Cl2(0.5 g, 0.6 mmol) in DMF (10 mL) and water (2 mL) was sparged with nitrogen and stirred at 80 °C for 5 h. The reaction mixture was quenched with water (250 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluting with a gradient of 100:0 to 90:10 pet. ether in EtOAc, to obtain rac-2-((1R,2R)-2-(2-bromo-6- chlorophenyl)cyclopropyl)ethan-1-ol (1.5 g, 5.4 mmol, 34% yield).

[0337] Step 2: tert-Butyl (R)-3-(((2-((1RS,2RS)-2-(2-bromo-6- chlorophenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate. To a solution of rac-2-((1R,2R)-2-(2-bromo-6-chlorophenyl)cyclopropyl)ethan-1-ol (1.6 g, 5.8 mmol) and TEA (4 mL, 29 mmol) in THF (16 mL) was added 4-nitrophenyl chloroformate (1.9 g, 9.3 mmol) at 0 °C under N2and the mixture stirred at 20 °C for 2 h. To the mixture was added tert-butyl (R)-3- amino-3-methylpyrrolidine-1-carboxylate (1.5 g, 7.6 mmol), the mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched with water (40 mL) then extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, andconcentrated. The residue was purified by prep-TLC, eluting with a 2:1 mixture of pet. ether in EtOAc, to provide tert-butyl (R)-3-(((2-((1RS,2RS)-2-(2-bromo-6- chlorophenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (0.5 g, 1.0 mmol, 17% yield). m / z (ESI): 447.2 [M-t-Bu+H]+.

[0338] Step 3: tert-Butyl (R)-3-(((2-((1RS,2RS)-2-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpyrrolidine-1- carboxylate, Intermediate GG. To a mixture of tert-butyl (R)-3-(((2-((1RS,2RS)-2-(2-bromo-6- chlorophenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (0.5 g, 1 mmol), B2Pin2(0.6 g, 2.5 mmol), Cs2CO3(0.9 g, 3 mmol) in 1,4-dioxane (10 mL) and water (0.1 mL) was added Pd(dppf)Cl2(0.07 g, 0.1 mmol). The reaction mixture was sparged with nitrogen and stirred at 100 °C for 1 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-20% EtOAc in pet. ether, to provide Intermediate GG (0.5 g, 0.8 mmol, 78% yield). m / z (ESI): 449.1 [M-Boc+H]+. Intermediates HH, HH-1 and HH-2: (6RS,8aRS)-6-(((4-(tert-butoxy)-7-chloro-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, (Intermediate HH), (6RS,8aRS)-6-(((4-(tert-butoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (Intermediate HH-1) and (6S,8aS)-6- (((4-(tert-butoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- pyrrolo[2,1-c][1,4]oxazine (Intermediate HH-2)

[0339] Step 1: (6RS,8aRS)-6-(((4-(tert-Butoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, Intermediate HH. To a solution of ((6RS,8aRS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methanol (Step 1 in Intermediate A, 6.5 g, 41.4 mmol) in THF (150 mL) was added NaHMDS (1 M in THF, 51.7 mL, 51.7 mmol). The reaction mixture was stirred at -40 °C for 0.5 h. A solution of 4-(tert-butoxy)-2,7-dichloro-8- fluoropyrido[4,3-d]pyrimidine (10 g, 34.5 mmol) in THF (50 mL) was added to the reaction mixture, and stirred at -40 °C for 1 h. The reaction mixture was quenched with H2O (50 mL) at 0 °C, andextracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to obtain (6RS,8aRS)-6-(((4-(tert-butoxy)-7-chloro-8- fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (13.6 g,33.1 mmol, 96% yield). m / z (ESI): 411.2 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.88 (s, 1 H), 4.54 - 4.59 (m, 1 H), 4.42 - 4.46 (m, 1 H), 3.70 - 3.76 (m, 2 H), 3.62 - 3.68 (m, 2 H), 3.34 - 3.39 (m, 1 H), 3.12 - 3.20 (m, 1 H), 2.98 - 3.12 (m, 2 H), 2.19 - 2.30 (m, 1 H), 1.86 - 1.96 (m, 1 H), 1.78 (s, 9 H), 1.70 - 1.75 (m, 1 H), 1.46 - 1.57 (m, 1 H)..

[0340] Step 2: (6RS,8aRS)-6-(((4-(tert-butoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2- yl)oxy)methyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (Intermediate HH-1) and (6S,8aS)-6- (((4-(tert-butoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H- pyrrolo[2,1-c][1,4]oxazine (Intermediate HH-2). The racemic mixture (6RS,8aRS)-6-(((4-(tert- butoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolo[2,1- c][1,4]oxazine (9.7 g, 23.6 mmol) was purified by SFC using a ChiralPak AD, 2 × 25 cm, 10 µm column with a mobile phase of 11% IPA (0.1% NH3.H2O) in CO2. Peak 1: Intermediate HH-1 (3.2 g, 7.7 mmol, 33% yield). m / z (ESI): 411.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1 H), 4.43 - 4.48 (m, 1 H), 4.24 - 4.29 (m, 1 H), 3.56 - 3.65 (m, 2 H), 3.44 - 3.55 (m, 2 H), 3.15 (t, J=10.4 Hz, 1 H), 2.95 - 3.03 (m, 1 H), 2.81 - 2.94 (m, 2 H), 2.04 - 2.15 (m, 1 H), 1.74 - 1.82 (m, 1 H), 1.71 (s, 9 H), 1.54 - 1.64 (m, 1 H), 1.27 - 1.38 (m, 1 H).. Peak 2: Intermediate HH-2 (2.1 g, 5.1 mmol, 22% yield). m / z (ESI): 411.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1 H), 4.44 - 4.48 (m, 1 H), 4.25 - 4.29 (m, 1 H), 3.57 - 3.66 (m, 2 H), 3.45 - 3.55 (m, 2 H), 3.15 (t, J=10.0 Hz, 1 H), 2.99 (d, J=8.4 Hz, 1 H), 2.82 - 2.94 (m, 2 H), 2.04 - 2.16 (m, 1 H), 1.74 (s, 1 H), 1.71 (s, 9 H), 1.56 - 1.66 (m, 1 H), 1.27 - 1.39 (m, 1 H).. Intermediate II, rac-tert-Butyl 6-(((2-((1R,2R)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-6-methyl-1,4-oxazepane-4-carboxylate.

[0341] Step 1: tert-Butyl 6-methyl-6-(((4-nitrophenoxy)carbonyl)amino)-1,4-oxazepane-4- carboxylate. To a stirred mixture of tert-butyl 6-amino-6-methyl-1,4-oxazepane-4-carboxylate (1.0 g, 4.3 mmol, Pharmablock, Inc.) and DIEA (0.6 g, 0.8 mL, 4.4 mmol) in DCM (30 mL) at 0 °C under N2was added 4-[(chlorocarbonyl)oxy]nitrobenzene (1 g, 5 mmol, Sigma-Aldrich Corporation), and the mixture stirred at room temperature for 18 h. The reaction mixture was concentrated and the residuepurified by chromatography, eluting with a gradient of 0-100% EtOAc in heptane, to provide tert- butyl 6-methyl-6-(((4-nitrophenoxy)carbonyl)amino)-1,4-oxazepane-4-carboxylate (1.1 g, 2.7 mmol, 62% yield). m / z (ESI): 341.1 (M-t-Bu+H)+.1H NMR (400Hz, CDCl3) δ ppm 8.24 (br d, J = 9.0 Hz, 2H), 7.40 – 7.33 (m, 2H), 6.71 (br s, 1H), 4.34 (brd, J = 14.6 Hz, 1H), 4.02 – 3.92 (m, 1H), 3.91 – 3.77 (m, 4H), 3.32 – 2.79 (m, 2H), 1.51 (s, 9H), 1.42 (s, 3H)..

[0342] Step 2: rac-tert-Butyl 6-(((2-((1R,2R)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-6-methyl-1,4-oxazepane-4-carboxylate. To a stirred mixture of sodium hydride (60 wt% in mineral oil, 0.33 g, 8.12 mmol, Sigma-Aldrich Corporation) in Me-THF (6 mL) at 0 °C under N2was added Intermediate B (1.6 g, 4.1 mmol) in Me-THF (6 mL). The resulting mixture was stirred at room temperature for 1 h. tert-Butyl 6-methyl- 6-(((4-nitrophenoxy)carbonyl)amino)-1,4-oxazepane-4-carboxylate (1.1 g, 2.7 mmol) was added and the resulting mixture stirred at 70 °C for 3 h. The reaction was quenched with aq. Na2CO3(10 wt%, 100 mL) and extracted with EtOAc (100 mL). The organic phase was washed with Na2CO3(10 wt%, 2 x 100 mL), brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0-100% EtOAc in heptane, followed by reversed phase chromatography, eluting with a gradient of 0-100% ACN (0.1% TFA) in water (0.1% TFA), to provide rac-tert-butyl 6-(((2-((1R,2R)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethoxy)carbonyl)amino)-6-methyl-1,4-oxazepane-4-carboxylate (1.0 g, 1.6 mmol, 58% yield). m / z (ESI): 677.1, 679.0 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 7.99 (s, 1H), 7.66 (s, 1H), 5.65 (br d, J = 9.2 Hz, 1H), 4.08 – 3.94 (m,4H), 3.83 – 3.70 (m, 5H), 3.28 – 3.15 (m, 1H), 3.11 – 2.93 (m, 1H), 2.56 – 2.44 (m, 1H), 2.19 – 2.09 (m, 3H), 1.86 –1.75 (m, 2H), 1.73 – 1.67 (m, 1H), 1.58 (br s, 2H), 1.51 – 1.44 (m, 11H), 1.44 – 1.39 (m, 1H), 1.34 (s, 3H), 1.04 –0.94 (m, 1H), 0.60 – 0.42 (m, 1H).

[0343] Step 3: rac-tert-Butyl 6-(((2-((1R,2R)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-6-methyl-1,4-oxazepane-4-carboxylate, Intermediate II. To a stirred mixture of rac-tert- butyl 6-(((2-((1R,2R)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-6-methyl-1,4-oxazepane-4-carboxylate (1.0 g, 1.5 mmol) in EtOAc (15 mL) at room temperature was added Cs2CO3(1 g, 3 mmol), B2Pin2(0.9 g, 3 mmol, Ambeed, Inc.), Pd(OAc)2(35 mg, 0.2 mmol, Sigma-Aldrich Corporation) and tris(4- methoxyphenyl)phosphine (66 mg, 0.2 mmol, AA BLOCKS LLC). The reaction mixture was sparged with N2and stirred at 75 °C for 1 h. The mixture was filtered and concentrated, and the crude material was purified by chromatography, eluting with a gradient of 0-100% EtOAc in heptane, to provide Intermediate II (0.77 g, 1.1 mmol, 70% yield). m / z (ESI): 725.0 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 8.16 (br s, 1H), 7.71 (s, 1H), 5.66 (dd, J = 9.1, 2.6 Hz, 1H), 5.51 (br s,1H), 4.05 – 3.94 (m, 4H), 3.90 – 3.71 (m, 6H), 3.71 – 3.56 (m, 1H), 3.29 – 3.14 (m, 1H), 3.11 – 2.94 (m, 1H), 2.55 –2.46 (m, 1H), 2.41 – 2.30 (m, 1H), 2.21 – 2.11 (m, 1H), 2.09 – 2.04 (m, 1H), 1.89 (br d, J = 7.5 Hz, 1H), 1.81 – 1.73(m, 2H), 1.73 – 1.66 (m, 1H), 1.49 – 1.43 (m, 21H), 1.35 – 1.32 (m, 4H), 0.56 (br s, 1H), 0.42 (br s, 1H). Intermediate JJ: tert-Butyl (3R,4R)-3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate.

[0344] Step 1: tert-Butyl (3R,4R)-3-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4-(fluoromethyl)pyrrolidine- 1-carboxylate. To a stirred mixture of Intermediate B (2.00 g, 5.00 mmol) in 2- methyltetrahydrofuran (1.2 mL) at room temperature under ambient atmosphere was added 1,1'- carbonyldiimidazole (0.90 g, 5.50 mmol). The resulting mixture was stirred at room temperature for 15 minutes then, tert-butyl (3R,4R)-3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate (2.2 g, 10 mmol, BLD pharma) was added as a solution in 2-methyltetrahydrofuran (1.2 mL). The resulting mixture was stirred at 80 °C for 48 h. The reaction mixture was concentrated to afford a mixture of tert-butyl (3R,4R)-3-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate.

[0345] Step 2: tert-Butyl (3R,4R)-3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate, Intermediate JJ. To a stirred mixture of tert-butyl (3R,4R)-3-(((2-((1RS,2RS)-2-(4-bromo-6-chloro- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4- (fluoromethyl)pyrrolidine-1-carboxylate (3.00 g, 4.66 mmol), Cs2CO3(2.3 g, 7 mmol) and B2Pin2(1.4 g, 5.6 mmol, Combi-Blocks Inc.) in EtOAc (18.5 mL) at room temperaure under N2was added Pd(OAc)2(0.1 g, 0.5 mmol, Sigma-Aldrich Corporation) and tris(4-methoxyphenyl)phosphine (0.2 g, 0.6 mmol, Ambeed, Inc.). The resulting mixture was sparged with nitrogen for 5 minutes and stirred at 80 °C for 3 h. The reaction mixture was filtered, and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0-80% EtOAc in heptane, to provide Intermediate JJ (1.0 g, 1.4 mmol, 30% yield). m / z (ESI): 691.4 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.00 (s, 1H), 7.86 – 7.79 (m, 3H), 5.78 (br d, J = 9.6 Hz, 3H), 4.58 (br d, J = 6.7 Hz, 1H), 4.47(br d, J= 5.4 Hz, 2H), 4.29 (br d, J = 4.2 Hz, 2H), 4.06 – 3.96 (m, 6H), 3.88 – 3.79 (m, 3H), 3.61 – 3.49 (m, 5H), 2.71 – 2.61 (m, 2H), 2.35 – 2.26 (m, 2H), 2.18 – 2.10 (m, 3H), 1.51 – 1.48 (m, 1H), 1.22 (s, 13H), 1.22 – 1.21 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -225.68 – -229.60 (m, 1F). Intermediate KK: tert-Butyl (3R)-3-(((2-((1R,2R)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-(fluoromethyl)pyrrolidine-1-carboxylate.

[0346] Step 1: tert-Butyl (3R)-3-(((2-((1R,2R)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-(fluoromethyl)pyrrolidine-1- carboxylate. To a stirred mixture of tert-butyl (3r)-3-amino-3-(fluoromethyl)pyrrolidine-1- carboxylate (0.39 g, 1.8 mmol, Pharmablock, Inc.) and DIEA (0.33 mL, 2 mmol) in DCM (7.1 mL) at room temperature was added 4-nitrophenyl chloroformate (0.40 g, 2.0 mmol, Acros Organics), and the resulting mixture was stirred at room temperature for 40 min. The mixture was concentrated, and diluted with MeCN (3.6 mL). Intermediate B (1.43 g, 3.57 mmol) and DIEA (1.15 mL, 9 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction was concentrated and purified via reversed phase chromatography, eluting with a gradient of 10-100% MeCN (0.1% formic acid) in water (0.1% formic acid), to provide tert-butyl (3R)-3-(((2-((1R,2R)-2- (4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-(fluoromethyl)pyrrolidine-1-carboxylate (0.94 g, 1.5 mmol, 82% yield). m / z (ESI): 643.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.98 - 8.02 (m, 1 H), 7.67 (s, 1 H), 5.59 - 5.71 (m, 1 H), 4.78 (s, 1 H), 4.44 - 4.69 (m, 2 H), 3.97 - 4.18 (m, 3 H),3.66 - 3.83 (m, 1 H), 3.43 - 3.57 (m, 4 H), 2.43 - 2.59 (m, 1 H), 2.02 - 2.21 (m, 6 H), 1.68 - 1.83 (m, 3 H), 1.58 -1.64 (m, 1 H), 1.48 (s, 9 H), 0.98 - 1.04 (m, 1 H), 0.47 - 0.59 (m, 1 H).

[0347] Step 2: tert-Butyl (3R)-3-(((2-((1R,2R)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-3-(fluoromethyl)pyrrolidine-1-carboxylate, Intermediate KK.

[0348] To a mixture of tert-butyl (3R)-3-(((2-((1R,2R)-2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-(fluoromethyl)pyrrolidine-1- carboxylate (1.1 g, 1.8 mmol) in EtOAc was added Cs2CO3(0.9 g, 2.7 mmol), B2Pin2(0.5 g, 2.1 mmol, Combi-Blocks Inc.), Pd(OAc)2(20 mg, 0.1 mmol, AK Scientific, Inc.), tris(4-methoxyphenyl)phosphine (63 mg, 0.20 mmol, Combi-Blocks Inc.). The mixture sparged with N2, and stirred at 80 °C for 3 h. The reaction mixture filtered and concentrated. The crude material was purified via reversed phase chromatography, eluting with a gradient of 10-100% MeCN (0.1% formic acid) in water (0.1% formic acid), to provide Intermediate KK (1.2 g, 1.7 mmol, 95% yield). m / z (ESI): 691.2 (M+H)+. Alternate Conditions (1) To a stirred mixture of 2-((1S,2S)-2-(4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)ethan-1-ol (2 g, 5.3 mmol) in Me-THF (9.42 mL) at room temperature under ambient conditions was added 1,1'-carbonyldiimidazole (0.9 g, 5.8 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at room temperature for 10 min. (2) To a stirred mixture of tert-butyl (3r)-3-amino-3-methyl-piperidine-1-carboxylate (3.5 g, 16.4 mmol, Angel Pharmatech Ltd.) and DIEA (3.18 g, 4.3 mL, 24.62 mmol) in ACN (32 mL) at 0 °C under nitrogen was added 4-nitrophenyl chloroformate (4.0 g, 20 mmol, Oakwood Products, Inc.). The resulting mixture was stirred at room temperature for 30 minutes. Then, rac-2-((1R,2R)-2-(4- bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (8.1 g, 21.1 mmol) and DIEA (5.3 g, 7.2 mL, 41.2 mmol) were added. The resulting mixture was stirred at 80 °C for 27 h. The reaction mixture was concentrated and purified by column chromatography on silica gel, eluting with a gradient of 10-100% ACN (0.1% formic acid) in water (0.1% formic acid).

[0349] Intermediates in Table 19 were prepared following the procedure described above for Intermediate KK, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 19, ,Table 26: Additional Intermediates Prepared in an Analogous Manner to Intermediate KK.Intermediate LL: 7-Chloro-8-fluoro-4-(methoxymethoxy)-2-methylpyrido[4,3-d]pyrimidine

[0350] Step 1: 7-Chloro-8-fluoro-2-methylpyrido[4,3-d]pyrimidin-4-ol. To a stirred mixture of 4,7-dichloro-8-fluoro-2-methylpyrido[4,3-d]pyrimidine (0.5 g, 2.2 mmol, PharmaBlock) in 1-butanol (6 mL) at room temperature under ambient atmosphere was added HCl (2 M, 7.1 g, 6 mL, 12 mmol). The resulting mixture was stirred at 100 °C for 1 h. The reaction mixture was diluted with EtOAc andsaturated aqueous sodium bicarbonate. The aqueous phase was extracted with EtOAc, dried over sodium sulfate, filtered and concentrated. The product was purified by trituration with heptane and filtered to give 7-chloro-8-fluoro-2-methylpyrido[4,3-d]pyrimidin-4-ol (0.4 g, 2 mmol, 93% yield). m / z (ESI): 214.2 (M+H)+.

[0351] Step 2: 7-Chloro-8-fluoro-4-(methoxymethoxy)-2-methylpyrido[4,3-d]pyrimidine, Intermediate LL. To a stirred mixture of 7-chloro-8-fluoro-2-methylpyrido[4,3-d]pyrimidin-4-ol (1 g, 5 mmol) and DIEA (4.2 mL, 24 mmol) in DCM (24 mL) at 0 °C under nitrogen was added bromomethyl methyl ether (1 g, 0.6 mL, 7 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with sat. aq. Na2CO3(20 mL) and extracted with DCM (3 x 15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by chromatography, eluting with a gradient of 0-100% EtOH in EtOAc (1:3, 2% TEA) in heptane, to provide Intermediate LL (0.4 g, 1.7 mmol, 83% yield). m / z (ESI): 258.0 (M+H)+. Intermediate MM: tert-Butyl (3R)-3-(((2-((1S,2S)-2-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -indazol-5-yl)cyclopropyl)ethoxy)carbonyl) amino)-3-methylpiperidine-1-carboxylate.

[0352] Step 1: tert-Butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-yn-1- yl)oxy)silane. To a solution of (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (175 g, 949 mmol) in THF (1.75 L) was added n-BuLi (2.5 M in n-hexane, 494 mL, 1.23 mol) dropwise at -78 °C under N2, then stirred at -78 °C for 1 h. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (230 g, 1.23 mol) in THF (800 mL) was added to the reaction mixture at -78 °C under N2fand stirred at -78 °C for 2 h. The reaction mixture was acidified (pH ~6) by addition of HCl (4 M in EtOAc) at 0 °C. The mixture was concentrated, and filtered. The filtrate was concentrated to obtain tert- butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-yn-1-yl)oxy)silane (800 g, crude).1H NMR (400 MHz, CDCl3) δ ppm 3.76 (t, J=7.6 Hz, 2 H), 2.49 (t, J=7.6 Hz, 2 H), 1.27 (s, 12 H), 0.89 (s, 9 H), 0.06 (s, 6 H)..

[0353] Step 2: (Z)-tert-Butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3- en-1-yl)oxy)silane. To a solution of tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)but-3-yn-1-yl)oxy)silane (105 g, 338 mmol) in DCM (1 L) under nitrogen was added bis(cyclopentadienyl)zirconium chloride hydride (105 g, 406 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with H2O (2 L) and extracted with DCM (3 x 500 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 100:1 to 0:1 pet. ether in EtOAc, twice to obtain (Z)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (300 g, 961 mmol, 58% yield).1H NMR (400 MHz, CDCl3) δ ppm 6.43 - 6.54 (m, 1 H), 5.39 - 5.46 (m, 1 H), 3.67 (t, J=6.8 Hz, 2 H), 2.61 - 2.68 (m, 2 H), 1.27 (s, 12 H), 0.90 (s, 9 H), 0.07 (s, 6 H)..

[0354] Step 3: tert-Butyldimethyl(2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopropyl)ethoxy)silane. To a solution of diethylzinc (1 M in PhMe, 500 mL, 500 mmol) in DCM (300 mL) under nitrogen was added TFA (57.0 g, 499 mmol) in DCM (200 mL) dropwise at 0 °C and then stirred at 0 °C for 0.5 h. A solution of diiodomethane (134 g, 500 mmol) in DCM (200 mL) was added dropwise to the mixture and stirred at 0 °C for 0.5 h. A solution of (Z)-tert- butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxy)silane (100 g, 320 mmol) in DCM (300 mL) was added dropwise to the mixture and stirred at 0 °C for 12 h. The reaction mixture was quenched with H2O and filtered. The solid residue was washed with DCM (1 L), then the filtrate was extracted with DCM (2 x 1.5 L). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluting with a gradient of 100:1 to 10:1 pet. ether in EtOAC, to obtain tert- butyldimethyl(2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)ethoxy)silane (200 g, 613 mmol, 64% yield).1H NMR (400 MHz, CDCl3) δ ppm 3.60 - 3.71 (m, 2 H), 1.61 - 1.67 (m, 2 H), 1.23 (d, J=6.8 Hz, 12 H), 1.10 - 1.18 (m, 1 H), 0.90 (s, 9 H), 0.77 - 0.81 (m, 1 H), 0.37 - 0.45 (m, 1 H), 0.06 (s, 6 H), -0.15 - -0.03 (m, 1 H).

[0355] Step 4: Potassium trifluoro((1S,2S)-2-(2-hydroxyethyl)cyclopropyl)borate. To a solution of tert-butyldimethyl(2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopropyl)ethoxy)silane (40 g, 123 mmol) in MeOH (400 mL) was added KHF2(76 g, 981 mmol) in water (200 mL) dropwise at 0 °C. The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated and the residue suspended in MeOH (500 mL) and triturated for 30 minutes. The mixture was filtered and the filtrate was concentrated. The residue was triturated with MTBE (500 mL) then filtered to obtain potassium trifluoro((1S,2S)-2-(2- hydroxyethyl)cyclopropyl)borate (110 g, 573 mmol, 93% yield).1H NMR (400 MHz, METHANOL- d4) δ ppm 3.51 - 3.75 (m, 2 H), 1.50 - 1.67 (m, 1 H), 1.04 - 1.41 (m, 2 H), 0.23 - 0.70 (m, 2 H), -0.69 - -0.17 (m, 1 H).

[0356] Step 5: 2-((1S,2S)-2-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethan-1-ol. A mixture of 4-bromo-6-fluoro-5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (20 g, 47.1 mmol), potassium trifluoro((1S,2S)-2-(2-hydroxyethyl)cyclopropyl)borate (13.5 g, 70.6 mmol), Pd(dppf)Cl2(7 g, 9 mmol) and K3PO4(35 g, 165 mmol) in 1,4-dioxane (400 mL) and water (80 mL) was sparged with nitrogen and stirred at 110 °C for 12 h. The reaction mixture was diluted with H2O (1.5 L) and extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluting with a gradient of 100:1 to 0:1 of pet. ether in EtOAc, to obtain 2- ((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (30 g, 78 mmol, 41% yield). m / z (ESI): 383.1 [M+H]+.

[0357] Step 6: 2-((1S,2S)-2-(4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate. To a solution of 2-((1S,2S)-2-(4-bromo-6-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (5.00 g, 13.05 mmol) and TEA (9 mL, 65 mmol) in THF (25 mL) was added a solution of 4-nitrophenyl chloroformate (4.2 g, 20.9 mmol) in THF (25 mL) at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to provide 2-((1S,2S)-2-(4-bromo-6-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate (36 g, crude), which was used further purification.

[0358] Step 7: tert-Butyl (3R)-3-(((2-((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate. To a solution of 2-((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethyl (4-nitrophenyl) carbonate (36 g, 65.6 mmol) in THF (360 mL) was added tert- butyl (R)-3-amino-3-methylpiperidine-1-carboxylate (21 g, 98 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (3 x 400 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 100:1 to 0:1 of pet.ether in EtOAc, to obtain tert-butyl (3R)-3-(((2-((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (30 g, 48 mmol, 73% yield). m / z (ESI): 523.2 [M-Boc+H]+.

[0359] Step 8: tert-Butyl (3R)-3-(((2-((1S,2S)-2-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (Intermediate MM). A mixture of tert-butyl (3R)-3-(((2-((1S,2S)-2-(4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (5 g, 8 mmol), B2Pin2(10.2 g, 40.1 mmol), Cs2CO3(7.8 g, 24 mmol) and Pd(dppf)Cl2(0.6 g, 0.8 mmol) in 1,4- dioxane (100 mL) and H2O (10 mL) was sparged with nitrogen. The mixture was stirred at 100 °C for 1 h. The reaction mixture was diluted with H2O (600 mL) and extracted with EtOAc (3 x 600 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluting with a gradient of 100:1 to 0:1 of pet. ether in EtOAc, to obtain Intermediate MM (30 g, 45 mmol, 93% yield). m / z (ESI): 671.5 (M+H)+. Intermediate VV: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-((tetrahydro-2H-pyran-4- yl)oxy)pyrido[4,3-d]pyrimidine.

[0360] Step 1: 4-(tert-Butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a stirred mixture of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (1.5 g, 6.0 mmol, LabNetwork Inc.) in THF (12 mL) at -78 °C under nitrogen was added sodium tert-butoxide (2 M in THF, 6 mL, 12 mmol, Oakwood Products, Inc.). The resulting mixture was stirred at -78 °C for 10 minutes. The reaction mixture was diluted with sat. aq. NH4Cl (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography, eluting with a gradient of 0-60% EtOH in EtOAc (1:3) in heptane, to provide 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (1.3 g, 4.4 mmol, 74% yield). m / z (ESI): 234.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 1.73 - 1.77 (m, 9 H) 9.04 - 9.17 (m, 1 H).19F NMR (376 MHz, DMSO-d6) δ ppm -136.06 - -132.27 (m, 1 F).

[0361] Step 2: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-((tetrahydro-2H-pyran-4- yl)oxy)pyrido[4,3-d]pyrimidine, Intermediate VV.

[0362] To a stirred mixture of tetrahydro-2h-pyran-4-ol (0.68 g, 0.63 mL, 6.62 mmol, Combi- Blocks Inc.) in tetrahydrofuran (14 mL) at 0 °C under nitrogen, was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 5.29 mL, 5.29 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at 0 °C for 30 minutes. To this mixture was added 4-(tert-butoxy)-2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidine (1.28 g, 4.41 mmol) as a solution in tetrahydrofuran (7.0 mL). The resulting mixture was warmed to room temperature and stirred for 1 h 15 min. The reaction mixture was diluted with sat. aq. solution of ammonium chloride (20 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 gel eluting with a gradient of 0-60% ethanol / ethyl acetate (1:3, 2% Et3N) in heptane, to afford 4- (tert-butoxy)-7-chloro-8-fluoro-2-((tetrahydro-2H-pyran-4-yl)oxy)pyrido[4,3-d]pyrimidine (1.15 g, 3.23 mmol, 73% yield). m / z (ESI): 356.0 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 1.69 - 1.84 (m, 11 H) 2.01 - 2.21 (m, 2 H) 3.46 - 3.68 (m, 2 H) 3.80 - 4.06 (m, 2 H) 5.17 - 5.45 (m, 1 H) 8.76 - 9.07 (m, 1 H).19F NMR (376 MHz, DMSO-d6) δ ppm -136.84 (s, 1 F).

[0363] The intermediate in Table 23 was prepared following the procedure described above for Intermediate VV, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 23.Table 27.. , , . , . Intermediate XX: tert-Butyl (R)-3-(((2-((1RS,2RS)-2-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1- carboxylate.

[0364] Step 1: rac-2-((1R,2R)-2-(2-Bromo-6-chlorophenyl)cyclopropyl)ethan-1-ol. A mixture of 1-bromo-3-chloro-2-iodobenzene (1.0 g, 3.2 mmol), potassium trifluoro((1S,2S)-2-(2- hydroxyethyl)cyclopropyl)borate (1.2 g, 6.3 mmol), K3PO4(2.0 g, 9.5 mmol) and Pd(dppf)Cl2-CH2Cl2(52 mg, 0.63 mmol) in DMF (10 mL) and water (2 mL) was sparged with nitrogen and stirred at 80 °C for 5 h. The reaction mixture was quenched with H2O (250 mL) and then extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by column chromatography on silica gel eluting with a gradient of 100:0 to 90:10 pet. ether in EtOAc to provide rac-2-((1R,2R)-2-(2- bromo-6-chlorophenyl)cyclopropyl)ethan-1-ol (1.5 g, 5.4 mmol, 34% yield).

[0365] Step 2: tert-Butyl (R)-3-(((2-((1RS,2RS)-2-(2-bromo-6- chlorophenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate. To a solution of rac-2-((1R,2R)-2-(2-bromo-6-chlorophenyl)cyclopropyl)ethan-1-ol (1.3 g, 4.7 mmol) in THF (13 mL) was added TEA (3.3 mL, 23.6 mmol) and 4-nitrophenyl chloroformate (1.5 g, 7.5 mmol) at 0 °C under N2 and the mixture stirred at room temperature for 2 h. To this mixture was added tert-butyl (R)-3-amino-3-methylpiperidine-1-carboxylate (1.3 g, 6.1 mmol) and the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient of 100:1 to 80:20 of pet. ether in EtOAc. The product was further purified by reversed phase chromatography eluting with a gradient of 55-85% H2O to provide tert-butyl (R)-3-(((2-((1RS,2RS)-2-(2-bromo-6- chlorophenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (0.7 g, 1.4 mmol, 30% yield). m / z (ESI): 459.1 [M-t-Bu+H]+.1H NMR (400 MHz, CDCl3) δ ppm 7.47 - 7.50 (m, 1 H), 7.29 - 7.34 (m, 1 H), 7.01 (t, J=8.0 Hz, 1 H), 4.54 - 5.25 (m, 1 H), 3.97 - 4.09 (m, 2 H), 3.76 - 3.96 (m, 2 H), 2.67 - 2.98 (m, 2 H), 2.08 - 2.16 (m, 1 H), 1.98 (m, 1 H), 1.53 - 1.68 (m, 3 H), 1.51 (s, 1 H), 1.46 (d, J=3.6 Hz, 9 H), 1.41 - 1.44 (m, 1 H), 1.35 - 1.40 (m, 1 H), 1.32 (s, 3 H), 0.86 - 1.02 (m, 1 H), 0.40 - 0.60 (m, 1 H).

[0366] Step 3: tert-Butyl (R)-3-(((2-((1RS,2RS)-2-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1- carboxylate, Intermediate XX. To a solution of tert-butyl (R)-3-(((2-((1RS,2RS)-2-(2-bromo-6- chlorophenyl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (0.7 g, 1.3 mmol), Cs2CO3(1.3 g, 3.9 mmol) and B2Pin2(1.7 g, 6.6 mmol) in 1,4-dioxane (13.6 mL) and water (1.36 mL) was added Pd(dppf)Cl2(0.1 g, 0.1 mmol). The reaction mixture was sparged with nitrogen and stirred at 100 °C for 1 h. The reaction mixture was quenched with H2O (20 mL) then extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by chromatography eluting with a gradient of 100:0 to 80:20 pet. ether in EtOAc to provide Intermediate XX (0.5 g, 0.9 mmol, 67% yield). m / z (ESI): 585.4 [M+Na]+. SECTION 2: Synthesis of Example Compounds

[0367] Provided in this section is the synthesis of examples described herein. It would be understood that compounds described herein (such as compounds of Formula (I), Formula (I-B), Formula (II), Formula (II-B), Formula (III), Formula (III-B), Formula (IV), Formula (IV-B), Formula (V) or Formula (V-B), or compounds listed in Table 1, Table 2 or compounds of Embodiments 1-220, or a pharmaceutically acceptable salt of any of the foregoing) whose preparation is not specifically described in this section could be prepared in an analogous manner. Example 1.019 & 1.021: (11S,13S,19R)-9-Chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one and (11R,13R,19R)-9-chloro-31-fluoro-25-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one

[0368] Step 1. tert-Butyl (3R)-3-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate.

[0369] To a stirred solution of rac-2-((1R,2R)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)cyclopropyl)ethan-1-ol (Intermediate B, 1.77 g, 4.43 mmol) in 2- methyltetrahydrofuran (8 mL) was added 1,1'-carbonyldiimidazole (0.79 g, 4.9 mmol). The reaction mixture was stirred at room temperature for 1.5 h. Then, (3R)-(+)-1-(tert-butoxycarbonyl)-3- aminopyrrolidine (1.5 mL, 8.9 mmol) in 2 mL 2-methyltetrahydrofuran was added and the reaction mixture was heated at 80 °C for 24 h. The mixture was cooled to room temperature and diluted with saturated aqueous NaHCO3solution. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% EtOAc in hexane, to provide tert-butyl (3R)-3-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate (2.51 g, 4.10 mmol, 93% yield). m / z (ESI): 611.0 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 7.98 (s, 1H), 7.65 (s, 1H), 5.63 (br d, J = 9.0 Hz, 1H), 4.69 (br s, 1H), 4.20 (br s, 1H), 4.09 (br s, 1H), 4.06-3.98 (m, 1H), 3.75 (br t, J = 9.0 Hz, 1H), 3.66-3.51 (m, 1H), 3.40 (br s, 2H), 3.23-3.08 (m, 1H), 2.48 (br d, J = 10.2 Hz, 1H), 2.16-2.04 (m, 5H), 1.85-1.67 (m, 4H), 1.46 (s, 12H), 1.03-0.94 (m, 1H), 0.51 (br s, 1H).

[0370] Step 2. tert-Butyl (3R)-3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5 yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate. To a 40-mL vial was added cesium carbonate (2.00 g, 6.13 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.35 g, 5.31 mmol) and tert-butyl (3R)-3-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate (2.50 g, 4.09 mmol) in ethyl acetate (8 mL). The reaction mixture was flushed with nitrogen, then Pd(OAc)2(92 mg, 0.41 mmol) and tris(4-methoxyphenyl)phosphine (0.17 g, 0.49 mmol) was added. The reaction mixture was heated to 80 °C for 4.5 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and rinsed with EtOAc. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% EtOAc in hexane, to provide a mixture of tert-butyl (3R)- 3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate and tert-butyl (3R)-3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate (2.22 g, 3.37 mmol, 82% yield, 4:1 mixture respectively). The mixture was used as is without further purification. m / z (ESI): 659.4 (M+H)+.

[0371] Step 3. tert-Butyl (3R)-3-(((2-((1RS,2RS)-2-((4R)-4-(4-(tert-butoxy)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate. A 40-mL vial was charged with tert-butyl (3R)-3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1- carboxylate (2.22 g, 3.37 mmol), 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate A, 1.39 g, 3.37 mmol), potassium phosphate tribasic (1.79 g, 8.42 mmol), methanesulfonato(diadamantyl-n-butylphosphino)- 2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (0.25 g, 0.34 mmol), 2- methyltetrahydrofuran (14 mL) and water (2 mL). The reaction mixture was heated to 80 °C for 3 h. After cooling to room temperature, the reaction mixture was purified by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH with 1% TEA in heptane, to provide tert-butyl (3R)-3-(((2-((1RS,2RS)-2-((4R)-4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate (1.75 g, 1.92 mmol, 57% yield). m / z (ESI): 909.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.23 – 9.16 (m, 1H), 7.88 – 7.69 (m, 2H), 5.74 – 5.67 (m, 1H), 5.39 – 5.19 (m, 1H), 4.86 – 4.55 (m, 1H), 4.37 – 4.22 (m, 2H), 4.04 (br t, J = 10.2 Hz, 1H), 3.99 – 3.84 (m, 2H), 3.83 – 3.72 (m, 1H), 3.55 (br d, J = 5.2 Hz,1H), 3.37 (br s, 2H), 3.32 – 3.21 (m, 2H), 3.19 – 3.05 (m, 2H), 3.04 – 2.95 (m, 1H), 2.61 – 2.41 (m, 1H), 2.33 – 2.23 (m, 2H), 2.21 – 2.05 (m, 5H), 2.01 – 1.87 (m, 4H), 1.84 – 1.79 (m, 9H), 1.78 – 1.65 (m, 5H), 1.45 (s, 9H), 0.67 (br d, J = 5.0 Hz, 1H), 0.48 (br s, 1H), -0.41 (br s, 1H).19F NMR (376 MHz, CDCl3) δ ppm -136.49 (br d, J = 46.8 Hz, 1F), -172.96 – -173.06 (m, 1F).

[0372] Step 4.2-((1RS,2RS)-2-((R)-6-Chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5- yl)cyclopropyl)ethyl ((R)-pyrrolidin-3-yl)carbamate. To a 40-mL vial was added tert-butyl (3R)-3- (((2-((1RS,2RS)-2-((4R)-4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 5-yl)cyclopropyl)ethoxy)carbonyl)amino)pyrrolidine-1-carboxylate (1.75 g, 1.92 mmol) in isopropanol (2 mL). Then HCl (4 M in 1,4-dioxane, 12 mL, 48 mmol) was added and the reaction was stirred at room temperature for 1 h, was then concentrated and azeotroped with heptanes. The crude material was used in the next step without further purification. m / z (ESI): 669.1 (M+H)+.

[0373] Step 5. (11R,13R,19R)-9-Chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one and (11S,13S,19R)-9-chloro-31-fluoro-25-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one. A 250-mL round-bottom flask was charged with 2- ((1RS,2RS)-2-((R)-6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)cyclopropyl)ethyl ((R)- pyrrolidin-3-yl)carbamate (1.77 g, 2.65 mmol) and 1,1'-dimethyltriethylamine (4.6 mL, 27 mmol) in acetonitrile (470 mL) and dimethyl sulfoxide (59 mL). PyBOP (benzotriazol-1-yl- oxytrispyrrolidinophosphonium hexafluorophosphate) (1.51 g, 2.91 mmol) was added in one portion, then the reaction was stirred at room temperature for 18 h. The reaction mixture was filtered and the MeCN in the filtrate was removed under reduced pressure. The residue in DMSO was diluted with saturated NaHCO3solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by reversed phase column chromatography on a C18 column, eluting with a gradient of 5–40% 0.1% formic acid in CH3CN / H2O, followed by purification using an XBridge C18 column, eluting with a gradient from 45-75% acetonitrile with 0.1% NH4OH in water with 0.1% NH4OH, to generate 20 mg of (11R,13R,19R)-9-chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)- yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one: m / z (ESI): 651.1 (M+H)+.1H NMR (400 MHz,METHANOL-d4) δ ppm 9.07 (s, 1H), 8.08 (s, 1H), 7.78 (d, J = 1.0 Hz, 1H), 5.50 – 5.33 (m, 1H), 4.73 (br d, J = 11.9 Hz, 1H), 4.52 (d, J = 11.1 Hz, 2H), 4.46 – 4.35 (m, 2H), 4.00 (br s, 3H), 3.85 (br d, J = 11.1 Hz, 1H), 3.67 – 3.55 (m, 2H), 3.52 – 3.45 (m, 2H), 3.23 – 3.14 (m, 1H), 2.56 – 2.41 (m, 1H), 2.40 – 2.28 (m, 2H), 2.27 – 2.20 (m, 1H), 2.17 – 2.08 (m, 2H), 2.05 – 1.96 (m, 1H), 1.92 – 1.82 (m, 3H), 1.45 (br d, J = 13.6 Hz, 1H), 1.15 – 1.04 (m, 1H), 0.52 (br d, J = 4.6 Hz, 1H), 0.40 – 0.27 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -141.49 (br s, 1F), -173.78 (s, 1F) and 9 mg of (11S,13S,19R)-9-chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)- yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one: m / z (ESI): 651.25 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.20 (s, 1H), 8.18 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 5.40 – 5.19 (m, 1H), 4.98 (s, 1H), 4.36 (d, J = 10.5 Hz, 2H), 4.21 (d, J = 10.5 Hz, 1H), 4.00 (dd, J = 6.6, 2.6 Hz, 1H), 3.71 (br dd, J = 12.5, 2.3 Hz, 1H), 3.53 (ddd, J = 12.9, 10.6, 4.6 Hz, 1H), 3.46 – 3.37 (m, 1H), 3.35 – 3.34 (m, 2H), 3.29 – 3.24 (m, 1H), 3.24 – 3.21 (m, 1H), 3.20 – 3.15 (m, 1H), 3.01 (td, J = 9.4, 5.9 Hz, 1H), 2.39 – 2.08 (m, 5H), 2.04 – 1.95 (m, 2H), 1.95 – 1.85 (m, 1H), 1.84 – 1.72 (m, 1H), 1.38 – 1.23 (m, 1H), 0.77 – 0.62 (m, 1H), 0.52 – 0.36 (m, 2H), 0.13 – -0.03 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -136.70 (m, 1F), -173.61 (s, 1F). Table 4: Additional Examples 1.001-1.006, 1.022, 1.025-1.026, 1.029-1.033, 1.035-1.039, 1.046- 1.047, 1.054, 1.056, 1.061, 1.064, 1.073, 1.076-1.078, 1.084-1.087 and 1.100-1.101. Prepared in an Analogous Manner to Example 1.019 and 1.021.Table 5: Additional Examples 1.001-1.006, 1.022, 1.025-1.026, 1.029-1.033, 1.035-1.039, 1.046- 1.047, 1.054, 1.056, 1.061, 1.064, 1.073, 1.076-1.078, 1.084-1.087 and 1.100-1.101. Prepared in an Analogous Manner to Example 1.019 and 1.021., ., . , , . , . . , .. , , . , , . , , . , .. . , , . . , .. , . , . . , .. , , . , . , .Table 6. Conditions for Chiral SFC Separation.Example 1.058 & 1.057: (11R,13R,19R,21R)-9-Chloro-31-fluoro-25-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-21-methyl-16-oxa- 5,6,18,22,24,26,30-heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one and (11S,13S,19R,21R)-9-chloro-31-fluoro-25- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-21-methyl-16-oxa- 5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one

[0374] Step 1. tert-Butyl (2R,4R)-4-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-2-methylpyrrolidine-1- carboxylate. To a stirred solution of rac-2-((1R,2R)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (Intermediate B, 1.39 g, 3.48 mmol) in 2- methyltetrahydrofuran (6.5 mL) was added 1,1'-carbonyldiimidazole (0.62 g, 3.8 mmol). The reaction mixture was stirred at room temperature for 15 minutes. Then, tert-butyl (2R,4R)-4-amino-2- methylpyrrolidine-1-carboxylate (1.40 g, 6.96 mmol) in 2-methyltetrahydrofuran (1 mL) was added and the reaction mixture was heated at 80 °C for 21 h. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% EtOAc in hexane, to provide tert-butyl (2R,4R)-4-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-2- methylpyrrolidine-1-carboxylate (2.10 g, 3.35 mmol, 96% yield). m / z (ESI): 646.8 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 8.02 – 7.96 (m, 1H), 7.71 – 7.65 (m, 1H), 5.68 – 5.62 (m, 1H), 4.62 (br s, 1H), 4.26 (br dd, J = 3.4, 1.4 Hz, 1H), 4.14 – 4.09 (m, 2H), 3.81 – 3.70 (m, 1H), 3.65 – 3.55 (m, 1H), 3.28 – 3.15 (m, 1H), 2.53 – 2.42 (m, 1H), 2.21 – 2.02 (m, 5H), 1.89 – 1.64 (m, 5H), 1.49 – 1.44 (m, 10H), 1.32 – 1.26 (m, 2H), 1.23 (br d, J = 6.1 Hz, 3H), 1.05 – 0.97 (m, 1H).

[0375] Step 2. tert-Butyl (2R,4R)-4-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-2-methylpyrrolidine-1-carboxylate. To a 40-mL vial was added cesium carbonate (1.64 g, 5.03 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.02 g, 4.03 mmol) and tert-butyl (2R,4R)-4-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-2-methylpyrrolidine-1-carboxylate (2.10 g, 3.35 mmol), Pd(OAc)2(36 mg, 0.17 mmol), and tris(4-methoxyphenyl)phosphine (0.12 g, 0.33 mmol) in ethyl acetate (6.5 mL). The reaction mixture was flushed with nitrogen and then heated to 80 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and rinsed with EtOAc. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% EtOAc in hexane, to provide tert-butyl (2R,4R)-4-(((2-((1RS,2RS)-2-(6- chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-2-methylpyrrolidine-1-carboxylate (0.53 g, 0.78 mmol, 23% yield). m / z (ESI): 673.0 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 8.18 (s, 1H), 7.88 (s, 1H), 5.86 – 5.72 (m, 1H), 4.18 – 3.76 (m, 6H), 3.59 – 3.49 (m, 1H), 3.25 – 3.15 (m, 1H), 2.51 – 2.22 (m, 2H), 2.18 – 1.65 (m, 8H), 1.55 – 1.40 (m, 20H), 1.41 – 1.19 (m, 10H).

[0376] Step 3. tert-Butyl (2R,4R)-4-(((2-((1RS,2RS)-2-(4-((S)-4-(tert-butoxy)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-2- methylpyrrolidine-1-carboxylate. A 40-mL vial was charged with tert-butyl (2R,4R)-4-(((2- ((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-2-methylpyrrolidine-1-carboxylate (0.53 g, 0.78 mmol), 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate A, 0.32 g, 0.78 mmol), potassium phosphate tribasic (0.50 g, 2.4 mmol), methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino- 1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (86 mg, 0.12 mmol), 2- methyltetrahydrofuran (7.0 mL) and water (0.7 mL). The reaction mixture was heated to 80 °C for 3 h. After cooling to room temperature, the reaction mixture was purified by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH (with 1% TEA) in heptanes, to provide tert-butyl (2R,4R)-4-(((2-((1RS,2RS)-2-(4-((S)-4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-2- methylpyrrolidine-1-carboxylate (0.59 g, 0.64 mmol, 82% yield). m / z (ESI): 922.8 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.2-9.3 (m, 1H), 8.0-8.0 (m, 1H), 7.7-7.8 (m, 1H), 5.8-5.9 (m, 1H), 5.2-5.4 (m, 1H), 4.3-4.4 (m, 3H), 3.8-4.1 (m, 7H), 3.4-3.6 (m, 1H), 3.1-3.3 (m, 5H), 3.0-3.1 (m, 1H), 2.4-2.5 (m, 2H), 2.2-2.4 (m, 4H), 2.1-2.2 (m, 4H), 1.85 (s, 9H), 1.7-1.8 (m, 4H), 1.45 (br s, 12H), 1.1-1.2 (m, 4H).19F NMR (376 MHz, METHANOL-d4) δ ppm -139.2--137.8 (m, 1F), -174.6--172.6 (m, 1F).

[0377] Step 4.2-((1RS,2RS)-2-(6-Chloro-4-((S)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5- yl)cyclopropyl)ethyl ((3R,5R)-5-methylpyrrolidin-3-yl)carbamate. To a 40-mL vial was added tert-butyl (2R,4R)-4-(((2-((1RS,2RS)-2-(4-((S)-4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-2- methylpyrrolidine-1-carboxylate (0.35 g, 0.37 mmol) in dichloromethane (7.5 mL). Then HCl (4 M in 1,4-dioxane, 2.8 mL, 11.2 mmol) was added and the reaction was stirred at room temperature for 20 minutes and concentrated. The resulting solid was dissolved in MeOH and subjected to SCX column to free base. The crude material was used in the next step without further purification. m / z (ESI): 682.8 (M+H)+.

[0378] Step 5. (11R,13R,19R,21R)-9-Chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-21-methyl-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one and (11S,13S,19R,21R)-9-chloro-31-fluoro-25- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-21-methyl-16-oxa- 5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one. A 250-mL round-bottom flask was charged with 2-((1RS,2RS)-2-(6-chloro-4-((S)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin- 7-yl)-1H-indazol-5-yl)cyclopropyl)ethyl ((3R,5R)-5-methylpyrrolidin-3-yl)carbamate (0.25 g, 0.36 mmol) and 1,1'-dimethyltriethylamine (0.65 mL, 3.7 mmol) in tetrahydrofuran (74 mL). PyBOP (benzotriazol-1-yl-oxytrispyrrolidinophosphonium hexafluorophosphate) (0.72 g, 1.50 mmol) was added in one portion, then the reaction was stirred at room temperature for 26 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH (with 1% TEA) in heptanes, to provide a mixture of (11R,13R,19R,21R)-9-chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-21-methyl-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one and (11S,13S,19R,21R)-9-chloro-31-fluoro-25-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-21-methyl-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one. m / z (ESI): 664.9 (M+H)+. The material was further purified by HPLC using an XBridge C18, 19 x 100 mm, 5 um, with a gradient of 20–60% acetonitrile with 0.1% NH4OH in water with 0.1% NH4OH, followed by SFC purification using a DEAP, 21 x 150 mm, 5 um column with a mobile phase of 20% methanol in CO2at a flow rate of 80 mL / min to generate peak 1 as ((11R,13R,19R,21R)-9-chloro-31-fluoro-25- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-21-methyl-16-oxa- 5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one) (4.1 mg, 1.7% yield). m / z (ESI): 665.2 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.04 (s, 1H), 8.11 (s, 1H), 7.79 (s, 1H), 5.2-5.4 (m, 1H), 4.9-5.0 (m, 1H), 4.70 (br d, 1H, J=12.1 Hz), 4.4-4.4 (m, 1H), 4.2-4.3 (m, 1H), 3.97 (br s, 1H), 3.2-3.3 (m, 3H), 3.0-3.1 (m, 1H), 2.1-2.3 (m, 4H), 1.9-2.1 (m, 6H), 1.5-1.6 (m, 3H), 1.4-1.5 (m, 1H), 1.1-1.2 (m, 4H), 0.5-0.6 (m, 1H), 0.3-0.4 (m, 1H).19F NMR (376 MHz, METHANOL-d4) δ ppm -141.10 (br d, J = 17.3 Hz, 1F), -173.67 (s, 1F). Also isolated peak 2 as ((11S,13S,19R,21R)-9-chloro-31-fluoro-25- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-21-methyl-16-oxa- 5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one) (2.9 mg, 1.2% yield, 85% NMR purity) with the remaining 15% being isomer peak 1. m / z (ESI): 665.2 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.24 (s, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 5.43 – 5.22 (m, 1H), 4.42 – 4.38 (m, 1H), 4.29 – 4.25 (m, 1H), 4.03 – 3.98 (m, 1H), 3.88 – 3.82 (m, 1H), 3.27 – 3.16 (m, 3H), 3.08 – 3.00 (m, 1H), 2.40 – 2.14 (m, 5H), 2.06 – 1.99 (m, 2H), 1.98 – 1.85 (m, 3H), 1.58 – 1.53 (m, 3H), 1.38 – 1.30 (m, 2H), 1.18 – 1.15 (m, 3H), 0.64 (s, 1H), 0.52 – 0.38 (m, 2H).19F NMR (376 MHz, METHANOL-d4) δ ppm -136.32 – - 137.39 (m, 1F), -173.68 (s, 1F). Table 7: Additional Examples 1.059-1.060, 1.062-1.063, 1.065, 1.068-1.069, 1.103 and 1.115- 1.116. Prepared in an Analogous Manner to Example 1.058 and 1.057..Table 8. Analytical Data for Examples 1.059-1.060, 1.062-1.063, 1.065, 1.068-1.069, 1.103 and 1.115-1.116.. . , , . . , , . . , , . . , ,.Table 9. Conditions for Chiral SFC Separation.Example 1.014 & 1.007: (11R,13R,19S,20R)-9-Chloro-20,31-difluoro-25-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one (Example 1.014) and (11S,13S,19S,20R)-9-chloro-20,31-difluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa- 5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one (Example 1.007).

[0379] Step 1. tert-Butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4-fluoropyrrolidine-1- carboxylate. To a stirred solution of rac-2-((1R,2R)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-5-yl)cyclopropyl)ethan-1-ol (Intermediate B, 1.09 g, 2.73 mmol) in 2- methyltetrahydrofuran (5 mL) was added 1,1'-carbonyldiimidazole (0.49 g, 3.00 mmol). The reaction mixture was stirred at room temperature for 1 h, then tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine- 1-carboxylate (1.1 mL, 5.5 mmol, Pharmablock, Inc.) in 1 mL of 2-methyltetrahydrofuran was added. The reaction mixture was stirred and heated at 80 °C for 16 h. After cooling to room temperature, the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0– 60% EtOAc in hexane, to provide tert-butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4- fluoropyrrolidine-1-carboxylate (1.70 g, 2.70 mmol, 99% yield). m / z (ESI): 629.9 (M+H)+.

[0380] Step 2. tert-Butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate. To a 20-mL vial was added cesium carbonate (1.50 g, 4.60 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.03 g, 4.05 mmol) and tert-butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate (1.70 g, 2.70 mmol) in ethyl acetate (5.5 mL). The mixture was sparged with N2for 5 min, then Pd(OAc)2(61 mg, 0.27 mmol) and tris(4-methoxyphenyl)phosphine (0.11 g, 0.32 mmol) were added. The reaction mixture was heated at 80 °C under N2for 2 h. After cooling to room temperature, the mixture was filtered through a pad of celite, rinsed with EtOAc. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–60% EtOAc in hexanes, to provide a mixture of tert-butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4- fluoropyrrolidine-1-carboxylate and tert-butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4-fluoropyrrolidine-1- carboxylate (1.5 g, 2.2 mmol), 4:1 mixture respectively. The mixture was used as is without further purification.

[0381] Step 3. tert-Butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(6-chloro-4-((S)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate. A 40-mL vial was charged with tert-butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)- 4-fluoropyrrolidine-1-carboxylate (1.2 g, 1.8 mmol), 7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (Intermediate C, 0.78 g, 1.80 mmol), potassium phosphate tribasic (0.94 g, 4.4 mmol), cataCXium A Pd G3 (0.13 g, 0.18 mmol) and degassed.2-Methyltetrahydrofuran (7.5 mL) / water (0.75 mL) were added, and the reaction mixture was heated to 80 °C for 4.5 h. After cooling to room temperature, the reaction mixture was dried with Na2SO4. The crude material was purified purified by column chromatography on silica gel, eluting with a gradient of 0–80% 3:1 EtOAc / EtOH (with 1% TEA) in heptanes, to provide tert-butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(6-chloro-4-((S)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin- 7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4- fluoropyrrolidine-1-carboxylate (1.13 g, 1.19 mmol, 67% yield). m / z (ESI): 952.9 (M+H)+.

[0382] Step 4.2-((1RS,2RS)-2-(6-Chloro-4-((S)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)cyclopropyl)ethyl ((3S,4R)-4-fluoropyrrolidin-3-yl)carbamate. To the solution of tert-butyl (3S,4R)-3-(((2-((1RS,2RS)-2-(6-chloro-4-((S)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-4-fluoropyrrolidine-1- carboxylate (1.13 g, 1.18 mmol) in DCM (6 mL) was added 1,1,1-trifluoroacetic acid (2.5 mL, 35 mmol). The reaction mixture was stirred at room temperature for 3 h. The volatiles were evaporated in vacuo and the residue was redissolved in DCM and concentrated to give 2-((1RS,2RS)-2-(6-chloro-4- ((S)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)cyclopropyl)ethyl ((3S,4R)-4- fluoropyrrolidin-3-yl)carbamate. m / z (ESI): 769.2 (M+H)+.

[0383] Step 5. (11R,13R,19S,20R)-9-Chloro-20,31-difluoro-25-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one and (11S,13S,19S,20R)-9-chloro-20,31-difluoro-25- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa- 5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one. To the solution of 2-((1RS,2RS)-2-(6-chloro-4-((S)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)cyclopropyl)ethyl ((3S,4R)-4- fluoropyrrolidin-3-yl)carbamate (0.91 g, 1.20 mmol) in DMF (140 mL) was added cesium carbonate (3.08 g, 9.44 mmol). The reaction mixture was heated to 80oC with stirring for 1.5 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and brine / water. The aqueous layer was back extracted with EtOAc, and the combined organics was washed with 1:1 brine / water, dried (Na2SO4) and concentrated. The crude material was purified by reversed phase preparative HPLC using a C18 column, eluting with a gradient of 5–95% 0.1% TFA in CH3CN / H2O, to provide (11RS,13RS,19S,20R)-9-chloro-20,31-difluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one 2,2,2-trifluoroacetate (0.26 g, 0.34 mmol, 29% yield).

[0384] The sample was purified via SFC using a Chiralcel OD, 2 x 25 cm, 5 µm column with a mobile phase of 50% MeOH with 0.2% DEA using a flowrate of 80 mL / min to generate 21 mg of peak 1 as (11R,13R,19S,20R)-9-chloro-20,31-difluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one (ee of 98%, 89% chemical purity), m / z (ESI, +ve ion): 669.0(M+H)+and 67 mg of peak 2 as 11S,13S,19S,20R)-9-chloro-20,31-difluoro-25-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-16-oxa-5,6,18,22,24,26,30- heptaazaheptacyclo[25.3.1.1~19,22~.0~2,10~.0~3,7~.0~11,13~.0~23,28~]dotriaconta- 1(31),2,4,7,9,23,25,27,29-nonaen-17-one (ee of 98%, 95% chemical purity). m / z (ESI): 669.0 (M+H)+.1H NMR (600 MHz, DMSO-d6) δ ppm 9.34 (s, 1 H), 8.14 (s, 1 H), 7.81 (s, 1 H), 7.62 (br d, J=5.43 Hz, 1 H), 5.19 - 5.42 (m, 1 H), 4.91 - 5.19 (m, 3 H), 4.22 - 4.29 (m, 1 H), 4.20 (d, J=10.42 Hz, 1 H), 4.01 (d, J=10.27 Hz, 1 H), 3.93 (br s, 1 H), 3.76 (br d, J=14.67 Hz, 1 H), 3.34 (s, 1 H), 2.99 - 3.14 (m, 4 H), 2.76 - 2.92 (m, 1 H), 1.99 - 2.20 (m, 5 H), 1.70 - 1.90 (m, 4 H), 1.29 - 1.40 (m, 1 H), 1.09 - 1.15 (m, 1 H), 0.73 (br d, J=3.96 Hz, 1 H), 0.28 - 0.45 (m, 2 H), -0.04 - 0.11 (m, 1 H). Peak assignment determined by SFC with Chiralcel OD column with 50% MeOH with 0.2% DEA. Table 10: Additional Examples 1.008-1.013, 1.015-1.018, 1.104-1.015 and 1.108-1.109. Prepared in an Analogous Manner to Examples 1.014 and 1.007, . ,Table 11. Analytical Data for Examples 1.008-1.013, 1.015-1.018, 1.104-1.015 and 1.108-1.109.. , , . . , , . . , , . . ,. , . , . , , . , . , , . .Table 12. Conditions for Chiral SFC Separation.Example 1.072: (11Z,18R)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-18-methyl-15-oxa-5,6,17,21,23,25,29- heptaazahexacyclo[24.3.1.1~18,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,11,22,24,26,28-decaen-16-one.tr

[0385] Step 1. tert-Butyl (R)-3-methyl-3-(((4-nitrophenoxy)carbonyl)amino)pyrrolidine-1- carboxylate. To a stirring solution of tert-butyl (3R)-3-amino-3-methylpyrrolidine-1-carboxylate (0.54 g, 2.70 mmol, Pharmablock, Inc.) and N,N-diisopropylethylamine (0.53 mL, 3.0 mmol) in dichloromethane (12 mL) was added 4-nitrophenyl chloroformate (0.6 g, 3.0 mmol) and the reaction mixture was allowed to stir at room temperature for 40 min. The mixture was then concentrated, and the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0– 60% EtOAc in hexanes, to yield tert-butyl (R)-3-methyl-3-(((4- nitrophenoxy)carbonyl)amino)pyrrolidine-1-carboxylate (0.58 g, 1.60 mmol, 59% yield). m / z (ESI): 388.0 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 8.24-8.30 (m, 2 H), 7.33-7.40 (m, 2 H), 5.05-5.25 (m, 1 H), 3.33-3.71 (m, 5 H), 2.21-2.61 (m, 1 H), 1.80-2.03 (m, 1 H), 1.48-1.52 (m, 11 H).

[0386] Step 2. tert-Butyl (3R)-3-(((((Z)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate. To a 100- mL round-bottomed flask was added (Z)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)but-3-en-1-ol (Intermediate D, 0.93 g, 2.40 mmol) in 2-methyltetrahydrofuran (6 mL). The mixture was cooled to 0 °C, then sodium hydride (60 wt% in mineral oil, 0.19 g, 4.80 mmol) was added. The resulting reaction mixture was stirred at 0 °C for 45 min. tert-Butyl (R)-3-methyl-3-(((4- nitrophenoxy)carbonyl)amino)pyrrolidine-1-carboxylate (0.58 g, 1.60 mmol) in 2- methyltetrahydrofuran (2 mL) was added and the reaction mixture was stirred and heated to 75 °C for 48 h. After cooling to room temperature, the mixture was quenched via the addition of saturatedaqueous ammonium chloride and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude oil was purified by reversed phase column chromatography on a C18 column, eluting with a gradient of 5–100% 0.1% formic acid in CH3CN / H2O, to yield tert-butyl (3R)-3-(((((Z)-4-(4-bromo- 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3- methylpyrrolidine-1-carboxylate (0.34 g, 0.55 mmol, 34% yield). m / z (ESI): 632.8 (M+Na)+.

[0387] Step 3. tert-Butyl (3R)-3-(((((Z)-4-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3- methylpyrrolidine-1-carboxylate. A vial was charged with tris(4-methoxyphenyl)phosphine (20 mg, 0.056 mmol), palladium acetate (6.3 mg, 0.028 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (0.18 g, 0.72 mmol), cesium carbonate (0.27 g, 0.84 mmol), tert-butyl (3R)-3-(((((Z)- 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1- yl)oxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (0.34 g, 0.56 mmol) and ethyl acetate (1.2 mL). The reaction mixture was sparged with nitrogen and then heated to 80 °C with stirring for 3 h. After cooling to room temperature, the reaction was filtered through celite, and the filtrate was concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–85% EtOAc in hexanes, to provide tert-butyl (3R)-3-(((((Z)-4-(6-chloro-1-(tetrahydro- 2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)but-3-en-1- yl)oxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (0.16 g, 0.23 mmol, 42% yield). m / z (ESI): 658.9 (M+H)+.

[0388] Step 4. tert-Butyl (3R)-3-(((((Z)-4-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3- methylpyrrolidine-1-carboxylate. To a 40 mL vial was charged with 4-(tert-butoxy)-7-chloro-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate A, 0.11 g, 0.25 mmol), tert-butyl (3R)-3-(((((Z)-4-(6-chloro-1-(tetrahydro-2H-pyran-2- yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)but-3-en-1- yl)oxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (0.14 g, 0.21 mmol), methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (31 mg, 0.042 mmol), potassium phosphate tribasic (0.14 g, 0.64 mmol), 2- methyltetrahydrofuran (1.2 mL), and water (0.12 mL). The reaction mixture was degassed by sparging with nitrogen and then placed on a preheated 80 °C stir plate for 1.5 h. After cooling to room temperature, the organic layer was decanted from the aqueous layer and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–65% 3:1 EtOAc / EtOH (with 1% TEA) in heptanes, to yield tert-butyl (3R)-3-(((((Z)-4-(4-(4-(tert-butoxy)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3- methylpyrrolidine-1-carboxylate (78 mg, 0.086 mmol, 40% yield). m / z (ESI): 908.8 (M+H)+.

[0389] Step 5. (Z)-4-(6-Chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)but-3-en-1-yl ((R)- 3-methylpyrrolidin-3-yl)carbamate. To a 20-mL vial was charged with tert-butyl (3R)-3-(((((Z)-4- (4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but- 3-en-1-yl)oxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate (78 mg, 0.086 mmol), dichloromethane (1 mL), and hydrogen chloride (4.0 M in dioxane, 0.75 mL, 3.0 mmol). The reaction mixture was stirred at room temperature for 35 minutes and then concentrated to dryness. The crude material was loaded onto a SCX column with methanol, washed with methanol, and eluted with 2 M ammonia in methanol to yield (Z)-4-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)but-3-en-1-yl ((R)-3-methylpyrrolidin-3-yl)carbamate (57 mg, 0.085 mmol, 99% yield). m / z (ESI): 668.8 (M+H)+.

[0390] Step 6. (11Z,18R)-9-Chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-18-methyl-15-oxa-5,6,17,21,23,25,29- heptaazahexacyclo[24.3.1.1~18,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,11,22,24,26,28-decaen-16-one. To a 100-mL round-bottom flask was added (Z)-4-(6- chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4- hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)but-3-en-1-yl ((R)-3-methylpyrrolidin-3- yl)carbamate (54 mg, 0.081 mmol), acetonitrile (6.5 mL), dimethyl sulfoxide (1.5 mL), and DIPEA (42 μL, 0.24 mmol). To this was added with vigorous stirring bromotris(dimethylamino)phosphonium hexafluorophosphate (50 mg, 0.13 mmol) and the reaction mixture was stirred for at room temperature 1.5 h and then concentrated. The crude material was purified by reversed phase column chromatography on a C18 column, eluting with a gradient of 5–100% 0.1% formic acid in CH3CN / H2O, to yield (11Z,18R)-9-chloro-30-fluoro-24-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-18-methyl-15-oxa-5,6,17,21,23,25,29- heptaazahexacyclo[24.3.1.1~18,21~.0~2,10~.0~3,7~.0~22,27~]hentriaconta- 1(30),2,4,7,9,11,22,24,26,28-decaen-16-one formate (8.0 mg, 0.011 mmol, 14% yield). m / z (ESI): 651.0 (M+H)+.1H NMR (500 MHz, METHANOL-d4) δ ppm 9.09 – 9.27 (m, 1 H), 8.40 – 8.52 (m, 1 H), 8.09 – 8.20 (m, 1 H), 7.73 – 7.97 (m, 2 H), 6.34 – 6.52 (m, 1 H), 5.38 – 5.57 (m, 3 H), 4.45 – 4.64 (m, 3 H), 3.59 – 3.78 (m, 6 H), 2.20 – 2.64 (m, 6 H), 2.01 – 2.10 (m, 4 H), 1.66 – 1.82 (m, 1 H), 1.52 (br s, 3 H), 0.93 – 0.94 (m, 3 H).19F NMR (471 MHz, METHANOL-d4) δ ppm -76.34 – -73.92 (m), - 173.87 (s).Example 1.102: (11Z,18R)-31-Fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-9,18-dimethyl-15-oxa-5,6,17,22,24,26,30- heptaazahexacyclo[25.3.1.1~18,22~.0~2,10~.0~3,7~.0~23,28~]dotriaconta- 1(31),2,4,7,9,11,23,25,27,29-decaen-16-one.

[0391] The title compound was prepared in an analogous fashion to Example 1.072 using tert- butyl (3R)-3-amino-3-methylpyrrolidine-1-carboxylate (CAS#: 2199214-46-3, Pharmablock, Inc.) in Step 1 and (Z)-4-(4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-ol (Intermediate L) in Step 2 with N,N-diisopropylethylamine in acetonitrile. m / z (ESI): 1.101 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 12.96 - 13.07 (m, 1 H), 9.18 - 9.33 (m, 1 H), 7.90 - 8.06 (m, 1 H), 7.50 - 7.58 (m, 1 H), 6.40 - 7.02 (m, 2 H), 4.80 - 5.49 (m, 4 H), 3.79 - 4.28 (m, 3 H), 3.50 - 3.60 (m, 1 H), 2.96 - 3.17 (m, 4 H), 2.77 - 2.90 (m, 1 H), 2.28 - 2.42 (m, 4 H), 1.95 - 2.20 (m, 4 H), 1.46 - 1.88 (m, 7 H), 1.27 (br d, J=6.9 Hz, 4 H).19F NMR (376 MHz, DMSO-d6) δ ppm -137.71 (s, 1 F), - 172.05 (s, 1 F). Example 1.113: (11Z,18R)-9-Chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-18-methyl-15-oxa-5,6,17,22,24,26,30- heptaazahexacyclo[25.3.1.1~18,22~.0~2,10~.0~3,7~.0~23,28~]dotriaconta- 1(31),2,4,7,9,11,23,25,27,29-decaen-16-one.

[0392] Step 1. tert-Butyl (3R)-3-(((((Z)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate. To a stirred mixture of N,N-diisopropylethylamine (3.3 mL, 19 mmol) and tert-butyl (3R)-3-amino-3-methyl- piperidine-1-carboxylate (1.00 g, 4.67 mmol) in acetonitrile (31 mL) was added 4-nitrophenyl chloroformate (1.04 g, 5.13 mmol). The resulting mixture was stirred at room temperature for 1 h. To this was added (Z)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-ol (Intermediate D, 2.34 g, 6.07 mmol) and the reaction was heated to 80 °C for 72 h. After cooling to room temperature, the reaction mixture was concentrated and the crude oil was purified by reversed phase column chromatography on a C18 column, eluting with a gradient of 5–100% 0.1% formic acid in CH3CN / H2O, to yield tert-butyl (3R)-3-(((((Z)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (1.95 g, 3.12 mmol, 66% yield). m / z (ESI): 647.0 (M+Na)+.1H NMR (400 MHz, CDCl3) δ ppm 7.99 - 8.03 (m, 1 H), 7.55 - 7.76 (m, 1 H), 6.27 - 6.46 (m, 1 H), 5.89 - 6.03 (m, 1 H), 5.62 - 5.73 (m, 1 H), 3.52 - 4.10 (m, 6 H), 2.79 - 2.98 (m, 1 H), 2.41 - 2.61 (m, 1 H), 2.19 (s, 4 H), 1.64 - 1.86 (m, 4 H), 1.55 - 1.63 (m, 5 H), 1.45 - 1.49 (m, 9 H), 1.29 - 1.33 (m, 3 H).

[0393] Step 2. tert-Butyl (3R)-3-(((((Z)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpyrrolidine-1-carboxylate. To a stirred mixture of palladium acetate (70 mg, 0.31 mmol), cesium carbonate (1.52 g, 4.67 mmol), tert-butyl (3R)-3-(((((Z)-4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (1.95 g, 3.12 mmol) in ethyl acetate (12 mL) was added 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (1.02 g, 4.05 mmol). The resulting mixture was stirred at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–85% EtOAc in hexanes, to provide tert-butyl (3R)-3-(((((Z)-4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1- carboxylate (1.52 g, 2.25 mmol, 72% yield). m / z (ESI) 694.9 (M+Na)+.

[0394] Step 3. tert-Butyl (3R)-3-(((((Z)-4-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3- methylpiperidine-1-carboxylate. To a stirred mixture of methanesulfonato(diadamantyl-N- butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(II) dichloromethane adduct (0.32 g, 0.45 mmol), tert-butyl (3R)-3-(((((Z)-4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1- carboxylate (1.52 g, 2.25 mmol), and 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate A, 0.93 g, 2.25 mmol) in 2-methyltetrahydrofuran (14 mL) and water (1.4 mL) was added potassium phosphate (1.43 g, 6.78 mmol). The resulting mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the organic layer was decanted from the aqueous layer and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–65% (3:1 EtOAc / EtOH with 1% TEA) in heptanes, to yield tert-butyl (3R)-3-(((((Z)-4-(4-(4-(tert-butoxy)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7- yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-en-1-yl)oxy)carbonyl)amino)-3- methylpiperidine-1-carboxylate (1.42 g, 1.53 mmol, 68% yield). m / z (ESI): 923.2 (M+H)+.

[0395] Step 4. (Z)-4-(6-Chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)but-3-en-1-yl ((R)- 3-methylpiperidin-3-yl)carbamate. To a round-bottom flask was charged with tert-butyl (3R)-3- (((((Z)-4-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but- 3-en-1-yl)oxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (1.25 g, 1.35 mmol), dichloromethane (15 mL), and hydrogen chloride (4.0 M in dioxane, 12 mL, 48 mmol) dropwise. The reaction mixture was stirred at room temperature for 35 minutes and then concentrated to dryness to yield (Z)-4-(6-chloro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 4-hydroxypyrido[4,3-d]pyrimidin-7-yl)-1H-indazol-5-yl)but-3-en-1-yl ((R)-3-methylpiperidin-3- yl)carbamate (0.92 g, 1.30 mmol, 99% yield). m / z (ESI): 683.2 (M+H)+.

[0396] Step 5. (11Z,18R)-9-Chloro-31-fluoro-25-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-18-methyl-15-oxa-5,6,17,22,24,26,30- heptaazahexacyclo[25.3.1.1~18,22~.0~2,10~.0~3,7~.0~23,28~]dotriaconta- 1(31),2,4,7,9,11,23,25,27,29-decaen-16-one. To a stirred mixture (Z)-4-(6-chloro-4-(8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-hydroxypyrido[4,3-d]pyrimidin- 7-yl)-1H-indazol-5-yl)but-3-en-1-yl ((R)-3-methylpiperidin-3-yl)carbamate (0.92 g, 1.30 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.4 mmol) in acetonitrile (112 mL) and dimethyl sulfoxide (22 mL) was added bromotris(dimethylamino)phosphonium hexafluorophosphate (0.83 g, 2.20 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated to remove acetonitrile and the crude material was purified by reversed phase column chromatography on a C18 column, eluting with a gradient of 5–100% 0.1% formic acid in CH3CN / H2O, followed by purification by column chromatography on silica gel, eluting with a gradient of 0–100% 3:1 EtOAc / EtOH (with 1% TEA) in heptane to yield (11Z,18R)-9-chloro-31-fluoro-25-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-18-methyl-15-oxa-5,6,17,22,24,26,30- heptaazahexacyclo[25.3.1.1~18,22~.0~2,10~.0~3,7~.0~23,28~]dotriaconta- 1(31),2,4,7,9,11,23,25,27,29-decaen-16-one (0.14 g, 0.21 mmol, 15% yield). m / z (ESI): 655.2 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 - 13.38 (m, 1 H), 9.12 - 9.41 (m, 1 H), 8.01 - 8.25 (m, 1 H), 7.76 - 7.92 (m, 1 H), 6.79 - 7.05 (m, 1 H), 6.37 - 6.51 (m, 1 H), 5.36 - 5.51 (m, 2 H), 4.79 - 5.23 (m, 1 H), 4.13 - 4.20 (m, 1 H), 3.86 - 4.06 (m, 2 H), 3.53 - 3.61 (m, 1 H), 3.34 - 3.48 (m, 1 H), 3.00 - 3.17 (m, 4 H), 2.80 - 2.90 (m, 1 H), 1.97 - 2.18 (m, 4 H), 1.64 - 1.89 (m, 7 H), 1.44 - 1.53 (m, 1 H), 1.04 - 1.33 (m, 4 H).19F NMR (376 MHz, DMSO-d6) δ ppm -137.39 - -137.21 (m, 1 F), - 172.06 - -172.03 (m, 1 F). Stereochemistry was confirmed by x-ray crystallographic analysis. Example 1.027 & 1.034: (11S,13S,19R)-9-Chloro-32-fluoro-26-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-19-methyl-16-oxa-5,6,18,23,25,27,31- heptaazaheptacyclo[26.3.1.1~19,23~.0~2,10~.0~3,7~.0~11,13~.0~24,29~]tritriaconta- 1(32),2,4,7,9,24,26,28,30-nonaen-17-one (Example 1.027) and (11R,13R,19R)-9-chloro-32-fluoro- 26-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-19-methyl-16- oxa-5,6,18,23,25,27,31- heptaazaheptacyclo[26.3.1.1~19,23~.0~2,10~.0~3,7~.0~11,13~.0~24,29~]tritriaconta- 1(32),2,4,7,9,24,26,28,30-nonaen-17-one (Example 1.034).

[0397] Step 1. tert-Butyl (R)-3-methyl-3-(((4-nitrophenoxy)carbonyl)amino)piperidine-1- carboxylate. To a mixture of tert-butyl (3R)-3-amino-3-methyl-piperidine-1-carboxylate (1.71 g, 8.00 mmol), dichloromethane (53 mL), and N,N-diisopropylethylamine (1.5 mL, 8.8 mmol) was cooled to 0oC was added 4-nitrophenyl chloroformate (1.69 g, 8.40 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–60% EtOAc in heptane, to provide tert-butyl (R)-3-methyl-3-(((4-nitrophenoxy)carbonyl)amino)piperidine-1-carboxylate (0.94 g, 2.48 mmol, 78% yield). m / z (ESI): 402.1 (M+Na)+.

[0398] Step 2. rac-tert-Butyl (3R)-3-(((2-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate. A mixture of 2-(2-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethan- 1-ol (Intermediate B, 1.39 g, 3.48 mmol) in 2-methyltetrahydrofuran (15 mL) was cooled cooled to 0 oC. Sodium hydride (60 wt% in mineral oil, 0.21 g, 5.20 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was then added to the solution of tert-butyl (R)- 3-methyl-3-(((4-nitrophenoxy)carbonyl)amino)piperidine-1-carboxylate (0.88 g, 2.30 mmol) in THF (5 mL). The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by reversed phase chromatography on a C18 column, eluting with a gradient of 0.1% formic acid in CH3CN / H2O. The product containing fractions wereconcentrated in vacuo and the residue was diluted with DCM and basified with aqueous Na2CO3solution. The aqueous layer was extracted with DCM and the organic layer was dried over Na2SO4, filtered, and concentrated to give rac-tert-butyl (3R)-3-(((2-(2-(4-bromo-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (0.47 g, 0.73 mmol, 32% yield). m / z (ESI): 661.1 / 663.2 (M+Na)+.

[0399] Step 3. rac-tert-Butyl (3R)-3-(((2-(2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3- methylpiperidine-1-carboxylate. A suspension of rac-tert-butyl (3R)-3-(((2-(2-(4-bromo-6-chloro- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3- methylpiperidine-1-carboxylate (0.46 g, 0.72 mmol), bis(pinacolato)diborane (0.36 g, 1.40 mmol), tris(4-methoxyphenyl)phosphine (76 mg, 0.22 mmol), palladium(II) acetate (24 mg, 0.11 mmol) and cesium carbonate (0.58 g, 1.80 mmol) in ethyl acetate (6 mL) was purged with N2, then heated at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered through celite, washed with EtOAc, then concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–80% EtOAc in heptane, to provide rac-tert-butyl (3R)-3- (((2-(2-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (0.43 g, 0.62 mmol, 86% yield). m / z (ESI): 687.4 (M+H)+.

[0400] Step 4. rac-tert-Butyl (3R)-3-(((2-(2-(4-(4-(tert-butoxy)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropyl)ethoxy)carbonyl)amino)-3- methylpiperidine-1-carboxylate. A 20-mL vial was charged with 4-(tert-butoxy)-7-chloro-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (Intermediate A, 0.27 g, 0.65 mmol), rac-tert-butyl (3R)-3-(((2-(2-(6-chloro-1-(tetrahydro-2H-pyran- 2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5- yl)cyclopropyl)ethoxy)carbonyl)amino)-3-methylpiperidine-1-carboxylate (0.43 g, 0.62 mmol), potassium phosphate (0.40 g, 1.90 mmol), cataCXium A Pd G3 (CAS No.1651823-59-4) (68 mg, 0.093 mmol), 2-methyltetrahydrofuran (5 mL) and water (0.5 mL). The reaction mixture was purged with nitrogen and then heated at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0–100% EtOAc in heptane, followed by reve...

Claims

What is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein; X is -CH2- or -O- Z is C-H, C-halogen, C-CN, C-C1-4alkyl, C-C1-4haloalkyl, C-C1-4alkoxy, C-C1-4haloalkoxy, C-C3-7cycloalkyl or N; Q is CH, C-halogen, C-C1-4alkyl, C-C1-4haloalkyl or N; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4alkyl, C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkylene, C2-4alkenyl, 5-7 membered heteroaryl, -S(O)2-C1-4alkyl, -S(O)2N(Rz)2, -C(O)Rz, -C(O)ORz, -C(O)N(Rz)2, -C1-4alkylene-C(O)-C1-4alkyl, -C1-4alkylene-C(O)N(Rz)2, C1-4alkylene-S(O)2-C1-4alkyl, or -S-C1-4alkyl; L2is a bond, C1-6alkylene, -O-C1-6alkylene, -S-C1-6alkylene, NRz, O or S, wherein each C1-6alkylene, -O-C1-6alkylene and -S-C1-6alkylene chain is substituted with 0-2 occurrences of R2;2. The compound or salt of claim 1, wherein the compound is a compound of Formula (I-B):or a pharmaceutically acceptable salt thereof, wherein;each Rzindependently is hydrogen or C1-4 alkyl.

3. The compound or salt of claim 1 or 2, wherein Z is N and Q is CH.

4. The compound or salt of claim 1 or 2, wherein Z is N and Q is N.

5. The compound or salt of any of claims 1-4, wherein L2is -O-methylene, -O-ethylene or -O-n- propylene substituted with 0-2 occurrences of R2.

6. The compound or salt of claim 5, wherein L2is -O-methylene substituted with 0 occurrences of R2.

7. The compound or salt of any of claims 1-6, wherein R1is heterocycloalkyl substituted with 0-3 occurrences of R’.

8. The compound or salt of claim 7, wherein R1is 7a-(hexahydro-lH-pyrrolizinyl). 5-(l- azabicyclo[3.2.0]heptanyl), 2-azetidinyl or 2-pyrrolidinyl substituted with 0-3 occurrences of R5.

9. The compound or salt of claim 8, wherein R1is 7a-(liexahydro-lH-pyrrolizinyl). 2-azetidinyl or 2-pyrrolidinyl substituted with one occurrence of R5.

10. The compound or salt of any of claims 1-9, wherein R5is halogen, -O-C2-4 alkynyl, =C(RW)2 or C1-4 alky l.

11. The compound of claim 10. wherein R5is fluorine, methyl or =C(H)(F)12. The compound or salt of claim 8, wherein L2is -O-methylene substituted with 2 occurrences of R2.

13. The compound or salt of claim 12, wherein both R2are deuterium.

14. The compound or salt of claim 8, wherein L2is -O-n-propylene substituted with two occurrences of R2.

15. The compound or salt of claim 14, wherein two geminal R2groups, together with the atom to which they are attached, form a spiro-cyclopropyl group further substituted with two occurrences of Rw.

16. The compound or salt of claim 15, wherein R1is -N(RZ)2 and both Rzare methyl.

17. The compound or salt of any of claims 1-16, wherein -18. The compound or salt of claim 17, wherein -L2-R1is19. The compound or salt of any of claims 1-18, wherein X is O.

20. The compound or salt of claim 19. wherein n is 1, m is 2 and p is 0.

21. The compound or salt of claim 19, wherein n is 1, m is 2 and p is 1.

22. The compound or salt of claim 21. wherein R5is CM alkyl .

23. The compound or salt of claim 19, wherein n is 1, m is 1 and p is 0.

24. The compound or salt of claim 19, wherein25. The compound or salt of any of claims 1-24, wherein X is -CH2-26. The compound or salt of claim 25, wherein n is 1, m is 2 and p is 0.

27. The compound or salt of claim 26, wherein28. The compound or salt of claim 25, wherein n is 1, m is 2 and p is 1.

29. The compound or salt of claim 28, wherein Rxis hydroxyl, halogen, CM haloalky 1, or C1-4 alkyl.

30. The compound or salt of claim 28, wherein31. The compound or salt of claim 25, wherein n is 1, m is 1 and p is 0.

32. The compound or salt of claim 31, wherein33. The compound or salt of claim 25, wherein n is 1, m is 1 and p is 1.

34. The compound or salt of claim 33. wherein Rxis hydroxyl, halogen or Ci.4alkyl.

35. The compound or salt of claim 34, whereinor (36. The compound or salt of claim 35, whereinis37. The compound or salt of claim 25, wherein n is 1, m is 1 and p is 2.

38. The compound or salt of claim 37, wherein one Rxis hydroxyl and the other Rxis Ci-4 alkyl.

39. The compound or salt of claim 38. wherein40. The compound or salt of claim 25, wherein n is 0 and in is 1 or m is 0 and n is 1 and p is 0.25841. The compound or salt of claim 40, wherein42. The compound or salt of claim 41, wherein (i) n is 0. m is 1 and p is 1 or (ii) m is 0, n is 1 and p is 1.

43. The compound or salt of claim 42, wherein Rxis hydroxyl, halogen, C1.4 alkyl, Ci-4 alkoxy or Ci -4 hydroxy alkylene.

44. The compound or salt of claim 43, wherein— 1— is45. The compound or salt of claim 44, whereinor46. The compound or salt of claim 25, wherein n is 0, m is 0 and p is 0.

47. The compound or salt of claim 46, wherein48. The compound or salt of any of claims 1-47, wherein L1isO' or49. The compound or salt of any of claims 1-48, wherein R1is hydrogen, hydroxyl, halogen. Ci-4 alkyl or Ci-4 alkoxy.

50. The compound or salt of claim 49. wherein R4is hydrogen or halogen.

51. The compound or salt of claim 49, wherein R4is fluorine.

52. The compound or salt of any of claims 1-51, wherein each of R6a’ Rsband R6cindependently is hydrogen, halogen, Ci-4 alkyl, Ci-4 alkoxy or Ci-4 haloalky 1.

53. The compound or salt of claim 52, wherein each of R6band R6cis hydrogen and R6ais chlorine.

54. The compound or salt of claim 52, wherein each of R6band RScis hydrogen and RSais methyl.

55. The compound or salt of any of claims 1-54. wherein R6dis hydrogen.

56. The compound or salt of any of claims 1-54. wherein R6dis -C(O)-Me57. The compound or salt of claim 1, wherein the compound is:26126259. The compound or salt of claim 1. wherein the compound is:

60. A pharmaceutical composition comprising the compound or salt according to any one of claims 1-59 and a pharmaceutically acceptable excipient.

61. A compound or salt according to any one of claims 1-59 or the pharmaceutical composition according to claim 60 for use as a medicament.

62. A compound or salt according to any one of claims 1-59 or the pharmaceutical composition according to claim 60 for use in treating cancer.

63. A compound or salt according to any one of claims 1-59 or the pharmaceutical composition according to claim 60 for use in treating cancer, wherein one or more cells of the cancer express a KRAS G12D, G12V, G12A, G12S, G12R. G13D, Q61H. Q61L, Q61R or G12C mutant protein.

64. The compound, salt or pharmaceutical composition for use of claim 62 or 63, 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.

65. A use of the compound or salt according to any one of claims 1-59 or the pharmaceutical composition according to claim 60 in the preparation of a medicament for treating cancer.

66. A use of the compound or salt according to any one of claims 1-59 or the pharmaceutical composition according to claim 60 in the preparation of a medicament for treating cancer, wherein one or more cells of the cancer express a KRAS G12D. G12V, G12A. G12S, G12R, G13D. Q61H, Q61L, Q61R or G12C mutant protein.

67. The use according to claim 65 or 66, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer ty pes, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

68. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or salt according to any one of claims 1-59 or a pharmaceutical composition according to claim 60.

69. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or salt according to any one of to any one of claims 1-59 or a pharmaceutical composition according to claim 60. wherein one or more cells of the cancer express a KRAS G12D. G12V, G12A. G12S. G12R, G13D. Q61H. Q61L, Q61R or G12C mutant protein.

70. The method 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, hepatobiliary7cancer, 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.

71. The method according to claim 69 or 70, 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.

72. The method according to claim 71, wherein the cancer is non-small cell lung cancer.

73. The method according to claim 71, wherein the cancer is colorectal cancer.

74. The method according to claim 71, wherein the cancer is pancreatic cancer.

75. The method according to any one of claims 68-74, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D, G12V. G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutant protein prior to administration of the compound, salt or composition.

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