Macrocyclic amino compounds as modulators of KRAS and uses therof

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 compormds, and compositions for treatment of, for example, a KRAS G12D, G12V, G12A, G12S, G12R. G13D, Q61H. Q61L, Q61R or G12C disorder.

Description

10938-WO01-SEC MACROCYCLIC AMINO COMPOUNDS AS MODULATORS OF KRAS AND USES THEROF CROSS REFERENCE TO PRIOR APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 640,102, filed April 29, 2024. FIELD

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

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

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

[0005] Attempts to develop inhibitors of mutated KRAS proteins have historically been thwarted by the absence of druggable pockets on the surface of the protein (Cox et al., 2014). In 2013, Shokat and colleagues identified covalent inhibitors of a common (O’Bryan, 2019) oncogenic mutant of 110938-WO01-SEC 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 acceptaZ is C-H, C-halogen, C-CN, C-C1-4alkyl, C-C1-4haloalkyl, C-C1-4alkoxy, C-C1-4haloalkoxy, C-C3-7cycloalkyl or N; Q is CH, C-halogen, C-C1-4 alkyl, C-C1-4 haloalkyl or N; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; q 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, C2-4haloalkenyl, 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; L3is 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; -L1-L2- is -L2, -N(Rz)C(O)-L2, -C(O)-L2-, -OC(O)-L2, -C(O)O-L2, -OC(O)-O-L2,10938-WO01-SEC -S(O)-L2, C1-4alkylene-C(O)-L2, C1-4alkylene-C(O)O-L2, -C1-4alkylene-OC(O)O-L2, -C1-4alkylene- OC(O)-L2, -C1-4alkylene-O-L2, -C1-4alkylene-S(O)2-L2, -C1-4alkylene-S-L2, -C1-4alkylene-S(O)-L2, - O-5-6 membered heteroaryl-L2, -C1-4alkylene-5-6 membered heteroaryl-L2, -C1-4hydroxyalkylene-5- 6-membered heteroaryl-L2or a 5-6 membered heteroaryl-L2; L2is C1-6alkylene, C1-6alkylene-O-, C1-6alkylene-O-C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C3-7cycloalkylene, C1-4alkylene-C3-7cycloalkylene, C1-4haloalkylene-C3-7cycloalkylene, C3-7cycloalkylene-C1-4alkylene, C1-6hydroxyalkylene or C1-6haloalkylene; 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 R2is independently halogen, deuterium, hydroxyl or C1-4 alkyl, wherein two geminal groups, together with the atom to which they are attached, form a spiro-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; A is C6-10aryl or 5-10 membered heteroaryl and is substituted with q occurrences of R6; 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, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, =C(Rw)2or -O-C2-4alkynyl; each R6independently is halogen, hydroxyl, cyano, -N(Rz)2, -C(O)Rz, -C(O)ORz, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4alkynyl, 5-7 membered heterocyclyl or C3-6cycloalkyl or two R6taken together on adjacent carbon atoms form a C3-7cycloalkyl; each Rwindependently is C1-4alkyl, C1-4alkoxy, halogen, hydroxyl or C1-4haloalkyl; T is C1-4alkylene, -S(O)2-, -C(O)-, -C1-4alkylene-C(O)-, C1-4alkylene-S(O)2- or -S-; Rvis hydrogen, C1-4alkyl, -C(O)-C1-4alkyl, -C(O)-O-C1-4alkyl or C1-4haloalkyl Ryis C1-4alkyl, C1-4haloalkyl, hydroxyl, cyano or -N(Rz)2; and each Rzis independently 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. 310938-WO01-SEC

[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, 410938-WO01-SEC 2, 3, 4, 5, or 6 carbon atoms (or any combination of the foregoing), as well as all subgroups in the indicated range (e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, or 5-6 carbon atoms, or any combination of the foregoing ranges)). A “C1-4alkyl” includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Nonlimiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl.

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

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

[0018] The term “cycloalkyl” refers to a saturated, hydrocarbon monocyclic ring, or a saturated, hydrocarbon polycyclic ring system containing the indicated number of carbon atoms as ring members in the ring or ring system. No ring in a cycloalkyl ring or ring system has s double bond, a heteroatom, or is aromatic. When a cycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. For example, C5cycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring or ring system. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C3-510938-WO01-SEC7cycloalkyl 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., phen ) or a polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) aromatic hydrocarbon ring syste ngthe indicated number of carbon atoms. For example, C10aryl refers to an aryl group that has 10 carbon atoms in the ring system (e.g., naphthyl). When an aryl group is a polycyclic ring system, each ring in the ring system is aromatic, and no ring in the ring system contains a heteroatom. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a C6-14aryl includes aryl groups having 6-14 (e.g., 6, 10, or 14) carbon atoms in the ring or ring system (or combinations of the foregoing), as well as all subgroups in the indicated range (e.g., 6-10 or 10-14 carbon atom ring members in the ring or ring system, or combinations of the foregoing). Nonlimiting examples of aryl groups include phenyl, naphthyl, and anthracenyl.

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

[0021] The term “heterocycloalkyl” refers to a saturated, monocyclic ring or saturated, polycyclic ring system comprising carbon atoms and one or more heteroatoms (e.g., one or more of N, O, and S), and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring). When a heterocycloalkyl is a ring system, two or more rings may be joined together in a fused-, bridged-, or spiro-connected fashion. No ring in a heterocycloalkyl ring or ring system contains a double bond or is aromatic. For example, a heterocycloalkyl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to a ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heterocycloalkyl group having 5-7 total ring atoms and 1-3 heteroatoms independently selected 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 610938-WO01-SEC and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing is independently selected from N, O, and S. Nonlimiting examples of heterocycloalkyl groups include but are not limited to aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene-yl, pyrazolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, oxathiolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, dioxanyl, dithianyl, morpholinyl, thiomorpholinyl, azepanyl, hexahydro-1H-pyrrolizinyl, and 1,4- diazepanyl.

[0022] The term “heteroaryl” refers to a monocyclic aromatic ring comprising carbon and one or more heteroatoms and having the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring), or a polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) aromatic ring system having one or more heteroatoms and the indicated number of total ring atoms (the sum of carbon atoms and heteroatoms in the ring system). When a heteroaryl group is a polycyclic ring system, each ring in the ring system is aromatic. For example, a heteroaryl group having 5 total atoms and 2 heteroatoms independently selected from N, O, and S, refers to an aromatic ring having 3 carbon atoms and 2 heteroatoms, wherein each heteroatom of the ring independently is N, O, or S. Where a range is indicated, all members of that range and all subgroups within that range are envisioned. For example, a heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S refers to an aromatic ring having a total number of ring atoms in the indicated range (e.g., 5, 6, or 7 total atoms, or any combination of the foregoing), as well as encompassing all subgroups (e.g., 5-6 or 6-7 total ring atoms, or any combination of the foregoing), wherein 1, 2, or 3 of the atoms in the ring are heteroatoms and each heteroatom is independently selected from N, O, and S. A heteroaryl having 5-7 total ring atoms and 1-3 heteroatoms independently selected from N, O, and S encompasses rings containing, for example, 4 carbon atoms and 1 heteroatom, 3 carbon atoms and 2 heteroatoms, 2 carbon atoms and 3 heteroatoms, 5 carbon atoms and 1 heteroatom, 4 carbon atoms and 2 heteroatoms, 3 carbon atoms and 3 heteroatoms, 6 carbon atoms and 1 heteroatom, 5 carbon atoms and 2 heteroatoms, and 4 carbon atoms and 3 heteroatoms, wherein each heteroatom of the foregoing independently is selected from N, O, and S. Nonlimiting examples of monocyclic heteroaryl groups include: pyrrolyl, furanyl, thiophene-yl (or thienyl), pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (or pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. Nonlimiting examples of bicyclic heteroaryl groups include benzofuranyl, benzothienyl, benzimidazolyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, furopyridinyl (e.g., furo[2,3-b]pyridinyl), imidazopyridinyl (imidazo[4,5-b]pyridinyl), imidazothiazolyl (e.g., imidazo[4,5-d]thiazolyl), indolizinyl, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl (e.g., oxazolo[5,4-b]pyridinyl), phthalazinyl, pteridinyl, purinyl, 710938-WO01-SEC pyrrolopyridyl (e.g., pyrrolo[2,3-b]pyridyl), quinolinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, cinnolinyl, isoquinolyl, pyrazolopyridinyl (e.g., pyrazolo[3,4-b]pyridinyl), and thiazolopyrindinyl (e.g., thiazolo[5,4-b]pyridinyl). Nonlimiting examples of tricyclic heteroaryl groups include carbazolyl, 4,5-benzindolyl, dibenzofuranyl, dibenzothiophene-yl, phenazinyl, and acridinyl.

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

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

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

[0026] The term “hydroxyalkylene” or “hydroxylalkylene” refers to a saturated straight chain alkylene or saturated branched chain alkylene containing the indicated number of carbon atoms substituted with one or two hydroxy groups in place of a hydrogen, provided that if two hydroxy groups are present they are not both on the same carbon atom. Nonlimiting examples hydroxyalkylene include but are not limited to, hydroxymethylene, 2-hydroxyethylene, 2-hydroxypropylene, 3- hydroxypropylene, l-(hydroxymethyl)-2- methylpropylene, 2-hydroxybutylene, 3-hydroxybutylene, 4- 810938-WO01-SEC 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 ato 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 C1-910938-WO01-SEC4deuteroalkyl 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 cyclohexylenering cyclohexylene ring can be depicted as, for example

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

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

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

[0040] The term “vicinal” refers to substitcent atoms along a chain or within a ring. Vicinal R groups along a chain and within a ring can be depicted 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 1010938-WO01-SEC groups along a chain and within a ring can be depicte , 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 are detailed in Greene, T. W., Wuts, P. G, “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book, such as Wuts, P.G.M. and Greene, T.W. “Greene’s Protective Groups in Organic Synthesis,” Fourth Edition, John Wiley & Sons, Hoboken: 2007).

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

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

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

[0046] The term “pharmaceutically acceptable salt” refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound and that is not biologically or otherwise undesirable for its end use. Pharmaceutically acceptable salts include, for example, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or formed with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid). Pharmaceutically acceptable salts also include, for example, salts formed when an acidic proton present in the parent compound either is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or associates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N- 1110938-WO01-SEC 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 -L1-L2- as provided herein are to be inserted into Formula (I) such that the left hand side is attached to the nitrogen- containing heterocycloalkyl group and the right hand side is attached to the aryl ring. For example, - is10938-WO01-SEC Example 1-001-2.COMPOUNDS OF FORMULA (I)

[0051] Provided herein as Embodiment 1 are compounds of Formula (I): or a pharmaceutically acceptaZ 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; q 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, C2-4haloalkenyl, 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; L3is 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; -L1-L2- is -L2, -N(Rz)C(O)-L2, -C(O)-L2-, -OC(O)-L2, -C(O)O-L2, -OC(O)-O-L2, e- 2, -10938-WO01-SEC O-5-6 membered heteroaryl-L2, -C1-4alkylene-5-6 membered heteroaryl-L2, -C1-4hydroxyalkylene-5- 6-membered heteroaryl-L2or a 5-6 membered heteroaryl-L2; L2is C1-6alkylene, C1-6alkylene-O-, C1-6alkylene-O-C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C3-7cycloalkylene, C1-4alkylene-C3-7cycloalkylene, C1-4haloalkylene-C3-7cycloalkylene, C3-7cycloalkylene-C1-4alkylene, C1-6hydroxyalkylene or C1-6haloalkylene; 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 R2is independently 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; A is C6-10aryl or 5-10 membered heteroaryl and is substituted with q occurrences of R6; 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 R6independently is halogen, hydroxyl, cyano, -N(Rz)2, -C(O)Rz, -C(O)ORz, C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C2-4alkynyl, 5-7 membered heterocyclyl or C3-6cycloalkyl or two R6taken together on adjacent carbon atoms form a C3-7cycloalkyl; each Rwindependently is C1-4alkyl, C1-4alkoxy, halogen, hydroxyl or C1-4haloalkyl; T is C1-4alkylene, -S(O)2-, -C(O)-, -C1-4alkylene-C(O)-, C1-4alkylene-S(O)2- or -S-; Rvis hydrogen, C1-4alkyl, -C(O)-C1-4alkyl, -C(O)-O-C1-4alkyl or C1-4haloalkyl Ryis C1-4alkyl, C1-4haloalkyl, hydroxyl, cyano or -N(Rz)2; and each Rzis independently hydrogen or C1-4alkyl.

[0052] Provided herein as Embodiment 2 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (I): or a pharmaceutically accepta1410938-WO01-SEC 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; q 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, C2-4haloalkenyl, 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, -C1-4 alkylene-C(O)N(Rz)2, C1-4 alkylene-S(O)2-C1-4alkyl, or -S-C1-4alkyl; L3is 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; -L1-L2- is -L2, -N(Rz)C(O)-L2, -C(O)-L2-, -OC(O)-L2, -C(O)O-L2, -OC(O)-O-L2, -OC(S)-O-L2, -O-L2, -N(Rz)C(O)O-L2, -OC(O)N(Rz)-L2, -N(Rz)-L2, -S(O)2-L2, -S-L2, -C1-4alkylene-OC(O)-L , -C1-4alkylene-O-L , -C1-4alkylene-S(O)2-L , -C1-4alkylene-S-L , -C1-4alkylene-S(O)-L2, - O-5-6 membered heteroaryl-L2, -C1-4 alkylene-5-6 membered heteroaryl-L2, -C1-4 hydroxyalkylene-5- 6-membered heteroaryl-L2or a 5-6 membered heteroaryl-L2; L2is C1-6alkylene, C1-6alkylene-O-, C1-6alkylene-O-C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C3-7cycloalkylene, C1-4alkylene-C3-7cycloalkylene, C1-4haloalkylene-C3-7cycloalkylene, C3-7cycloalkylene-C1-4alkylene, C1-6hydroxyalkylene or C1-6haloalkylene; 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 R2is independently 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; A is C6-10aryl or 5-10 membered heteroaryl and is substituted with q occurrences of R6; 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 R6independently is 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 two R6taken together on adjacent carbon atoms form a C3-7cycloalkyl; 1510938-WO01-SEC each Rwindependently is C1-4alkyl, C1-4alkoxy, halogen, hydroxyl or C1-4haloalkyl; T is C1-4alkylene, -S(O)2-, -C(O)-, -C1-4alkylene-C(O)-, C1-4alkylene-S(O)2- or -S-; Rvis hydrogen, C1-4alkyl, -C(O)-C1-4alkyl, -C(O)-O-C1-4alkyl or C1-4haloalkyl Ryis C1-4alkyl, C1-4haloalkyl, hydroxyl, cyano or -N(Rz)2; and each Rzis independently hydrogen or C1-4alkyl.

[0053] 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 acceptaZ, Q, p, q, Rx, L2, L1, L3, R1, R2, R4, R5, R6, Rw, Rv, T, Ryand Rzare as defined above for Formula (I).

[0054] Provided herein as Embodiment 4 is the compound or salt of Embodiment 1, wherein the compound is a compound of Formula (III): or a pharmaceutically acceptae sa o sa compoun , w ere n , Z, Q, p, q, Rx, L2, L1, L3, R1, R2, R4, R5, R6, Rw, Rv, T, Ryand Rzare as defined above for Formula (I).

[0055] Provided herein as Embodiment 5 is the compound or salt of any of Embodiments 1-4, wherein Z is C-H, C-F, C-CN, C-CH3, C-CF3, C-OMe, C-Cl or N. Provided herein as Embodiment 6 is the compound or salt of Embodiment 5, wherein Z is N. Provided herein as Embodiment 7 is the compound or salt of Embodiment 5, wherein Z is CH. Provided here as Embodiment 8 is the compound or salt of Embodiment 5, wherein Z is CF. 1610938-WO01-SEC

[0056] Provided herein as Embodiment 9 is the compound or salt of any of Embodiments 1-8, wherein Q is CH or N. Provided herein as Embodiment 10 is the compound or salt of Embodiment 9, wherein Q is CH. Provided herein as Embodiment 11 is the compound or salt of Embodiment 9, wherein Q is N.

[0057] Provided herein as Embodiment 12 is the compound or salt of any of Embodiments 1-4, wherein Z is N and Q is CH. Provided herein as Embodiment 13 is the compound or salt of any of Embodiments 1-4, wherein Z is N and Q is N.

[0058] Provided herein as Embodiment 14 is the compound or salt of any of Embodiments 1-13, wherein L3is -O-methylene, -O-ethylene or -O-n-propylene substituted with 0-2 occurrences of R2. Provided herein as Embodiment 15 is the compound or salt of Embodiment 14, wherein L3is -O- methylene substituted with 0 occurrences of R2. Provided herein as Embodiment 16 is the compound or salt of Embodiment 15, wherein R1is heterocycloalkyl substituted with 0-3 occurrences of R5.

[0059] Provided herein as Embodiment 17 is the compound or salt of Embodiment 16, wherein R1is 7a-(hexahydro-1H-pyrrolizinyl) substituted with 0-3 occurrences of R5. Provided herein as Embodiment 18 is the compound or salt of Embodiment 17, wherein R1is unsubstituted 7a- (hexahydro-1H-pyrrolizinyl).

[0060] Provided herein as Embodiment 19 is the compound or salt of Embodiment 17, wherein R1is 7a-(hexahydro-1H-pyrrolizinyl) substituted with one occurrence of R5. Provided herein as Embodiment 20 is the compound or salt of Embodiment 19, wherein R5is halogen. Provided herein as Embodiment 21 is the compound or salt of Embodiment 19, wherein R5is fluorine.

[0061] Provided herein as Embodiment 22 is the compound or salt of any of Embodiments 14-21, wherein . Provided herein as Embodiment 23 is the compound or salt ofEmbodiment 22, wherein .

[0062] Provided hereihe compound or salt of any of Embodiments 1-23, wherein n is 1 and m is 1. Provided herein as Embodiment 25 is the compound or salt of Embodiment 24, wherein p is 0. Provided herein as Embodiment 26 is the compound or salt of Embodiment 25, wherein Rvis hydrogen or C1-4 alkyl. Provided herein as Embodiment 27 is the compound or salt of Embodiment 26, wherein Rvis methyl. Provided herein as Embodiment 28 is the compound or salt of Embodiment 26, wherein Rvis hydrogen. Provided herein as Embodiment 29 is the compound or salt of Embodiment 25, wherein Rvis -C(O)-C1-4alkyl. Provided herein as Embodiment 30 is the compound or salt of Embodiment 29, wherein Rvis -C(O)-CH3. 1710938-WO01-SEC

[0063] Provided herein as Embodiment 31 is the compound or salt of Embodiment 25, wherein . Provided herein as Embodiment 32 is the compound or salt ofEmbodiment 31, wherein .

[0064] Provided herei nd or salt of Embodiment 25, wherein. Provided herein as Embodiment 34 is the compound or salt ofEmbodiment 33, wherein . Provided herein as Embodiment 35 isthe compound or salt of Embodiment 33, wherei .

[0065] Provided herein as Embodiment 36 isbodiments 1-35, wherein n is 1 and m is 2. Provided herein as Embodiment 37 is the compound or salt of Embodiment 36, wherein p is 0. Provided herein as Embodiment 38 is the compound or salt of Embodiment 37, wherein Rvis hydrogen. Provided herein as Embodiment 39 is the compound or salt of Embodiment 37, wherein Rvis -C(O)-C1-4alkyl. Provided herein as Embodiment 40 is the compound or salt of Embodiment 39 wherein Rvis -C(O)-CH3.

[0066] Provided herein as Embodiment 41 is the compound or salt of any of Embodiments 36-38, . Provided herein as Embodiment 42 is the compoundor salt of Embodiment 41, wherein . Provided herein as1810938-WO01-SEC Embodiment 43 is the compound or salt of Embodiment 41, wherei is. Provided herein as Embodiment 44 is the compound or salt of any of Embodiments 39-. Provided herein as Embodiment 45 is thecompound or salt of Embodiment 44, wherei dedherein as Embodiment 46 is the compound or salt of Embodiment 44, where is.vided herein as Embodiment 47 is the compound or salt of Embodiment 36, wherein p is 1. Provided herein as Embodiment 48 is the compound or salt of Embodiment 47, wherein Rxis C1-4alkyl. Provided herein as Embodiment 49 is the compound or salt of Embodiment 48, wherein Rxis methyl. Provided herein as Embodiment 50 is the compound or salt of Embodiment 49, wherein Rvis hydrogen.

[0068] Provided herein as Embodiment 51 is the compound or salt of any of Embodiments 47-50, wherein . Provided herein as Embodiment 52 is the compound1910938-WO01-SEC or salt of Embodiment 51, wherein . Provided herein asEmbodiment 53 is the compound or salt of Embodiment 51, wherei is. rovided herein as Embodiment 54 is the compound or salt of any of Embodiments 1-53,wherein -L1-L2- is -methylene-O-L2. Provided herein as Embodiment 55 is the compound or salt of Embodiment 54, wherein L2is n-butylene.

[0070] Provided herein as Embodiment 56 is the compound or salt of Embodiment 54, wherein -L1-L2- is . Provided herein as Embodiment 57 is the compound or salt ofEmboidment 56, wherein -L1-L2- i . Provided herein as Embodiment 58 is the compound o2-L - is . Provided herein as Embodiment 59 is the compound or salt of Embodiment57, wherein .

[0071] Pr0 is the compound or salt of any of Embodiments 1-53, wherein -L1-L2- is -O-C(O)-O-L2. Provided herein as Embodiment 61 is the compound or salt of Embodiment 60, wherein L2is ethylene or n-propylene.

[0072] Provided herein as Embodiment 62 is the compound or salt of Embodiment 60, wherein - . Provided herein as Embodiment 63 is thecompound or salt of Embodiment 62, wherein -L1-L2- i . Provided herein asEmbodiment 64 is the compound or salt of Embodiment 62, wherein -L1-L2- i .2010938-WO01-SEC

[0073] Provided herein as Embodiment 65 is the compound or salt of any of Embodiments 1-64, wherein A is C6-10aryl. Provided herein as Embodiment 66 is the compound or salt of Embodiment 65, wherein A is phenyl or naphthyl. Provided herein as Embodiment 67 is the compound or salt of Embodiment 66, wherein q is 0.

[0074] Provided herein as Embodiment 68 is the compound or salt of Embodiment 66, wherein q is 1. Provided herein as Embodiment 69 is the compound or salt of Embodiment 68, wherein R6is C1-4alkyl, hydroxyl, halogen or C1-4haloalkyl. Provided herein as Embodiment 70 is the compound or salt of Embodiment 69, wherein R6is halogen. Provided herein as Embodiment 71 is the compound or salt of Embodiment 70, wherein R6is fluoro or chloro.

[0075] Provided herein as Embodiment 72 is the compound or salt of Embodiment 66, wherein q is 2. Provided herein as Embodiment 73 is the compound or salt of Embodiment 72, wherein each R6is independently C1-4alkyl, hydroxyl, halogen or C1-4haloalkyl. Provided herein as Embodiment 74 is the compound or salt of Embodiment 73, wherein each R6is independently hydroxyl or halogen. Provided herein as Embodiment 75 is the compound or salt of Embodiment 74, wherein one R6is hydroxyl and the other R6is fluoro.

[0076] Provided herein as Embodiment 76 is the compound or salt of any of Embodiments 1-64, 7 isthe compound or salt of Embodiment 76, wherei . Provided herein asded .4, wherein A is 5-10 membered heteroaryl. Provided herein as Embodiment 81 is the compound or salt 2110938-WO01-SEC of Embodiment 80, wherein A is 4-indazolyl. Provided herein as Embodiment 82 is the compound or salt of Embodiment 81, wherein q is 0.

[0078] Provided herein as Embodiment 83 is the compound or salt of Embodiment 81, wherein q is 1. Provided herein as Embodiment 84 is the compound or salt of Embodiment 83, wherein R6is C1-4alkyl, halogen or C1-4haloalkyl. Provided herein as Embodiment 85 is the compound or salt of Embodiment 84, wherein R6is hydrogen, C1-4alkyl or halogen. Provided herein as Embodiment 86 is the compound or salt of Embodiment 85, wherein R6is fluoro. Provided herein as Embodiment 87 is the compound or salt of Embodiment 85, wherein R6is chloro. Provided herein as Embodiment 88 is the compound or salt of Embodiment 85, wherein R6is methyl. Provided herein as Embodiment 89 is the compound or salt of Embodiment 85, wherein R6is ethyl. Provided herein as Embodiment 90 is the compound or salt of Embodiment 85, wherein R6is hydrogen.

[0079] Provided herein as Embodiment 91 is the compound or salt of Embodiment 72, wherein q is 2. Provided herein as Embodiment 92 is the compound or salt of Embodiment 91, wherein R6is halogen or 5-7 membered heterocyclyl. Provided herein as Embodiment 93 is the compound or salt of Embodiment 92, wherein one R6is halogen and the other R6is 5-7 membered heterocyclyl. Provided herein as Embodiment 94 is the compound or salt of Embodiment 93, wherein one R6is chloro and the other R6is 2-tetrahydropyranyl.

[0080] Provided herein as Embodiment 95 is the compound or salt of any of Embodiments 1-64, . 4,wherein . Providedherein as Embodiment 97 is the compound or salt of Embodiment 96, where or2210938-WO01-SEC 96, ofEmbodiment 96, wherei . Provided herein as Embodiment 100 is thecompound or salt of Embodiment 95, wherei .

[0082] Provided herein as Embodiment 1 r salt of any of Embodiments 1-100, 4wherein R is hydrogen, hydroxyl, halogen, C1-4alkyl or C1-4alkoxy. Provided herein as Embodiment 102 is the compound or salt of Embodiment 101, wherein R4is halogen or C1-4alkyl. Provided herein as Embodiment 103 is the compound or salt of Embodiment 101, wherein R4is fluorine. Provided herein as Embodiment 104 is the compound or salt of Embodiment 101, wherein R4is methyl.

[0083] Provided herein as Embodiment 105 is the compound or salt of Embodiment 1, wherein the compound is: Table 1 Compound Compound Compound ,2310938-WO01-SEC Compound Compound Compound , , , ,2410938-WO01-SEC Compound Compound Compound , ,

[0084] Provided herein as Embodiment 106 is the compound or salt of Embodiment 1, wherein the the10938-WO01-SEC .. Provided herein as Embodiment 109 is the.compound . Provided herein as Embodiment 111 is thecompound or salt of Embodiment 1, wherein the compoun . Provided herein as Embodiment 112 is the compound or sa2610938-WO01-SEC compound . Provided herein as Embodiment 113 is thecompound or salt of Embodiment 1, wherein the compoun . Provided herein as Embodiment 114 is the compound or scompound . Provided herein as Embodiment 115 is thecompound or salt of Embodiment 1, wherein the compoun . Provided herein as Embodiment 116 is the compound or sa. Provided herein as Embodiment 117 is thecompound or salt of Embodiment 1, wherein the compoun .2710938-WO01-SEC Provided herein as Embodiment 118 is the compound or salt of Embodiment 1, wherein the . Provided herein as Embodiment 119 is the.. Provided herein as Embodiment 121 is thecompound or salt of Embodiment 1, wherein the compoun . Provided herein as Embodiment 122 is the compound or sacompound . Provided herein as Embodiment 123 is the2810938-WO01-SEC compound or salt of Embodiment 1, wherein the compoun . Provided herein as Embodiment 124 is the compound or sacompound . Provided herein as Embodiment 125 is thecompound or salt of Embodiment 1, wherein the compoun . Provided herein as Embodiment 126 is the compound or sa. Provided herein as Embodiment 127 is the2910938-WO01-SEC compound or salt of Embodiment 1, wherein the compoun . Provided herein as Embodiment 128 is the compound or sa. Provided herein as Embodiment 129 is thecompound or salt of Embodiment 1, wherein the compoun .

[0085] It is understood that selections of values of eachformation of stable or chemically feasible compounds. Stereoisomers

[0086] 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, 3010938-WO01-SEC 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.

[0087] If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of the structure. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated, unless otherwise noted. Forexample,represent . Similarly, for example, the chemicalname (4R)-4-methoxy-5-meth oindole 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.

[0088] 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.

[0089] 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 3110938-WO01-SEC 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

[0090] As known by those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes other tautomers of said structural formulrepresents . Similarly, for example, the chemical name (4R,5R)-4- methoxy- o-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

[0091] 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-labelled compounds of the compounds disclosed herein, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium (2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances. As such, the term “deuterated” refers to the substitution of one or more hydrogen atoms with one or more deuterium atoms on a particular structure or functional group. 3210938-WO01-SEC Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. Isotopically- labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying GENERAL SYNTHETIC PROCEDURES and EXAMPLES sections using an appropriate isotopically-labeled reagent in place of the non-labelled reagent previously employed. BIOLOGICAL ACTIVITY

[0092] In some cases, the compounds or salts disclosed herein (such as compounds of Formula (I), Formula (II) or Formula (III), or compounds listed in Table 1 or compounds of Embodiments 1-129,  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 Couple Exchange assay, AsPC-1 p-ERK assay, AsPC-1 CTG assay or the SW620 CTG assay, described in “SECTION 3: Biochemical and Cellular Assays.” In some cases, the compounds disclosed herein, and pharmaceutically acceptable salts of the foregoing, have an IC50value of between 0.001 to 0.200 µM. FORMULATION AND ROUTE OF ADMINISTRATION

[0093] While it may be possible to administer a compound disclosed herein alone in the uses described, the compound administered normally will be present as an active ingredient in a pharmaceutical composition. Thus, further provided herein is a pharmaceutical composition comprising a compound or salt disclosed herein (such as compounds of Formula (I), Formula (II) or Formula (III), or compounds listed in Table 1 or compounds of Embodiments 1-129, 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. 3310938-WO01-SEC

[0094] 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.

[0095] 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.

[0096] 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.

[0097] Provided herein as Embodiment 130 is pharmaceutical composition comprising the compound or salt of any one of Embodiments 1 to 129, and a pharmaceutically acceptable excipient. METHODS OF USE

[0098] The compounds described herein (such as compounds of Formula (I), Formula (II) or Formula (III), or compounds listed in Table 1 or compounds of Embodiments 1-129, 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 3410938-WO01-SEC 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).

[0099] 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.

[0100] In several embodiments, as disclosed elsewhere herein, a method of treating a patient is provided. In several embodiments, the method comprises administering a therapeutic amount of a compound or salt disclosed herein (such as compounds of Formula (I), Formula (II) or Formula (III), or compounds listed in Table 1 or compounds of Embodiments 1-129, or a pharmaceutically acceptable salt of any of the foregoing) to a patient.

[0101] 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.

[0102] Another aspect of the disclosure provides a compound or salt disclosed herein (such as compounds of Formula (I), Formula (II) or Formula (III), or compounds listed in Table 1 or compounds of Embodiments 1-129, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein, for use in treating cancer.

[0103] 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.

[0104] 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.

[0105] 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 3510938-WO01-SEC non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is colorectal cancer. In some cases, the cancer is pancreatic cancer.

[0106] Provided herein as Embodiment 131 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 129, or the composition of Embodiment 130.

[0107] Provided herein as Embodiment 132 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 129, or the composition of Embodiment 130, wherein one or more cells express KRAS G12D mutant protein.

[0108] Provided herein as Embodiment 133 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 129, or the composition of Embodiment 130, wherein one or more cells express KRAS G12V mutant protein.

[0109] Provided herein as Embodiment 134 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 129, or the composition of Embodiment 130, wherein one or more cells express KRAS G12A mutant protein.

[0110] Provided herein as Embodiment 135 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 129, or the composition of Embodiment 130, wherein one or more cells express KRAS G12S mutant protein.

[0111] Provided herein as Embodiment 136 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 129, or the composition of Embodiment 130, wherein one or more cells express KRAS G13D mutant protein.

[0112] Provided herein as Embodiment 137 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 129, or the composition of Embodiment 130, wherein one or more cells express KRAS Q61H mutant protein.

[0113] Provided herein as Embodiment 138 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 3610938-WO01-SEC compound according of any one of Embodiments 1 to 129, or the composition of Embodiment 130, wherein one or more cells express KRAS Q61L mutant protein.

[0114] Provided herein as Embodiment 139 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 129, or the composition of Embodiment 130, wherein one or more cells express KRAS Q61R mutant protein.

[0115] Provided herein as Embodiment 140 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 129, or the composition of Embodiment 130, wherein one or more cells express KRAS G12R mutant protein.

[0116] Provided herein as Embodiment 141 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 129, or the composition of Embodiment 130, wherein one or more cells express KRAS G12C mutant protein.

[0117] Provided herein as Embodiment 142 is the method according to any one of embodiments 131-141, 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.

[0118] Provided herein as Embodiment 143 is the method according to Embodiment 142, 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 144 is the method according to Embodiment 143, wherein the cancer is non-small cell lung cancer. Provided herein as Embodiment 145 is the method according to Embodiment 143, wherein the cancer is colorectal cancer. Provided herein as Embodiment 146 is the method according to Embodiment 143, wherein the cancer is pancreatic cancer.

[0119] Provided herein as Embodiment 147 is the compound or salt of any one of Embodiments 1 to 129, or the pharmaceutical composition of Embodiment 130 for use as a medicament.

[0120] Provided herein as Embodiment 148 is the compound or salt of any one of Embodiments 1 to 129, or the pharmaceutical composition of Embodiment 130 for use in the treatment of cancer. 3710938-WO01-SEC

[0121] Provided herein as Embodiment 149 is the use of the compound or salt of any one of Embodiments 1 to 129, or the pharmaceutical composition of Embodiment 130, for the manufacture of a medicament for the treatment of cancer.

[0122] Provided herein as Embodiment 150 is the use of the compound or salt of any one of Embodiments 147 to 149, 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.

[0123] Provided herein as Embodiment 151 is the method according to Embodiment 150, 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 152 is the method according to Embodiment 151, wherein the cancer is non-small cell lung cancer. Provided herein as Embodiment 153 is the method according to Embodiment 151, wherein the cancer is colorectal cancer. Provided herein as Embodiment 154 is the method according to Embodiment 151, wherein the cancer is pancreatic cancer. Combination therapy

[0124] The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound or salt disclosed herein (such as compounds of Formula (I), Formula (II) or Formula (III), or compounds listed in Table 1 or compounds of Embodiments 1-129, or a pharmaceutically acceptable salt of any of the foregoing). In one aspect, such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect. See, e.g., See, e.g., U.S. Patent No.10,519,146 B2, issued December 31, 2019; specifically, the sections from column 201 (line 37) to column 212 (line 46) and column 219 (line 64) to column 220 (line 39), which are herewith incorporated by reference.

[0125] 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, 3810938-WO01-SEC FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF18A inhibitor, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PI3K inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agent. In some cases, the second compound is administered as a pharmaceutically acceptable salt. In some cases, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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), 3910938-WO01-SEC 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.

[0130] 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.

[0131] 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.

[0132] 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]).

[0133] 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.

[0134] 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.

[0135] 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. 4010938-WO01-SEC

[0136] In yet another embodiment the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti- HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).

[0137] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody.

[0138] 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).

[0139] 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).

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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- 4110938-WO01-SEC 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0148] 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.

[0149] 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.

[0150] 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. 4210938-WO01-SEC

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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. .

[0156] 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.

[0157] 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- 4310938-WO01-SEC (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).

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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- 4410938-WO01-SEC thiazolidine-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H- purin-6-amine).

[0164] 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.

[0165] 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).

[0166] 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.

[0167] 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). 4510938-WO01-SEC

[0168] 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).

[0169] 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).

[0170] 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- 4610938-WO01-SEC 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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). 4710938-WO01-SEC

[0176] 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.

[0177] 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

[0178] 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.

[0179] 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.

[0180] In general, the compounds of Formula (I) can be synthesized according to Schemes I-III as shown below: 4810938-WO01-SEC

[0181] Compounds of Formula (I), (II), (III) and (I-1) can be prepared according to Scheme I. In step A, compound (I-2) undergoes SNAr reaction with 2,2,2-trifluoroethanol in the presence of a base such as KOt-Bu in a solvent such as THF to give compound (I-3). In step B, compound (I-3) undergoes SNAr reaction with R1-L3H in the presence of a base such as NaH, DBU, DIEA or TEA in a solvent such as 1,4-dioxane, THF or 2-MeTHF to give compound (I-4). In step C, compound (I-4) is coupled with an organometallic reagent such as (Bu3Sn)2in the presence of a catalyst such as PCy3Pd G2 in the presence of LiCl in a solvent such as 1,4-dioxane to give compound (I-5). In step D, compound (I-5) undergoes SNAr with an optionally substituted cyclic amine or aliphatic amine compound (I-6) in the presence of a base such as DIEA or TEA in a solvent such as DMSO, CH3CN or THF to give compound (I-7). In step E, compound (I-7) undergoes Stille-coupling with compound (I-8) in the presence of a catalyst such as cataCXium A Pd G3 in the presence of CuI and LiCl in a solvent such as DMF to give compound (I-9). In step F, compound (I-9) is treated with CDI, followed by treatment with a desilylating reagent such as TBAF in solvent such as THF or 2-MeTHF to give compounds of Formula (I-1). 4910938-WO01-SEC

[0182] Compounds of Formula (I), (II), (III) and (II-1) can be prepared according to Scheme II. In step A, compound (II-2) undergoes SNAr reaction with an optionally substituted cyclic amine or aliphatic amine compound (II-3) bearing an alcohol or a protected amine in a solvent such as DMF, acetonitrile or THF and in the presence of a base such as Hunig’s base (DIEA) and a coupling agent such as HATU to give compound (II-4). In step B, compound (II-4) is coupled with an organometallic reagent or a boronic acid (ester) attached to an aryl or heteroaryl ring bearing a terminal TBS protected alcohol (II-5) to give compound (II-6). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-MeTHF, THF, dioxane, 1,2-DME and water, and a catalyst such as cataCXium A Pd G3, with or without base such as potassium phosphate or sodium carbonate. In step C, compound (II-6) is treated with CDI, followed by treatment with a desilylating reagent such as TBAF in solvent such as THF to give compounds of Formula (II-1). 5010938-WO01-SEC

[0183] Compounds of Formula (I), (II), (III) and (III-1) can be prepared according to Scheme III. In step A, compound (III-2) undergoes etherfication reaction with a mesylate compound (III-3) in a solvent such as DMA or THF in the presence of a base such as NaH to give compound (III-4). In step B, compound (III-4) undergoes borylation reaction with B2Pin2and a palladium source such as Pd(OAc)2and a ligand such as tris(4-methoxyphenyl)phosphine in a solvent such as EtOAc and in the presence of a base such as Cs2CO3to give compound (III-5). In step C, compound (III-5) undergoes a Suzuki coupling reaction with compound (III-6). This coupling reaction proceeds in a solvent or mixture of solvents such as 2-MeTHF, THF, DME, 1,4-dioxane and water, and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate to give compound (III-7). In step D, compound (III-7) is treated with an acid, such as HCl in a solvent such as 1,4-dioxane or TFA in a solvent such as DCM to give compound (III-8). In step E, compound (III-8) is cyclized 5110938-WO01-SEC under conditions such as BrOP or PyBOP in the presence of a base such as DIEA in a solvent such as CH3CN and DMSO to give compounds of Formula (III-1).

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

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

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

[0187] This section provides specific examples of compounds of Formula (I) and methods of making the same. List of Abbreviations Ac acetyl5210938-WO01-SEC DCM dichloromethane DMA N,N-dimethylacetamide5310938-WO01-SEC NIS N-iodosuccinimide NMR nuclear magnetic resonance

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

[0189] Chromatography: Unless otherwise indicated, product-containing residues were purified by passing the material or concentrate through (a) Biotage High Capacity D column or (b) ISCO RediSep 5410938-WO01-SEC Gold High Performance column or (c) ISCO RediSep Rf HP C18 Gold column or (d) Biotage Isolute SCX-2 column; and eluting the product off the column with a solvent gradient as indicated.

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

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

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

[0193] Fluorine-19 NMR Spectra: Unless otherwise indicated, all19F NMR spectra were collected on a Bruker NMR instrument at 300, 400 or 500 MHz. SECTION 1: Synthesis of Intermediates

[0194] Provided in this section is the synthesis of various intermediates used to prepare compounds of Formula (I). All starting materials are either commercially available from Sigma-Aldrich, Combi- Blocks, Enamine, PharmaCore, PharmaBlock, Synnovator, Chemscene, AA blocks, Oakwood or Ambeed, or similar vendors, unless otherwise noted, or known in the art and may be synthesized by employing known procedures using ordinary skill. A Intermediates Intermediate A-1: 4-(Benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. 5510938-WO01-SEC2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 198 mmol) in THF (1.5 L) was added phenylmethanol (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 (1.5 L) and extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (2 x 500 mL), 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)+.

[0196] Step 2: 4-(Benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine, Intermediate A-1. 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 DIEA (31.9 g, 247 mmol), and the mixture was stirred at 100 °C for 2 h. Then, the reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated. The crude product was triturated with MBTE (100 mL) at 25 ℃ for 30 min to provide Intermediate A-1 (70 g, 79% yield). m / z (ESI): 447.1 (M+H)+. Intermediate A-2: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine.

[0197] 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 5610938-WO01-SEC added t-BuOK (1 M in THF, 190 mL, 190 mmol) dropwise at -60 ℃ and the reaction mixture was stirred at -60 °C for 2 h. The mixture was diluted with 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 rt 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).

[0198] Step 2: 4-(tert-Butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(tert-butoxy)-2,7- dichloro-8-fluoropyrido[4,3-d]pyrimidine (50.0 g, 172 mmol) and 4Å MS (10 g) in 1,4-dioxane (1 L) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (30.2 g, 190 mmol) and DIPEA (60.0 g, 431 mmol) in sequence. Then the mixture was stirred at 80 °C for 5 h. After cooling to rt, the reaction mixture was diluted with 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 rt for 1 h. The suspension was filtered, and the cake was concentrated under reduced pressure to give Intermediate A-2 (40 g, 97 mmol, 56% yield). m / z (ESI): 413.2 / 415.2 (M+H)+.   Intermediate A-3: rac-tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepane-1- carboxylate.

[0199] Step 1: 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (HBr salt). A racemic mixture of Intermediate A-1 (54 g, 121 mmol) with HBr (5.1 M in AcOH, 164 mL, 121 mmol) and AcOH (164 mL) was degassed and purged with N2(3x) and stirred at 20 °C for 1 h under N2atmosphere. The reaction mixture was triturated with EtOAc (300 mL) at 25 ℃ for 30 min to provide 7-chloro-8-fluoro-2-(((2R,7aS)-2- 5710938-WO01-SEC fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (67 g), as an HBr salt. m / z (ESI): 359.0 (M+H)+.

[0200] Step 2: rac-tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepane-1- carboxylate, Intermediate A-3. To a solution of rac-7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (HBr salt) (5.00 g, 11.4 mmol) in THF (20 mL), was added DIEA (5.99 mL, 34.3 mmol) and HATU (6.52 g, 17.1 mmol), and the mixture was stirred at 25 °C for 30 min. Next, tert-butyl 6-hydroxy-1,4-diazepane-1- carboxylate (2.47 g, 11.4 mmol) was added, and the mixture was stirred at 25 °C for 9.5 h. Then, the reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 0-90% pet. ether in EtOAc to provide Intermediate A-3 (4.20 g, 7.60 mmol, 66% yield). m / z (ESI): 555.3 (M+H)+. Intermediate A-4: tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-6-methyl-1,4-diazepane- 1-carboxylate.[ ] ep : - o o- - uo o- - , a - - uo o e a y o- -py o - a - yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. A mixture of Intermediate A-1 (30 g, 67.1 mmol) and HBr (5.1 M in AcOH, 90 mL, 67 mmol) in AcOH (90 mL) was degassed and purged with N2(3x), and the mixture was stirred at 20 °C for 2 h under N2atmosphere. The residue was diluted with EtOAc (200 mL) and filtered, stirred with EtOAc (100 mL) for 20 min, then filtered to provide 7-chloro-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol, as an HBr salt. Stereochemistry was determined absolutely.

[0202] Step 2: tert-Butyl 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-6-methyl-1,4-diazepane-1- carboxylate, Intermediate A-4. To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 5810938-WO01-SEC 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (HBr salt) (1.00 g, 2.30 mmol), DIEA (1.60 mL, 9.1 mmol), HATU (1.74 g, 4.6 mmol) in DMF (20 mL), was added tert-butyl 6-hydroxy-6- methyl-1,4-diazepane-1-carboxylate (0.79 g, 3.43 mmol) at 20 °C. The mixture was degassed and purged with N2(3x) and stirred at 20 °C for 8 h under N2atmosphere. The reaction mixture was diluted with H2O (50 mL) 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 residue was purified by prep-TLC, eluting with a mobile phase of 25% MeOH in EtOAc to provide Intermediate A-4 (1.27 g, 2.2 mmol, 98% yield). m / z (ESI): 569.6 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.19 (br t, J=46 Hz, 1H), 5.48 (m, 1H), 4.66 -4.57 (m, 2H), 4.44 – 4.34 (m, 3H), 3.99 – 3.83 (m, 1H), 3.74 – 3.65 (m, 3H), 3.49 – 3.43 (m, 3H), 3.20 - 2.96 (m, 3H), 2.42 – 2.40 (m, 2H), 2.36 – 2.13 (m, 4H), 1.48 – 1.35 (m, 12H).

[0203] The compound in Table 1-2 was prepared following the procedure described above for Intermediate A-4, using appropriate starting materials. All starting materials are commercially available or are described herein. Table 1-1 Int. Chemical Structure N LCMS: m / z (ESI # ame+ve ion); NMR Comments - id asIntermediate A-6: tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepane-1- carboxylate. 5910938-WO01-SEC [002. To a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (40 g, 158 mmol) in THF (600 mL) was added 2,2,2-trifluoroethan-1-ol (15.1 g, 151 mmol), followed by KOtBu (1.0 M in THF, 151 mL, 151 mmol), and the mixture was stirred at -60 °C for 2 h. The residue was diluted with H2O (2 L) and extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (2 x 1 L), dried over Na2SO4, filtered, and concentrated to provide crude material containing 2,7-dichloro-8-fluoro-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine, which was used for the next step.

[0205] 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 the crude containing 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (40 g, 127 mmol) in 1,4-dioxane (400 mL) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (24.2 g, 152 mmol), followed by DIEA (55.3 mL, 316 mmol), and the mixture was stirred at 65 °C for 1.5 h. Then, the mixture was diluted by addition of H2O (4 L) at 20 °C and extracted with EtOAc (3 x 2 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was triturated with 50% pet. ether in EtOAc at 25 ℃ for 3 h 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 (38 g).

[0206] Step 3: 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7- (tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. To a solution of 7-chloro-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidine (25 g, 57 mmol) in 1,4-dioxane (500 mL) was added PCy3Pd G2 (13.5 g, 22.8 mmol) and LiCl (12.1 g, 285 mmol), then bis(tributyltin) (132 g, 228 mmol) was added under N2atmosphere and the mixture was stirred at 80 °C for 12 h. The reaction was filtered, 6010938-WO01-SEC then quenched by addition of H2O (5 L) at 20 °C and extracted with EtOAc (3 x 5 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was triturated with DMSO at 20 ℃ for 12 h, then purified by column chromatography, eluting with a gradient of 0- 100% EtOAc in pet. ether to provide 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (28 g).

[0207] Step 4: tert-Butyl 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-7-(tributylstannyl)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepane-1- carboxylate, Intermediate A-6. To a solution of 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 1.44 mmol) in DMSO (4 mL), was added tert-butyl 6-hydroxy-1,4-diazepane-1-carboxylate (2.50 g, 11.5 mmol) and DIEA (2.02 mL, 11.5 mmol) at 20 °C. The reaction was warmed to 40 °C and stirred for 12 h under N2atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 20-100% EtOAc in pet. ether to provide Intermediate A-6 (1.00 g, 1.20 mmol, 86% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 9.24 (s, 1H), 5.28 (d, J=16 Hz, 1H), 4.41 – 4.21 (m, 4H), 3.64 – 2.88 (m, 14H), 2.15 – 2.05 (m, 5H), 1.59 – 1.24 (m, 27H), 0.89 (m, 9H).

[0208] The compound in Table 1-3 was prepared following the procedure described above for Intermediate A-6, using appropriate starting materials. All starting materials are commercially available or are described herein. Table 1-2 Int. # Chemical Structure Name LCMS: m / z (ESI + ve ion); NMR Comments -B Intermediates Intermediate B-1: tert-Butyl(2-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethoxy)dimethylsilane. 6110938-WO01-SEC [0020yl)ethynyl)triisopropylsilane. To a solution of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (80.0 g, 156 mmol) in DMF (800 mL) and toluene (200 mL) was added CuI (44.6 g, 234 mmol), followed by NIS (42.1 g, 187 mmol), and the mixture was stirred at 110 °C for 4 h. The combined reaction mixture was poured into H2O (1 L) and extracted with EtOAc (3 x 1 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide crude material containing ((2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (100 g), which was used in the next step.

[0210] Step 2: 1-Ethynyl-2-fluoro-8-iodo-6-(methoxymethoxy)naphthalene. To a solution of the crude material containing ((2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1- yl)ethynyl)triisopropylsilane (50 g, 98 mmol) in DMF (500 mL) was added CsF (74.1 g, 488 mmol). The mixture was stirred at 80 °C for 2 h, then diluted with H2O (1 L) and extracted with EtOAc (3 x 1 L). 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 0- 90% EtOAc in pet. ether to provide 1-ethynyl-2-fluoro-8-iodo-6-(methoxymethoxy)naphthalene (23 g, 65 mmol, 66% yield).

[0211] Step 3: 2-Fluoro-8-iodo-6-(methoxymethoxy)-1-vinylnaphthalene. To a solution of Schwartz's reagent (23.2 g, 90.0 mmol) in DCM (100 mL) was added 1-ethynyl-2-fluoro-8-iodo-6- (methoxymethoxy)naphthalene (16 g, 45 mmol) at 0 °C protected from light. Then the mixture was stirred at 20 °C for 12 h protected from light. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 1-10% of EtOAc in pet. ether to provide 2-fluoro-8-iodo- 6210938-WO01-SEC 6-(methoxymethoxy)-1-vinylnaphthalene (26 g, 73 mmol, 57% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.09 (d, J=2.50 Hz, 1 H), 7.63 (m, 1 H), 7.53 (m, 1 H), 7.42 (d, J=2.50 Hz, 1 H),7.28 - 7.33 (m, 1 H), 5.76 (m, 1 H), 5.55 (m, 1 H), 5.28 (s, 2 H), 3.54 (s, 3 H).

[0212] Step 4: 2-(2-Fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)ethan-1-ol. To a solution of 2-fluoro-8-iodo-6-(methoxymethoxy)-1-vinylnaphthalene (2.0 g, 5.6 mmol) in THF (10 mL) was added BH3.MeS2(1.0 M in THF, 2.79 mL, 27.9 mmol) at 0 °C. The mixture was degassed and purged with N2(3x) then warmed to 20 °C and stirred for 12 h under N2atmosphere. The mixture was cooled to 0 °C, NaOH (1.0 M in water, 27.9 mL, 27.9 mmol) was added, then the mixture was heated to 20 °C and stirred for 6 h. Then, the mixture was cooled to 0 °C, H2O2(3.14 mL, 30.8 mmol) was added, then the mixture was returned to 20 °C and stirred for 6 h. The mixture was cooled to 0 °C, sat. aq. Na2SO3(100 mL) was added dropwise to the mixture, and stirred for 20 min at 20 °C. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by prep-TLC, eluting with a gradient of 1-10% EtOAc in pet. ether to provide 2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen- 1-yl)ethan-1-ol (7.00 g, 18.6 mmol, 27% yield).1H NMR (400 MHz, CDCl3) δ ppm 8.09 (d, J=2.50 Hz, 1 H), 7.58 (m, 1 H), 7.39 (d, J=2.62 Hz, 1 H), 7.27 (s, 1 H), 5.22 (s, 2 H), 3.94 - 4.00 (m, 2 H) ,3.85 - 3.91 (m, 2 H), 3.49 (s, 3 H), 1.53 (s, 4 H).

[0213] Step 5: tert-Butyl(2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1- yl)ethoxy)dimethylsilane. To a solution of 2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1- yl)ethan-1-ol (3.00 g, 8.00 mmol) and Et3N (2.22 mL, 16 mmol) in DCM (30 mL), was added imidazole (1.09 g, 16 mmol) and TBSCl (1.8 g, 12 mmol) at 0 °C under N2. Then, the mixture was stirred at 20 °C for 3 h. The reaction mixture was diluted with H2O (15 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 1-10% EtOAc in pet. ether to provide tert-butyl(2-(2-fluoro-8-iodo-6- (methoxymethoxy)naphthalen-1-yl)ethoxy)dimethylsilane (6.50 g, 13.3 mmol, 93% yield).

[0214] Step 6: tert-Butyl(2-(2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)naphthalen-1-yl)ethoxy)dimethylsilane, Intermediate B-1. A mixture of tert- butyl(2-(2-fluoro-8-iodo-6-(methoxymethoxy)naphthalen-1-yl)ethoxy)dimethylsilane (3.00 g, 6.12 mmol), B2Pin2(2.33 g, 9.18 mmol), Cs2CO3(3.99 g, 12.2 mmol) and tris(p-methoxyphenyl)phosphine (0.22 g, 0.61 mmol) in EtOAc (5 mL) was degassed and purged with N2 (3x). Then, Pd(OAc)2 (0.14 g, 0.61 mmol) was added, and the mixture was stirred at 80 °C for 2 h under N2atmosphere. The residue was diluted with H2O (3 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (2 x 2 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluting with a gradient of 1-2% EtOAc in pet. ether to provide Intermediate B-1 (6.30 g, 13.2 mmol, 97% yield). 6310938-WO01-SEC

[0215] Compounds in Table 1-4 were prepared following the procedure described above for Intermediate B-1, using appropriate starting materials. All starting materials are commercially available or are described herein. Table 1-3 Int. # Chemical Structure Name LCMS: m / z (ESI + ve ion); NMR Comments B-21H NMR (400 MHz CDCl ) St 1 ((2- - 1- o as - 1- o asIntermediate B-4: tert-Butyl(3-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)propoxy)dimethylsilane.

[0216] Step 1: 3-(2-Bromo-6-chlorophenyl)propanoic acid. To a mixture of formic acid (11.8 g, 256 mmol) and Et3N (6.4 mL, 45.6 mmol) at 0 °C, was added 2-bromo-6-chlorobenzaldehyde (10.0 g, 6410938-WO01-SEC 45.6 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (6.57 g, 45.6 mmol), and the reaction mixture was stirred at 100 °C for 2 h. Then, the reaction mixture was quenched by addition of 6 N HCl and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 1-33% EtOAc in pet. ether to provide 3-(2-bromo-6- chlorophenyl)propanoic acid (10 g, 38 mmol, 83% yield).

[0217] Step 2: 3-(2-Bromo-6-chlorophenyl)propan-1-ol. To a mixture of 3-(2-bromo-6- chlorophenyl)propanoic acid (8.00 g, 30.4 mmol) in THF (80 mL) was added BH3∙THF (1.0 M in THF, 42.5 mL, 42.5 mmol) dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by addition of 20 mL MeOH at 0 °C and stirred at 0 °C for 30 min, then the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography, eluting with a gradient of 1-33% EtOAc in pet. ether to provide 3-(2-bromo-6-chlorophenyl)propan-1-ol (6.60 g, 26.4 mmol, 87% yield).

[0218] Step 3: (3-(2-Bromo-6-chlorophenyl)propoxy)(tert-butyl)dimethylsilane. To the mixture of 3-(2-bromo-6-chlorophenyl)propan-1-ol (6.60 g, 26.4 mmol) and imidazole (3.60 g, 52.9 mmol) in DCM (70 mL) was added TBSCl (5.98 g, 39.7 mmol) and Et3N (5.16 mL, 37.0 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. Then, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (5 x 30 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 0-10% EtOAc in pet. ether to provide (3-(2- bromo-6-chlorophenyl)propoxy)(tert-butyl)dimethylsilane (7.50 g, 20.6 mmol, 78% yield).

[0219] Step 4: tert-Butyl(3-(2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)propoxy)dimethylsilane, Intermediate B-4. To the mixture of (3-(2-bromo-6- chlorophenyl)propoxy)(tert-butyl)dimethylsilane (2.00 g, 5.50 mmol), Cs2CO3(5.37 g, 16.5 mmol) and B2Pin2(6.98 g, 27.5 mmol) in 1,4-dioxane (80 mL) was added Pd(dppf)Cl2(0.40 g, 0.55 mmol) at 20 °C, and the reaction mixture was stirred at 120 °C for 12 h. Then, the reaction mixture was quenched by addition of H2O (100 mL) at 20 °C and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 1-10% EtOAc in pet. ether to provide Intermediate B-4 (1.90 g, 4.60 mmol, 84% yield).1H NMR (400 MHz, CDCl3) δ ppm 7.66 (q, J=2.8Hz, 1H), 7.42 – 7.40 (m, 1H), 7.11 (t, J=12Hz, 1H), 3.73 (t, J=9.2 Hz, 2H), 3.06 (m, 2H), 1.79 – 1.76 (m, 2H), 1.55 (s, 12H), 0.92 (s, 9H), 0.08 (m, 6H). 6510938-WO01-SEC Intermediate B-5: 5-(3-((tert-Butyl-di-phenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran- 2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.

[0220] S5-yl)propanal. A mixture of NaHCO3(64.7 g, 770 mmol) and TBSCl (89 g, 339 mmol) in DMF (340 mL) was heated to 40 °C for 20 min, then cooled to 25 °C, before adding 4-bromo-6-chloro-5-iodo-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (136 g, 308 mmol), prop-2-en-1-ol (48.3 g, 832 mmol), and Pd(OAc)2(13.8 g, 61.6 mmol) were added. The resulting mixture was stirred at 75 °C for 13 h, then the reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over Na2SO4, filtered, and concentrated to provide crude material containing 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-5-yl)propanal (200 g), which was used in the next step.

[0221] Step 2: 3-(4-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propan-1- ol. To a solution of crude material containing 3-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)propanal (50.0 g, 135 mmol) in EtOH (300 mL) at 0 °C was added NaBH4(7.63 g, 202 mmol). The reaction was stirred at 20 °C for 1 h. The reaction mixture was quenched by addition of aq. NH4Cl (2 L) at 0 °C and extracted with EtOAc (3 x 2 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 0-100% EtOAc in pet. ether to provide (4-bromo-6-chloro-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-5-yl)propan-1-ol (120 g).1H NMR (400 MHz, CDCl3) δ ppm 7.96 (s, 1 H), 7.65 (s, 1 H), 5.64 (dd, J=9.2, 2.8 Hz, 1 H), 4.03 – 3.99 (m, 1 H), 3.78-3.75 (m, 3 H), 3.15 - 3.12 (m, 2 H), 2.52 - 2.47 (m, 1 H), 2.16- 2.05 (m, 2 H), 1.92 - 1.84 (m, 2 H), 1.79 - 1.65 (m, 3 H).

[0222] Step 3: 4-Bromo-5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-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)propan-1-ol (10.0 g, 27.0 mmol) in DCM (35 mL) and THF (35 mL) was added imidazole (2.73 g, 40.1 mmol) and TBDPSCl (7.56 mL, 29.4 mmol) at 0 °C, and the mixture was stirred at 20 °C for 2 h. Then, the reaction mixture was quenched by addition of H2O (150 mL), and 6610938-WO01-SEC then extracted with DCM (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 0-100% EtOAc in pet. ether to provide 4-bromo-5-(3-((tert- butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (32 g).

[0223] Step 4: 5-(3-((tert-Butyl-di-phenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran- 2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole, Intermediate B-5. To a solution of 4-bromo-5-(3-((tert-butyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazole (16.0 g, 26.0 mmol), B2Pin2(33.2 g, 131 mmol) and Cs2CO3(25.6 g, 78 mmol) in 1,4-dioxane (320 mL) and H2O (40 mL) was added Pd(dppf)Cl2(1.91 g, 2.60mmol) under N2, and the mixture was heated to 120 ℃ and stirred for 2 h under N2. Then, the reaction mixture was quenched by addition of H2O (300 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 0-100% EtOAc in pet. ether to provide Intermediate B-5 (40 g). m / z (ESI): 659.3 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 8.33 (s, 1 H), 7.73 – 7.70 (m, 5 H), 7.42 – 7.36 (m, 6 H), 5.66 (dd, J=8.8, 2.4 Hz, 1 H), 4.02-3.99 (m, 1 H), 3.82 – 3.72 (m, 3 H), 3.22 – 3.18 (m, 2 H), 2.56 – 2.48 (m, 1 H), 2.18 – 2.14 (m, 1 H), 2.06 (s, 1 H), 1.89 – 1.85 (m, 2 H), 1.78 – 1.73 (m, 2 H), 1.67 (s, 1 H), 1.34 (s, 12 H), 1.08 (s, 9 H).

[0224] 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 (Intermediate B-6).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 minutes, then but-3-en-1-ol (8.17 g, 113 mmol) and Pd(OAc)2(1.27 g, 5.66 mmol) was added under N2. The mixture was stirred at 80 °C for 12 h under N2. After cooling to room temperature, the residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, 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)+. 6710938-WO01-SEC

[0226] 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, then was quenched by addition of saturated NH4Cl and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 5–10% ethyl acetate in petroleum ether, to give 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butan-1-ol (11 g, 28 mmol, 73% yield). m / z (ESI): 387.0 / 389.0 (M+H)+.

[0227] Step 3.4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)butan-1-ol. A vial was charged with tris(4- methoxyphenyl)phosphine (1.45 g, 4.13 mmol, Ambeed, Inc.), palladium acetate (0.46 g, 2.06 mmol, Combi-Blocks Inc.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.93 g, 15.5 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)+.

[0228] Step 4.4-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-5-yl)butyl methanesulfonate. A 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)+.

[0229] The compound in Table 1-5 was prepared following the procedure described above for Intermediate B-5, using appropriate starting materials. All starting materials are commercially available or are described herein. 6810938-WO01-SEC Table 1-4 Int. # Chemical Structure Name LCMS : m / z (ESI + ve ion); NMR Comments B-61H NMR (400 MHz CDCl3) Step 3: TBSClIntermediate B-7: di-tert-Butyl 6-((4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)butoxy)methyl)-1,4-diazepane-1,4- dicarboxylate.

[0230] Step 1: di-tert-Butyl 6-(hydroxymethyl)-1,4-diazepane-1,4-dicarboxylate. To a solution of tert-butyl 6-(hydroxymethyl)-1,4-diazepane-1-carboxylate (3.20 g, 13.89 mmol) in DCM (30 mL) was added Et3N (5.81 mL, 41.7 mmol) and Boc2O (3.87 mL, 16.7 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 0-10% EtOAc in pet. ether to provide di-tert-butyl 6-(hydroxymethyl)-1,4-diazepane-1,4-dicarboxylate (4.30 g, 13.01 mmol, 94% yield).1H NMR (400 MHz, CDCl3) δ ppm 3.9-4.0 (m, 1H), 3.2-3.5 (m, 5H), 3.2- 3.7 (m, 3H), 3.0-3.1 (m, 1H), 2.1-2.3 (m, 1H), 1.47 (s, 18H).

[0231] Step 2: di-tert-Butyl 6-((4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-5-yl)butoxy)methyl)-1,4-diazepane-1,4-dicarboxylate. To a solution of NaH (0.73 g, 18.16 6910938-WO01-SEC mmol) was added di-tert-butyl 6-(hydroxymethyl)-1,4-diazepane-1,4-dicarboxylate (4.00 g, 12.11 mmol) in DMA (20 mL) dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 1 h, and then 4-(4-bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butyl methanesulfonate (2.82 g, 6.05 mmol) in DMA (10 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by H2O (100 mL) at 0 °C and then extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 1-50% EtOAc in pet. ether to provide di-tert-butyl 6-((4-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butoxy)methyl)-1,4-diazepane-1,4-dicarboxylate (2.55 g, 3.64 mmol, 56% yield). m / z (ESI): 699.0 (M+H)+.

[0232] Step 3: di-tert-Butyl 6-((4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-5-yl)butoxy)methyl)-1,4-diazepane-1,4- dicarboxylate, Intermediate B-7. To a solution of di-tert-butyl 6-((4-(4-bromo-6-chloro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)butoxy)methyl)-1,4-diazepane-1,4-dicarboxylate (0.50 g, 0.71 mmol) and B2Pin2(0.27 g, 1.10 mmol) in EtOAc (20 mL) was added Cs2CO3(0.47 g, 1.40 mmol), Pd(OAc)2(30 mg, 0.070 mmol), and tris(p-methoxyphenyl)phosphine (30 mg, 0.070 mmol) under N2, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 1-50% EtOAc in pet. ether to provide Intermediate B-7 (2.80 g). m / z (ESI): 747.0 (M+H)+. Intermediate B-9: tert-Butyl (R)-3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate.

[0233] Step 1: tert-Butyl (R)-3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate. To a solution of tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (5.00 g, 23.1 mmol) in ACN (50 mL) and H2O (10 mL), was added formaldehyde (5.63 g, 69.4 mmol), followed by NaBH(OAc)3(9.80 g, 46.2 mmol). Then, the mixture was stirred at 25 °C for 30 min. The reaction mixture was quenched by addition of sat. NaHCO3(100 mL) and extracted with EtOAc (4 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide a crude residue containing tert-butyl (R)-3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate (1.40 g), which was used for the next step.1H NMR (400 MHz, CDCl3) δ ppm 3.83 - 4.05 (m, 3 H), 3.61 (dd, J=12.7, 2.4 7010938-WO01-SEC Hz, 1 H), 3.09 - 3.34 (m, 2 H), 3.05 (br d, J=12.0 Hz, 1 H), 2.53 (s, 2 H), 2.44 - 2.49 (m, 1 H), 2.39 (br dd, J=11.2, 3.1 Hz, 1 H), 1.44 - 1.48 (m, 1 H), 1.45 (s, 8 H).

[0234] The compound in Table 1-6 was prepared following the procedure described above for Intermediate B-7, using appropriate starting materials. All starting materials are commercially available or are described herein. Table 1-5 Int. # Chemical Structure Name LCMS: m / z (ESI + ve ion); NMR Comments B 8 / ESI 64 3 M+H+d - as l) hSECTION 2: Synthesis of Example Compounds

[0235] Provided in this section is the synthesis of examples described herein. It would be understood that compounds described herein (such as compounds of Formula (I), Formula (II) or Formula (III), or compounds listed in Table 1 or compounds of Embodiments 1-129, 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. Method 1 Example 1-001: (16RS)-23,32-Difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-28-hydroxy-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one 2,2,2-trifluoroacetate. 7110938-WO01-SEC

[0236] -3- (methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepane-1-carboxylate, Intermediate 1-001.1. A mixture of Intermediate A-3 (0.50 g, 0.90 mmol), Intermediate B-1 (0.57 g, 1.20 mmol), K3PO4(0.57 g, 2.7 mmol) and cataCXium A Pd G3 (0.20 g, 0.27 mmol) in 2-MeTHF (5 mL) and water (0.5 mL) was degassed and purged with N2(3x) and stirred at 110 °C for 2 h under N2atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 20-100% EtOAc in pet. ether to give Intermediate 1-001.1 (0.74 g, 0.84 mmol, 29% yield). MS (ESI) m / z: 883.5 (M+H)+.

[0237] Step 2: rac-tert-Butyl 6-((1H-imidazole-1-carbonyl)oxy)-4-(7-(8-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 1,4-diazepane-1-carboxylate, Intermediate 1-001.2. To a solution of Intermediate 1-001.1 (0.21 g, 0.24 mmol) in THF (1 mL) was added CDI (0.19 g, 1.2 mmol), followed by 4Å molecular sieves (0.2 g, 0.2 mmol). Then, the mixture was stirred at 50 °C for 8 h. The reaction mixture was concentrated to provide a crude material containing Intermediate 1-001.2 (0.69 g), which was used in the next step. 7210938-WO01-SEC

[0238] Step 3: rac-tert-Butyl 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-33-(methoxymethoxy)-7-oxo-6,8-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina- 1(1,6)-diazepana-3(1,8)-naphthalenacyclooctaphane-14-carboxylate, Intermediate 1-001.3. To a solution of the crude material containing Intermediate 1-001.2 (0.23 g, 0.24 mmol) in THF (6 mL), was added TBAF (1.0 M in THF, 0.35 mL, 0.35 mmol). The mixture was stirred at 50 °C for 4 h. The reaction mixture was concentrated and purified by column chromatography, eluting with a gradient of 10-100% EtOAc in pet. ether to give Intermediate 1-001.3 (0.30 g, 0.40 mmol, 38% yield).

[0239] Step 4: 2,2,2-Trifluoroacetate-rac-28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-33-hydroxy-6,8-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,6)- diazepana-3(1,8)-naphthalenacyclooctaphan-7-one, Compound 1-001. To a solution of Intermediate 1-001.3 (0.15 g, 0.19 mmol) in DCM (1.2 mL), was added TFA (0.4 mL, 5.2 mmol). The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched by addition of sat. NaHCO3and extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC, eluting with a gradient of 5-35% ACN in (0.1% TFA) H2O over 8 min to give Compound 1-001 (83 mg, 0.11 mmol). MS (ESI) m / z: 651.3 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.37 (s, 1 H), 8.16 - 8.48 (m, 1 H), 7.90 (dd, J=9.18, 6.20 Hz, 1 H), 7.38 - 7.45 (m, 2 H), 7.11 (t, J=2.32 Hz, 1 H), 5.44 - 5.68 (m, 2 H), 5.12 (s, 1 H), 4.74 - 4.85 (m, 1 H), 4.63 - 4.71 (m, 1 H), 4.54 - 4.60 (m, 1 H), 4.00 - 4.09 (m, 3 H), 3.92 - 3.99 (m, 3 H), 3.83 - 3.90 (m, 1 H), 3.70 (s, 3 H), 3.49 (d, J=14.07 Hz, 1 H), 3.40 (s, 1 H), 3.29 - 3.35 (m, 1 H), 3.12 - 3.20 (m, 1 H), 2.31 - 2.38 (m, 1 H), 2.13 - 2.26 (m, 3 H), 1.99 - 2.09 (m, 1 H).19F NMR (376 MHz, DMSO-d6) δ ppm -117.83 (s, 1 F), -138.10 (s, 1 F), -172.80 (s, 1 F). Examples 1-001-1 and 1-001-2: (16R)-23,32-Difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-28-hydroxy-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one; and (16S)-23,32-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)- yl)methoxy)-28-hydroxy-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one.10938-WO01-SEC

[0240] Compound 1-001 was purified via SFC by using a Chiralpak IC 3 × 25 cm, 10 μm column with a mobile phase of 50% (0.1% NH3∙H2O) ACN over 13 min. The 1steluting peak was assigned as (16R)-23,32-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)- 28-hydroxy-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one (Compound 1-001-1) (23 mg, 0.036 mmol, 32% yield). m / z (ESI): 651.3 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (br s, 1 H), 9.25 (s, 1 H), 7.88 (dd, J=9.13, 6.13 Hz, 1 H), 7.34 - 7.48 (m, 2 H), 7.08 (d, J=2.38 Hz, 1 H), 5.20 - 5.40 (m, 2 H), 4.51 - 4.77 (m, 2 H), 3.86 - 4.07 (m, 3 H), 3.81 (br t, J=10.19 Hz, 1 H), 3.17 - 3.28 (m, 1 H), 3.27 (br d, J=5.13 Hz, 3 H), 2.98 - 3.14 (m, 5 H), 2.80 - 2.87 (m, 1 H), 2.55 (br d, J=6.63 Hz, 1 H), 2.29 - 2.38 (m, 1 H), 2.12 - 2.23 (m, 1 H), 2.00 - 2.10 (m, 2 H), 1.61 - 1.92 (m, 4 H).

[0241] The 2ndeluting peak was assigned as (16S)-23,32-difluoro-8-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-28-hydroxy-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one (Compound 1-001-2) (33 mg, 0.05 mmol, 45% yield). m / z (ESI): 651.3 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (br s, 1 H), 9.25 (s, 1 H), 7.80 - 7.96 (m, 1 H), 7.29 - 7.49 (m, 2 H), 7.08 (d, J=2.38 Hz, 1 H), 5.16 - 5.42 (m, 2 H), 4.74 (br t, J=5.69 Hz, 1 H), 4.51 - 4.62 (m, 1 H), 4.04 - 4.18 (m, 2 H), 3.87 - 4.02 (m, 2 H), 3.77 - 3.86 (m, 1 H), 3.18 - 3.29 (m, 4 H), 2.95 - 3.17 (m, 5 H), 2.79 - 2.88 (m, 1 H), 2.56 (br d, J=6.63 Hz, 1 H), 2.29 - 2.37 (m, 1 H), 2.11 - 2.21 (m, 1 H), 2.00 - 2.10 (m, 2 H), 1.71 - 1.92 (m, 3 H). Example 1-002: (26RS)-18-Chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-26-methyl-23,25-dioxa-1,3,5,9,14,15,28- heptaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6(32),7,9,11,13,16,18-nonaen-24-one. 7410938-WO01-SEC

[0242] (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-6-methyl-1,4-diazepane- 1-carboxylate, Intermediate 1-002.1. A mixture of Intermediate A-4 (0.80 g, 1.40 mmol), Intermediate B-5 (1.39 g, 2.11 mmol), K3PO4(0.89 g, 4.22 mmol) and cataCXium A Pd G3 (0.10 g, 0.14 mmol) in 2-MeTHF (8 mL) and water (1.6 mL) was degassed and purged with N2(3x) and stirred at 80 °C for 12 h under N2atmosphere. The reaction mixture was concentrated and purified by column chromatography, eluting with a two-component gradient from 25% EtOAc in pet. ether to 2% MeOH in EtOAc to provide Intermediate 1-002.1 (2 g). m / z (ESI): 1065.6 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 8.99 - 9.24 (m, 1 H), 7.73 (br d, J=10.9 Hz, 1 H), 7.41 - 7.58 (m, 5 H), 7.20 - 7.36 (m, 6 H), 5.63 (br t, J=8.6 Hz, 1 H), 5.08 - 5.33 (m, 1 H), 4.36 - 4.75 (m, 1 H), 4.10 - 4.35 (m, 3 H), 3.77 - 4.01 (m, 3 H), 3.43 - 3.75 (m, 7 H), 3.05 - 3.28 (m, 5 H), 2.91 (br d, J=4.0 Hz, 3 H), 2.35 - 2.58 (m, 2 H), 2.17 (br s, 1 H), 1.99 - 2.13 (m, 5 H), 1.55 - 1.93 (m, 13 H), 1.26 (br d, J=14.4 Hz, 4 H), 0.81 (br dd, J=17.9, 2.8 Hz, 8 H), 0.54 - 0.67 (m, 1 H). 7510938-WO01-SEC

[0243] Step 2: tert-Butyl 6-((1H-imidazole-1-carbonyl)oxy)-4-(7-(5-(3- ((tertbutyldiphenylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-6-methyl-1,4-diazepane-1-carboxylate, Intermediate 1-002.2. A mixture of Intermediate 1-002.1 (0.60 g, 0.56 mmol) and CDI (0.37 g, 2.3 mmol) in THF (3 mL) was degassed and purged with N2(3x), then stirred at 80 °C for 12 h under N2atmosphere. The reaction was concentrated to provide crude material containing Intermediate 1-002.2, which was used in the next step. m / z (ESI): 1159.7 (M+H)+.

[0244] Step 3: tert-Butyl 16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-36-methyl-5-oxo-11-(tetrahydro-2H-pyran-2-yl)-11H-4,6-dioxa-2(7,4)- pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)-diazepanacyclononaphane-34-carboxylate, Intermediate T1-003.3. To a solution of the crude material containing Intermediate T1-003.2 (0.65 g, 0.56 mmol) in THF (13 mL) was added TBAF (1.0 M in THF, 0.84 mL, 0.84 mmol) and the mixture was stirred at 60 °C for 12 h. Then, the reaction mixture was concentrated and purified by column chromatography, using a column pre-treated with 50% Et3N in pet. ether, eluting with a gradient of 0-33% EtOAc in pet. ether to provide Intermediate 1-002.3 (0.15 g). m / z (ESI): 853.5 (M+H)+.

[0245] Step 4: 16-Chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-36-methyl-11H-4,6-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)- diazepanacyclononaphan-5-one, Compound 1-002. A mixture of Intermediate 1-002.3 (0.30 g, 0.40 mmol) in DCM (3 mL) and TFA (1 mL) was degassed and purged with N2(3x), and then stirred at 25 °C for 1 h under N2atmosphere. The reaction was quenched by addition of sat. NaHCO3and concentrated. The crude material was purified by prep-HPLC, eluting with a gradient of 15-65% ACN in (10 mM NH4HCO3) H2O over 8 min to provide Compound 1-004 (48 mg, 0.070 mmol, 32% yield). m / z (ESI): 669.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.25 (s, 1 H), 7.65 – 7.82 (m, 2 H), 5.70 (br d, J=16.8 Hz, 1 H), 5.20 – 5.47 (m, 1 H), 4.74 – 4.85 (m, 1 H), 4.26 – 4.46 (m, 2 H), 3.51 – 3.83 (m, 5 H), 3.20 – 3.36 (m, 3 H), 2.96 – 3.15 (m, 3 H), 2.85 (br d, J=13.7 Hz, 1 H), 2.59 – 2.73 (m, 1 H), 2.16 – 2.44 (m, 4 H), 1.85 – 2.09 (m, 6 H), 1.57 (s, 3 H).19F (400 MHz, CDCl3) δ ppm - 139.27 (s, 1 F), -138.89 (s, 1 F), -172.98 (s, 1 F). Examples 1-002-1 and 1-002-2: (26S)-18-Chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-26-methyl-23,25-dioxa-1,3,5,9,14,15,28- heptaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6(32),7,9,11,13,16,18-nonaen-24-one and (26R)-18-chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)- 7610938-WO01-SEC yl)methoxy)-26-methyl-23,25-dioxa-1,3,5,9,14,15,28- heptaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6(32),7,9,11,13,16,18-nonaen-24-one. [0024 l OD 25 x3 cm, 10 μm column with a mobile phase of 50% (0.1% NH3∙H2O) IPA in liquid CO2over 12 min. The 1steluting peak was assigned as (26S)-18-chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-26-methyl-23,25-dioxa-1,3,5,9,14,15,28- heptaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta-2,4,6(32),7,9,11,13,16,18- nonaen-24-one (Compound 1-002-1). m / z (ESI): 669.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.24 (s, 1 H), 7.63 - 7.83 (m, 2 H), 5.69 (br d, J=17.1 Hz, 1 H), 5.18 - 5.45 (m, 1 H), 4.77 (br d, J=11.9 Hz, 1 H), 4.32 (br d, J=10.4 Hz, 1 H), 4.19 (br d, J=10.8 Hz, 1 H), 3.43 - 3.86 (m, 5 H), 3.17 - 3.40 (m, 4 H), 2.95 - 3.10 (m, 3 H), 2.85 (br d, J=13.5 Hz, 1 H), 2.61 - 2.75 (m, 1 H), 2.12 - 2.40 (m, 4 H), 1.85 - 1.99 (m, 5 H), 1.56 (s, 3 H).19F NMR (400 MHz, CDCl3) δ ppm -139.32 (s, 1 F), -173.18 (s, 1 F).

[0247] The 2ndeluting peak was assigned as (26R)-18-chloro-32-fluoro-4-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-26-methyl-23,25-dioxa- 1,3,5,9,14,15,28-heptaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6(32),7,9,11,13,16,18-nonaen-24-one (Compound 1-002-2). m / z (ESI): 669.3 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.25 (s, 1 H), 7.65 - 7.83 (m, 2 H), 5.70 (br d, J=16.9 Hz, 1 H), 5.19 - 5.44 (m, 1 H), 4.78 (br d, J=11.6 Hz, 1 H), 4.20 - 4.39 (m, 2 H), 3.48 - 3.82 (m, 4 H), 3.18 - 3.44 (m, 4 H), 2.96 - 3.15 (m, 3 H), 2.85 (d, J=13.5 Hz, 1 H), 2.60 - 2.75 (m, 1 H), 2.15 - 2.44 (m, 4 H), 1.84 - 2.08 (m, 6 H), 1.56 (s, 3 H).19F NMR (400 MHz, CDCl3) δ ppm -139.30 (s, 1 F), -173.00 (s, 1 F).

[0248] Compounds in Table 2-1 were prepared following the procedure described in Method 1, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-1 Ex. # Chemical Structure Name LCMS: m / z (ESI + ve ion); Comments7710938-WO01-SEC 1-003-1 (23R)-15-chloro- m / z (ESI): 629.2 (M+H)+. Step 1: 29-fluoro-4-1H NMR (400 MHz, Intermediates A- (((2R,7aS)-2- METHANOL-d4) δ ppm 9.15 (s, 4 and B-4 were e d ak 0 H y - - ed s ) n. y - e 5 in g10938-WO01-SEC 13,16,18-nonaen-19F NMR (377 MHz, CDCl3) δ mL / min; 24-one ppm -75.49 (s, 1 F), -138.82 (s, Stereochemistry 1 F). was assigned - e 5 in g yet o Example 1-005: (16RS)-23,32-Difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-16-methyl-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one. 7910938-WO01-SEC

[0249] phthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate, Intermediate 1-005.1. To a solution of Intermediate A-7 (0.23 g, 0.28 mmol) in DMF (2.3 mL) was added Intermediate B-2 (0.12 g, 0.28 mmol), copper(I) iodide (27 mg, 0.14 mmol), LiCl (36 mg, 0.84 mmol) and cataCXium A Pd G3 (41 mg, 0.060 mmol) at 20 °C. The mixture was degassed and purged with N2(3x). Then, the reaction was warmed to 40 °C and stirred for 2 h, then warmed to 80 °C for another 8 h under N2atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 10- 100% EtOAc in pet. ether to provide Intermediate 1-005.1 (23 mg, 0.030 mmol, 10% yield). m / z (ESI): 837.2 (M+H)+.

[0250] Step 2: tert-Butyl 6-((1H-imidazole-1-carbonyl)oxy)-4-(7-(8-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4- diazepane-1-carboxylate, Intermediate 1-005.2. To a solution of Intermediate 1-005.1 (23 mg, 0.030 mmol) in THF (0.1 mL), was added CDI (27 mg, 0.17 mmol) at 20 °C, and the mixture was degassed and purged with N2(3x). Then, the reaction was warmed to 40 °C and stirred for 12 h under 8010938-WO01-SEC N2atmosphere. The reaction was concentrated to provide a crude material containing Intermediate 1- 005.2 (26 mg). m / z (ESI): 931.7 (M+H)+.

[0251] Step 3: tert-Butyl 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-16-methyl-7-oxo-6,8-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,6)- diazepana-3(1,8)-naphthalenacyclooctaphane-14-carboxylate, Intermediate 1-005.3. To a solution of the material containing Intermediate 1-005.2 (26 mg, 0.030 mmol) in THF (0.25 mL), was added TBAF (1.0 M in THF, 82 µL, 0.082 mmol) at 20 °C, and the mixture was degassed and purged with N2(3x). Then, the reaction was warmed to 40 °C and stirred for 12 h under N2atmosphere. The reaction mixture was quenched by addition of 5 mL H2O, and then extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide a crude residue containing Intermediate 1-005.3. m / z (ESI): 749.6 (M+H)+.

[0252] Step 4: (16RS)-23,32-Difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-16-methyl-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one, Compound 1-005. To a solution of the crude material containing Intermediate 1-005.3 (15 mg, 0.020 mmol) in DCM (1 mL), was added dropwise 4 M HCl / dioxane (0.5 mL, 2 mmol) at 25 °C and the mixture was degassed and purged with N2(3x). Then, the reaction was stirred at 25 °C for 1 h under N2atmosphere. The reaction mixture was quenched by addition of sat. NaHCO3aq. (1.5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC, eluting with a gradient of 1-30% of ACN in (0.2% HCOOH) H2O to provide Compound 1-005 (2 mg, 3 µmol, 15% yield). m / z (ESI): 649.3 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.25 (s, 1H), 8.03-8.17 (m, 2H), 7.35-7.62 (m, 3H), 5.71-5.75 (m, 1H), 5.32- 5.50 (m, 1H), 4.75-4.80 (m, 1H), 4.59 (s, 2H), 4.36-4.43 (m, 2H), 4.01-4.09 (m, 1H), 3.85-3.91 (m, 1H), 3.70-3.75 (m, 1H), 3.48-3.54 (m, 1H), 3.37-3.44 (m, 2H), 3.06-3.16 (m, 2H), 2.98-3.10 (m, 1H), 2.50-2.69 (m, 2H), 2.25-2.41 (m, 1H), 2.17-2.25 (m, 1H), 2.03-2.15 (m, 2H), 1.91-1.98 (m, 1H), 1.31 (s, 3H), 0.82-0.92 (m, 2H).19F NMR (376 MHz, METHANOL-d4) δ ppm -115.19 (s, 1F), -138.74 (s, 1F), -173.77 (s, 1F). Example 1-006: (16RS)-23,32-Difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one. 8110938-WO01-SEC

[0253] hthalen-1- yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepane-1-carboxylate, Intermediate 1-006.1. To a solution of Intermediate A-6 (0.20 g, 0.25 mmol) in DMF (2 mL) was added Intermediate B-2 (0.11 g, 0.25 mmol) and bis(tri-tert-butylphosphine)palladium (25 mg, 0.049 mmol) at 20 °C, and the mixture was degassed and purged with N2(3x). The reaction was warmed to 100 °C and stirred for 3 h under N2atmosphere. Then, the reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting using a gradient of 33-50% MeOH in EtOAc to give Intermediate 1-006.1 (55 mg, 0.067 mmol, 27% yield).1H NMR (400 MHz, METHANOL-d4) δ ppm 9.21 – 9.18 (m, 1H), 7.97 (d, J=9.2Hz, 2H), 7.82 (d, J=11Hz, 2H), 7.48 (t, J=9.2 Hz, 3H), 7.33 – 7.27 (m, 1H), 5.41 – 5.27 (br d, J=52 Hz, 1H), 4.38 – 4.26 (m, 5H), 3.49 – 3.40 (m, 6H), 2.38 – 2.18 (m, 3H), 2.03 – 1.85 (m, 3H), 1.48 – 1.38 (m, 18H), 0.97 (m, 2H), 0.65 (s, 6H), -0.20 - -0.22 (d, J=9.2Hz, 5H).

[0254] Step 2: tert-Butyl 6-((1H-imidazole-1-carbonyl)oxy)-4-(7-(8-(2-((tert- butyldimethylsilyl)oxy)ethyl)-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazepane- 1-carboxylate, Intermediate 1-006.2. To a solution of Intermediate 1-006.1 (0.06 g, 0.07 mmol) in 8210938-WO01-SEC THF (0.5 mL) was added CDI (70 mg, 0.40 mmol) at 20 °C. The mixture was degassed and purged with N2(3x), then warmed to 40 °C and stirred for 12 h under N2atmosphere. The reaction mixture was concentrated to provide crude material containing Intermediate 1-006.2 (60 mg), which was used in the next step. m / z (ESI): 917.2 (M+H)+.

[0255] Step 3: tert-Butyl 28,37-difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7-oxo-6,8-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,6)-diazepana-3(1,8)- naphthalenacyclooctaphane-14-carboxylate, Intermediate 1-006.3. To a solution of the crude material containing Intermediate 1-006.2 (50 mg, 0.050 mmol) in THF (0.25 mL) was added TBAF (1.0 M in THF, 0.16 mL, 0.16 mmol) at 20 °C, and the mixture was degassed and purged with N2(3x). The reaction mixture was warmed to 40 °C and stirred for 12 h under N2atmosphere. Then, the reaction mixture was quenched with H2O (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 33-50% EtOAc in pet. ether to provide Intermediate 1-006.3 (20 mg, 0.030 mmol, 48% yield). m / z (ESI): 735.6 (M+H)+.

[0256] Step 4: 28,37-Difluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6,8-dioxa-2(4,7)-pyrido[4,3-d]pyrimidina-1(1,6)-diazepana-3(1,8)- naphthalenacyclooctaphan-7-one, Compound 1-006. To a solution of Intermediate 1-006.3 (20 mg, 0.020 mmol) in DCM (2 mL) was added 4 M HCl / dioxane (1 mL, 4 mmol) dropwise at 20 °C, and the mixture was degassed and purged with N2(3x). Then, the reaction mixture was stirred at 20 °C for 12 min under N2atmosphere. The reaction mixture was quenched by addition of sat. NaHCO3aq. (5 mL) and extracted with EtOAc (15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC, eluting with a gradient of 2-30% ACN in (0.2% HCOOH) H2O over 8 min to provide Compound 1-006 (2 mg, 0.002 mmol, 9% yield). m / z (ESI): 635.4 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.27 (s, 1H), 8.42 – 8.06 (m, 2H), 7.64 – 7.62 (m, 2H), 7.45 (t, J=9.2 Hz, 1H), 5.60 (d, J=16 Hz, 1H), 5.52 (d, J=52 Hz, 1H), 5.12 (s, 1H), 4.75 – 4.62 (m, 1H), 4.18 (q, J=8Hz, 2H), 3.93 – 3.90 (m, 2H), 3.88 – 3.83 (m, 5H), 3.47 – 3.44 (m, 1H), 3.39 - .38 (m, 4H), 2.64 – 2.63 (m, 2H), 2.37 – 2.33 (m, 4H), 2.13 – 2.0 (m, 1H).19F NMR (376 Hz, METHANOL-d4) δ ppm -112.67 (s, 1F), -137.39 (s, 1F), -173.61 (s, 1H). Examples 1-006-1 and 1-006-2: (16R)-23,32-Difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one; and (16S)-23,32-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)- yl)methoxy)-17,19-dioxa-3,7,9,11,14- 8310938-WO01-SEC pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one. [002 columnwith a mobile phase of 60% (0.1% NH3∙H2O) MeOH in liquid CO2over 20 min. The 1steluting isomer was assigned as (16R)-23,32-difluoro-8-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one (Compound 1-006-1) (17 mg). m / z (ESI): 635.7 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 9.20 (s, 1H), 8.10-7.99 (m, 2H), 7.59-7.55(m, 2H), 7.40 (t, J=9.2 Hz, 1H), 5.46 (d, J=16 Hz, 1H), 5.28 (d, J=52 Hz, 1H), 4.88 (s, 1H), 4.72-4.61 (m, 1H), 4.29 (q, J=8Hz, 2H), 4.09-3.86 (m, 3H), 3.61-3.48 (m, 1H), 3.44-3.35 (m, 1H), 3.27-3.18 (m, 4H), 3.11-2.96 (m, 2H), 2.89-2.72 (m, 1H), 2.55-2.41 (m, 1H), 2.39-2.10 (m, 3H), 2.01-1.83 (m, 3H), 1.52-1.22 (m, 1H).19F NMR (376 Hz, METHANOL-d4) δ ppm -115.03 (s, 1F), -138.11 (s, 1F), - 173.61 (s, 1F).

[0258] The 2ndeluting isomer was assigned as (16S)-23,32-difluoro-8-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolo[1,2-a]pyrrol-7a(5H)-yl)methoxy)-17,19-dioxa-3,7,9,11,14- pentaazahexacyclo[20.7.1.1~2,6~.1~11,16~.0~5,10~.0~26,30~]dotriaconta- 1(30),2(32),3,5,7,9,22,24,26,28-decaen-18-one (Compound 1-006-2) (16 mg). m / z (ESI): 635.7 (M+H)+.1H NMR (400 MHz, METHANOL-d4) δ ppm 1.01 (s, 1H), 8.14-8.01 (m, 2H), 7.60-7.55 (m, 2H), 7.40 (t, J=8 Hz, 1H), 5.49 (d, J=16 Hz, 1H), 5.30 (d, J=60 Hz, 1H), 4.85 (s, 1H), 4.75-4.69 (m, 1H), 4.30 (s, 2H), 4.11-3.85 (m, 3H), 3.59-3.52 (m, 1H), 3.46-3.37 (m, 1H), 3.23 (d, J=24 Hz, 4H), 3.10-2.98 (m, 2H), 2.93-2.85 (m, 1H), 2.55-2.46 (m, 1H), 2.40-2.20 (m, 2H), 2.15-2.10 (m, 1H), 2.02- 1.92 (m, 2H), 1.94-1.83 (m, 1H), 1.37-1.16 (m, 1H).19F NMR (376 Hz, METHANOL-d4) δ ppm - 115.09 (s, 1F), -138.22 (s, 1F), -173.61 (s, 1F). Alternate Conditions:

[0259] (1) A mixture of Intermediate A-5 (0.20 g, 0.35 mmol), Intermediate B-3 (0.18 g, 0.42 mmol), K3PO4(0.22 g, 1.1 mmol) and cataCXium A Pd G3 (26 mg, 0.035 mmol) in 2-MeTHF (2.1 mL) and H2O (0.3 mL) was degassed and purged with N2(3x). Then, the mixture was stirred at 80 °C for 12 h under N2atmosphere. The reaction mixture was concentrated and purified by prep-TLC, eluting with a mobile phase of 10% MeOH in EtOAc to provide the product. 8410938-WO01-SEC

[0260] Compounds in Table 2-2 were prepared following the procedure described in Method 2, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-2 Ex. # Chemical Structure Name LCMS: m / z (ESI + ve ion); NMR Comments 1-005-1 (16R)-2332- / z (ESI) 6492 (M+H)+Alt rn t as O) y as O) y8510938-WO01-SEC 1 F), -136.51 (s, 1 F), - 173.04 (s, 1 F).Example 1-007: (26RS)-18-Chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-24-oxa-1,3,5,9,14,15,28- heptaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaene.

[0261] trahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-5-yl)butoxy)methyl)-1,4-diazepane-1,4-dicarboxylate, Intermediate 1- 007.1. To a solution of Intermediate B-7 (0.20 g, 0.27 mmol) and Intermediate A-1 (0.12 g, 0.27 mmol) in 2-MeTHF (5 mL) and H2O (0.5 mL) was added K3PO4(0.17 g, 0.80 mmol) and cataXCium A Pd G3 (39 mg, 0.054 mmol), and the mixture was stirred at 110 °C for 3 h. Then, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, eluting with a gradient of 0-33% EtOAc in pet. ether to provide Intermediate 1-007.1 (0.85 g). m / z (ESI): 1031.6 (M+H)+.

[0262] Step 2: 7-(5-(4-((1,4-Diazepan-6-yl)methoxy)butyl)-6-chloro-1H-indazol-4-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol, Intermediate 1-007.2. To a solution of Intermediate 1-007.1 (0.30 g, 0.29 mmol) in DCM (2 mL), 8610938-WO01-SEC was added TFA (1 mL, 13 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h, then the reaction mixture was concentrated. The residue was purified by prep-HPLC, eluting with a gradient of 20-50% ACN in (0.05% NH3∙H2O and 10 mM NH4HCO3) H2O over 8 min to provide Intermediate 1-007.2 (0.15 g). m / z (ESI): 657.4 (M+H)+.

[0263] Step 3: 16-Chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-11H-5-oxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)- diazepanacyclononaphane, Compound 1-007. To a solution of Intermediate 1-007.2 (40 mg, 0.06 mmol) in ACN (1 mL) and DMSO (0.2 mL), was added BrOP (71 mg, 0.18 mmol) and DIPEA (0.03 mL, 0.18 mmol) and the mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (3 x 3 mL), dried over Na2SO4, filtered, and concentrated to provide Compound 1-007 (6 mg, 0.10 mmol, 16% yield). m / z (ESI): 639.3 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 12.93 - 13.71 (m, 1 H), 9.36 (br s, 1 H), 7.63 - 7.92 (m, 2 H), 5.16 - 5.44 (m, 1 H), 4.97 (br d, J=14.54 Hz, 1 H), 4.37 (br d, J=10.85 Hz, 1 H), 3.98 - 4.14 (m, 2 H), 3.60 - 3.74 (m, 2 H), 2.91 - 3.12 (m, 8 H), 2.82 (br d, J=5.84 Hz, 2 H), 2.10 - 2.40 (m, 5 H), 1.91 - 2.09 (m, 4 H), 1.72 - 1.89 (m, 3 H), 1.11 - 1.58 (m, 5 H).19F (376 MHz, DMSO-d6) δ ppm -143.11 - 142.80 (m, 1 F), -172.06 (br d, J=8.03 Hz, 1 F). Example 1-007-1: (26S)-18-Chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-24-oxa-1,3,5,9,14,15,28- heptaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaene

[0264] Step 1: di-tert-Butyl 16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-11H-5-oxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)- diazepanacyclononaphane-11,34-dicarboxylate, Intermediate 1-007.3. To a solution of Compound 1-007 (10 mg, 0.020 mmol) in THF (0.5 mL) was added Et3N (85 ^L, 0.060 mmol) and 8710938-WO01-SEC Boc2O (10 ^L, 0.04 mmol). Then the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated. The crude material was purified by prep-TLC, eluting with a gradient of 10-100% (0.04% TFA) H2O in ACN to provide Intermediate 1-007.3 (20 mg, 0.020 mmol). m / z (ESI): 839.5 (M+H)+.

[0265] Intermediate 1-007.3 was purified via SFC by using a REGIS (S,S) Whelk-O125 x 3 cm, 5 μm column, with a mobile phase of 60% (0.1% NH3∙H2O) EtOH in liquid CO2and a flow rate of 80 mL / min. The 1steluting peak was arbitrarily assigned as di-tert-butyl (36S)-16-chloro-28-fluoro-22- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11H-5-oxa-2(7,4)-pyrido[4,3- d]pyrimidina-1(4,5)-indazola-3(1,6)-diazepanacyclononaphane-11,34-dicarboxylate (Intermediate 1- 007.3-1) (3 mg, 0.004 mmol, 15% yield).

[0266] The 2ndeluting peak was arbitrarily assigned as di-tert-butyl (36R)-16-chloro-28-fluoro-22- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11H-5-oxa-2(7,4)-pyrido[4,3- d]pyrimidina-1(4,5)-indazola-3(1,6)-diazepanacyclononaphane-11,34-dicarboxylate (2 mg, 0.002 mmol, 10% yield).

[0267] Step 2: (26S)-18-Chloro-32-fluoro-4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo[1,2- a]pyrrol-7a(5H)-yl)methoxy)-24-oxa-1,3,5,9,14,15,28- heptaazahexacyclo[24.4.1.1~6,10~.0~2,7~.0~11,19~.0~12,16~]dotriaconta- 2,4,6,8,10(32),11,13,16,18-nonaene, Compound 1-007-2. To a solution of Intermediate 1-007.3-1 (3 mg g, 0.004 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.5 mmol) at 25 °C and the mixture was stirred for 2 h. The solution was concentrated to provide Compound 1-007-1 (3 mg). m / z (ESI): 639.4 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 13.30 (br s, 1H), 9.3-9.4 (m, 1H), 7.7-7.8 (m, 2H), 5.2-5.4 (m, 1H), 4.97 (br d, 1H, J=15.2 Hz), 4.38 (br d, 1H, J=10.2 Hz), 4.0-4.1 (m, 2H), 3.6-3.7 (m, 1H), 3.1-3.2 (m, 2H), 3.0-3.1 (m, 5H), 2.95 (s, 2H), 2.8-2.9 (m, 2H), 2.2-2.4 (m, 4H), 2.0-2.2 (m, 2H), 1.9-2.0 (m, 2H), 1.7-1.9 (m, 3H), 1.2-1.4 (m, 3H), 1.1-1.2 (m, 2H).19F NMR (377 MHz, CDCl3) δ ppm -73.42 (s, 3F), -143.00 (s, 1F), -172.07 (s, 1F).

[0268] (36R)-34-Acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-11H-4,6-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)- diazepanacyclononaphan-5-one (Compound 1-009-1) and (36S)-34-acetyl-16-chloro-28-fluoro-22- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11H-4,6-dioxa-2(7,4)- pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)-diazepanacyclononaphan-5-one (Compound 1- 009-2) 8810938-WO01-SEC

[0269] Step 1: 1-(4-(7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepan-1-yl)ethan-1-one and 5-(3- ((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol hydrobromide (2.16 g, 4.93 mmol) in N,N-dimethylformamide (20 mL) was added HATU (3.52 g, 9.25 mmol) and DIPEA (5.38 mL, 30.8 mmol). The mixture was stirred at room temperature for 0.5 h and then was added 1-(6-hydroxy-1,4-diazepan-1-yl)ethan-1-one hydrochloride (1.20 g, 6.16 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (5 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of petroleum ether / ethyl acetate = 1 / 0 to ethyl acetate / methanol = 3 / 1 to provide 1-(4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepan-1-yl)ethan-1-one as yellow solid. m / z (ESI): 497.2 (M+H)+.

[0270] Step 2: 1-(4-(7-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepan-1-yl)ethan-1-one. To a solution of 1-(4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-hydroxy-1,4-diazepan-1-yl)ethan-1-one (0.20 g, 0.40 mmol) and 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.32 g, 0.60 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was added K3PO4(0.26 g, 1.21 mmol) and cataCXium A Pd G3 (0.12 g, 0.16 mmol) in a sealed tube. The mixture was stirred at 110 °C for 2 h. A total of 5 batches were 8910938-WO01-SEC combined. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of petroleum ether / ethyl acetate = 1 / 0 to 0 / 1 to provide 1-(4-(7-(5-(3-((tert- butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6- hydroxy-1,4-diazepan-1-yl)ethan-1-one as yellow solid. m / z (ESI): 869.3 (M+H)+.

[0271] Step 3: 34-Acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-11-(tetrahydro-2H-pyran-2-yl)-11H-4,6-dioxa-2(7,4)-pyrido[4,3- d]pyrimidina-1(4,5)-indazola-3(1,6)-diazepanacyclononaphan-5-one. To a solution of 1-(4-(7-(5- (3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4- yl)-6-hydroxy-1,4-diazepan-1-yl)ethan-1-one (0.18 g, 0.21 mmol) in tetrahydrofuran (0.5 mL) was added CDI (0.10 g, 0.62 mmol). After addition, the mixture was stirred at 40 °C for 1 h. Then TBAF (1.0 M in THF, 0.31 mL, 0.31 mmol) in tetrahydrofuran (10 mL) was added dropwise at room temperature. The resulting mixture was stirred at 50 °C for 2 h. Two batches of the same reaction were combined and concentrated under reduced pressure. The residue was purified by prep-TLC on silica gel eluting with dichloromethane / EtOH = 6 / 1 to provide 34-acetyl-16-chloro-28-fluoro-22- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11-(tetrahydro-2H-pyran-2-yl)- 11H-4,6-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)-diazepanacyclononaphan-5-one (0.16 g) as yellow solid. m / z (ESI): 781.2 (M+H)+.

[0272] 34-Acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-11-(tetrahydro-2H-pyran-2-yl)-11H-4,6-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)- indazola-3(1,6)-diazepanacyclononaphan-5-one (20 mg, 0.026 mmol) was further purified by prep- HPLC (column: Waters Xbridge BEH C18100 x 25 mm, 10 um; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 35%-65%, 8 min) to provide 34-acetyl-16-chloro-28-fluoro-22-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11-(tetrahydro-2H-pyran-2-yl)-11H-4,6-dioxa- 2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)-diazepanacyclononaphan-5-one (8 mg) as white solid. m / z (ESI): 781.3(M+H)+.1H NMR (400 MHz, CDCl3) δ ppm 9.16 - 9.24 (m, 1 H), 7.84 (dd, J = 15.38, 1.91 Hz, 1 H), 7.67 - 7.74 (m, 1 H), 5.67 - 5.79 (m, 1 H), 5.34 - 5.41 (m, 1 H), 5.14 - 5.26 (m, 1 H), 4.61 - 5.01 (m, 2 H), 3.95 - 4.41 (m, 5 H), 3.71 - 3.86 (m, 3 H), 3.52 - 3.67 (m, 1 H), 3.34 - 3.46 (m, 1 H), 2.95 - 3.32 (m, 6 H), 2.64 - 2.76 (m, 1 H), 2.30 - 2.62 (m, 2 H), 2.19 - 2.28 (m, 3 H), 2.13 (s, 3 H), 1.83 - 2.01 (m, 5 H), 1.66 - 1.81 (m, 4 H), 1.01 - 1.07 (m, 1 H).19F NMR (376 MHz, CDCl3) δ ppm -138.51 (s, 1 F), -173.12 (s, 1 F).

[0273] Step 4: 34-Acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-11H-4,6-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)- 9010938-WO01-SEC diazepanacyclononaphan-5-one. To a solution of 34-acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11-(tetrahydro-2H-pyran-2-yl)-11H-4,6-dioxa- 2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)-diazepanacyclononaphan-5-one (0.14 g, 0.18 mmol) in dichloromethane (1 mL) was added TFA (0.5 mL, 6.49 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. The mixture was treated with 0.5 mL NH3•H2O until pH = 7. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18150 x 40, 7 um; mobile phase: [A: H2O (0.05% NH3H2O + 10 mM NH4HCO3); B: ACN]; B%: 35-65%, 8 min) to provide 34-acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-11H-4,6-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)- diazepanacyclononaphan-5-one (85 mg, 0.12 mmol, 68% yield) as white solid. m / z (ESI): 697.4 (M+H)+.

[0274] Step 5: (36R)-34-Acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-11H-4,6-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola- 3(1,6)-diazepanacyclononaphan-5-one and (36S)-34-acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-11H-4,6-dioxa-2(7,4)-pyrido[4,3- d]pyrimidina-1(4,5)-indazola-3(1,6)-diazepanacyclononaphan-5-one. The title compounds were separated by SFC (column: REGIS (S,S) WHELK-O1 (250 mm x 25 mm, 10 um); mobile phase: [A: CO2; B: EtOH:ACN=1:1 (0.1% NH3H2O)]; B%: 53%, 7 min) to yield two peaks:

[0275] Peak 1: (36R)-34-acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-11H-4,6-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)- diazepanacyclononaphan-5-one (20 mg, 0.029 mmol). m / z (ESI): 697.3 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 13.34 (s, 1 H), 9.43 (d, J=6.25 Hz, 1 H), 7.66 - 7.94 (m, 2 H), 5.19 - 5.39 (m, 2 H), 4.86 - 5.01 (m, 1 H), 4.61 (d, J=9.38 Hz, 1 H), 4.12 - 4.41 (m, 2 H), 3.91 - 4.12 (m, 3 H), 3.64 - 3.90 (m, 4 H), 3.47 - 3.59 (m, 1 H), 2.99 - 3.11 (m, 3 H), 2.80 - 2.92 (m, 2 H), 2.70 (dd, J=13.82, 9.07 Hz, 1 H), 2.12 (s, 3 H), 2.00 - 2.08 (m, 3 H), 1.71 - 1.88 (m, 5 H).19F NMR (377 MHz, DMSO-d6) δ ppm -141.36 (br s, 1 F), -172.16 (s, 1 F).

[0276] Peak 2: (36S)-34-acetyl-16-chloro-28-fluoro-22-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-11H-4,6-dioxa-2(7,4)-pyrido[4,3-d]pyrimidina-1(4,5)-indazola-3(1,6)- diazepanacyclononaphan-5-one (19 mg, 0.027 mmol). m / z (ESI): 697.3 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ ppm 13.34 (br s, 1 H), 9.33 - 9.55 (m, 1 H), 7.67 - 7.91 (m, 2 H), 5.20 - 5.38 (m, 2 H), 4.86 - 5.02 (m, 1 H), 4.57 - 4.65 (m, 1 H), 3.89 - 4.36 (m, 5 H), 3.44 - 3.87 (m, 5 H), 3.04 - 3.13 (m, 2 H), 2.70 - 3.02 (m, 4 H), 2.10 - 2.22 (m, 3 H), 2.01 - 2.09 (m, 3 H), 1.71 - 1.88 (m, 5 H).19F NMR (377 MHz, DMSO-d6) δ ppm -141.34 (d, J=4.40 Hz, 1 F), -174.22 - -170.99 (m, 1 F). 9110938-WO01-SEC

[0277] Compounds in Table 2-3 were prepared following the procedure described in Method 3, using appropriate starting materials. All starting materials are commercially available or are described in the Intermediates section above. Table 2-3Ex. # Chemical Structure NameLCMS: (ESI + ve ion) m / z;NMRComments10072 26S 18 hl 32 / ESI 6394 M+H+St 2 iat -2 iat dSECTION 3: Biochemical and Cellular Assays

[0278] Provided in this section is the biological evaluation of the specific examples provided herein. KRAS G12D Coupled Nucleotide Exchange Assay

[0279] Purified GDP-bound KRAS protein (aa 1-169), containing both G12D and C118A amino acid substitutions and an N-terminal His-tag, was pre-incubated in assay buffer (25 mM HEPES pH 9210938-WO01-SEC 7.4, 10 mM MgCl2, and 0.01% Triton X-100) with a compound dose-response titration for 2 hours. Following compound pre-incubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 min. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa 1-149), nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader, using AlphaScreen® technology, and data were analyzed using a 4-parameter logistic model to calculate IC50values. Phospho-ERK1 / 2 MSD Assay

[0280] AsPC-1 (ATCC® CRL-1682™) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1x penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). Sixteen hours prior to compound treatment, AsPC-1 cells were seeded in 96-well cell culture plates at a density of 25,000 cells / well and incubated at 37 °C, 5% CO2. A compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37 °C, 5% CO2for 2 hours. Following compound treatment, cells were washed with ice-cold Dulbecco's phosphate- buffered saline, no Ca2+or Mg2+(ThermoFisher Scientific 14190144), and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1 / 2 in compound-treated lysates was assayed using Phospho-ERK1 / 2 Whole Cell Lysate kits (Meso Scale Discovery K151DWD) according to the manufacturer’s protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000, and data were analyzed using a 4-parameter logistic model to calculate IC50values. AsPC-1 and SW620 CTG Assay Protocols

[0281] AsPC-1 (human pancreatic adenocarcinoma; ATCC CRL-1682) or SW620 (human colon adenocarcinoma; ATCC CCL-227) cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1x penicillin / streptomycin / L-glutamine. Cells were seeded in 384-well plates at a density of 3.33E+04 cells / mL and incubated at 37 °C, 5% CO2, overnight. Serially-diluted compound or DMSO was added to the cells, and plates were incubated at 37 °C, 5% CO2for 72 h. Cell viability was measured using a CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega) according to the manufacturer’s protocol. The luminescence signal of treated samples was normalized to DMSO control, and data were analyzed using a 4-parameter logistic model to calculate IC50values. Table 3: Compound G12D AsPC-1 p- AsPC-1 SW620 ^ ^ ^ )9310938-WO01-SEC Exchange (^M) 1-001-1 0003 00048 0095 --

[0282] The results presented in Table 3 have been generated with the in vitro assays described above. These assays may be used to test any other compound described herein to assess and characterize a compound’s biological activity. In view of the disclosure provided herein, compounds not specifically tested would be expected to have similar results.

[0283] Compounds showing activity in the coupled exchange assay are useful in the methods provided herein (see Section “METHODS OF USE”). REFERENCES Der, C. J.; Krontiris, T. G.; Cooper, G. M. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Nat Acad Sci 1982, 79, 3637-3640. Vojtek, A. B.; Der, C. J. Increasing complexity of the Ras signaling pathway. J. Biol. Chem. 1998, 273, 19925-19928. Malumbres, M.; Barbacid, M. RAS oncogenes: the first 30 years. Nat Rev Cancer 2003, 3, 459-465. Sridhar, S. S.; Seymour, L.; Shepherd, F. A. Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. The Lancet Oncology 2003, 4, 397-406. Holderfield, M.; Deuker, M. M.; McCormick, F.; McMahon, M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer 2014, 14, 455-467. 9410938-WO01-SEC Caunt, C. J.; Sale, M. J.; Smith, P. D.; Cook, S. J. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer 2015, 15, 577-592. Simanshu, D. K.; Nissley, D. V.; McCormick, F. RAS Proteins and Their Regulators in Human Disease. Cell 2017, 170, 17-33. Cox, A. D.; Fesik, S. W.; Kimmelman, A. C.; Luo, J.; Der, C. J. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov 2014, 13, 828-851. O'Bryan, J. P. Pharmacological targeting of RAS: Recent success with direct inhibitors. Pharmacol Res 2019, 139, 503-511. Ostrem, J. M.; Peters, U.; Sos, M. L.; Wells, J. A.; Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013, 503, 548–551. 95

Claims

10938-WO01-SEC What is claimed is:

1. A compound of Formula (I): or a pharmaceutically accepta Z is C-H, C-halogen,C-CN, C-C1-4a y, C-C1-4a oa y , 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; q 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, C2-4haloalkenyl, 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, -C1-4 alkylene-C(O)-C1-4alkyl, -C1-4alkylene-C(O)N(Rz)2, C1-4alkylene-S(O)2-C1-4alkyl, or -S-C1-4alkyl; L3is 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; -L1-L2- is -L2, -N(Rz)C(O)-L2, -C(O)-L2-, -OC(O)-L2, -C(O)O-L2, -OC(O)-O-L2, 22 z 2 z 2 z 2 2 2-C1-4alkylene- OC(O)-L2, -C1-4 alkylene-O-L2, -C1-4 alkylene-S(O)2-L2, -C1-4 alkylene-S-L2, -C1-4 alkylene-S(O)-L2, - O-5-6 membered heteroaryl-L2, -C1-4alkylene-5-6 membered heteroaryl-L2, -C1-4hydroxyalkylene-5- 6-membered heteroaryl-L2or a 5-6 membered heteroaryl-L2; L2is C1-6alkylene, C1-6alkylene-O-, C1-6alkylene-O-C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C3-7cycloalkylene, C1-4alkylene-C3-7cycloalkylene, C1-4haloalkylene-C3-7cycloalkylene, C3-7cycloalkylene-C1-4alkylene, C1-6hydroxyalkylene or C1-6haloalkylene; 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; 9610938-WO01-SEC each R2is independently 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; A is C6-10aryl or 5-10 membered heteroaryl and is substituted with q occurrences of R6; 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 R6independently is halogen, hydroxyl, cyano, -N(Rz)2, -C(O)Rz, -C(O)ORz, C1-4alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C2-4 alkynyl, 5-7 membered heterocyclyl or C3-6 cycloalkyl or two R6taken together on adjacent carbon atoms form a C3-7cycloalkyl; each Rwindependently is C1-4alkyl, C1-4alkoxy, halogen, hydroxyl or C1-4haloalkyl; T is C1-4alkylene, -S(O)2-, -C(O)-, -C1-4alkylene-C(O)-, C1-4alkylene-S(O)2- or -S-; Rvis hydrogen, C1-4alkyl, -C(O)-C1-4alkyl, -C(O)-O-C1-4alkyl or C1-4 haloalkyl Ryis C1-4alkyl, C1-4haloalkyl, hydroxyl, cyano or -N(Rz)2; and each Rzis independently hydrogen or C1-4alkyl.

2. A compound of Formula (I): or a pharmaceutically acceptaZ 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; q is 0, 1 or 2; 9710938-WO01-SEC each Rxindependently is hydroxyl, halogen, oxo, cyano, -N(Rz)2, C1-4alkyl, C1-4deuteroalkyl, C1-4alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C1-4hydroxyalkylene, C2-4alkenyl, C2-4haloalkenyl, 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; L3is 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; -L1-L2- is -L2, -N(Rz)C(O)-L2, -C(O)-L2-, -OC(O)-L2, -C(O)O-L2, -OC(O)-O-L2, -OC(S)-O-L2, -O-L2, -N(Rz)C(O)O-L2, -OC(O)N(Rz)-L2, -N(Rz)-L2, -S(O)2-L2, -S-L2, -C1-4alkylene-- , -1-4a ye e- - , -1-4a ye e-2- , -1-4a y e e- - , -1-4a ylene-S(O)-L2, - O-5-6 membered heteroaryl-L2, -C1-4 alkylene-5-6 membered heteroaryl-L2, -C1-4 hydroxyalkylene-5- 6-membered heteroaryl-L2or a 5-6 membered heteroaryl-L2; L2is C1-6alkylene, C1-6alkylene-O-, C1-6alkylene-O-C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C3-7cycloalkylene, C1-4alkylene-C3-7cycloalkylene, C1-4haloalkylene-C3-7cycloalkylene, C3-7cycloalkylene-C1-4alkylene, C1-6hydroxyalkylene or C1-6haloalkylene; 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 R2is independently 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; A is C6-10aryl or 5-10 membered heteroaryl and is substituted with q occurrences of R6; 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 R6independently is 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 two R6taken together on adjacent carbon atoms form a C3-7cycloalkyl; each Rwindependently is C1-4alkyl, C1-4alkoxy, halogen, hydroxyl or C1-4haloalkyl; T is C1-4alkylene, -S(O)2-, -C(O)-, -C1-4alkylene-C(O)-, C1-4alkylene-S(O)2- or -S-; Rvis hydrogen, C1-4alkyl, -C(O)-C1-4alkyl, -C(O)-O-C1-4alkyl or C1-4 haloalkyl Ryis C1-4alkyl, C1-4haloalkyl, hydroxyl, cyano or -N(Rz)2; and each Rzis independently hydrogen or C1-4alkyl.

2. The compound of claim 2, wherein the compound is a compound of Formula (II): 9810938-WO01-SEC or a pharmaceutically accept Z, Q, p, q, Rx, L2, L1, L3, R1, R2, 4 R5, R6R , , Rw, Rv, T, Ryand Rzare as defined above for Formula (I).

3. The compound of claim 2, wherein the compound is a compound of Formula (III): or a pharmaceutically acceptaZ, Q, p, q, Rx, L2, L1, L3, R1, R2, R4, R5, R6, Rw, Rv, T, Ryand Rzare as defined above for Formula (I).

4. The compound or salt of any of claims 1-3, wherein Z is C-H, C-F, C-CN, C-CH3, C-CF3, C- OMe, C-Cl or N.

5. The compound or salt of claim 4, wherein Z is N.

6. The compound or salt of any of claims 1-5, wherein Q is CH or N.

7. The compound or salt of claim 6, wherein Q is CH.

8. The compound or salt of any of claims 1-3, wherein Z is N and Q is CH.

9. The compound or salt of any of claims 1-8, wherein L3is -O-methylene, -O-ethylene or -O-n- propylene substituted with 0-2 occurrences of R2. 9910938-WO01-SEC 10. The compound or salt of claim 9, wherein L3is -O-methylene substituted with 0 occurrences of R2.

11. The compound or salt of claim 10, wherein R1is heterocycloalkyl substituted with 0-3 occurrences of R5.

12. The compound or salt of claim 11, wherein R1is 7a-(hexahydro-1H-pyrrolizinyl) substituted with 0-3 occurrences of R5.

13. The compound or salt of claim 12, wherein R1is 7a-(hexahydro-1H-pyrrolizinyl) with one occurrence of R5.

14. The compound or salt of claim 13, wherein R5is fluorine.

15. The compound or salt of claim 14, wherei .

16. The compound or salt of any of claims 1-15, w ere n n s an m is 1.

17. The compound or salt of claim 16, wherein p is 0.

18. The compound or salt of claim 17, wherein Rvis methyl.

19. The compound or salt of any of claims 16-18, wherei .

20. The compound or salt of any of claims 1-15, wherein n is 1 and m is 2.

21. The compound or salt of claim 20, wherein p is 0.

22. The compound or salt of claim 21 wherein Rvis hydrogen. 10010938-WO01-SEC 23. The compound or salt of any of claims 20-22, wherei. 24.or salt of claim 21, wherein Rvis -C(O)-CH3.

25. The compound or salt of claim 24, wherei or.

26. The compound or salt of claim 20, wherein p is 1.

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

28. The compound or salt of claim 27, wherei or.

29. The compound or salt of any of claims 1-28, wherein -L1-L2- is -methylene-O-L2.

30. The compound or salt of claim 29, wherein L2is n-butylene. 10110938-WO01-SEC 31. The compound or salt of claim 30, wherein -L1-L2- is or. 32.t of any one of claims 1-28, wherein -L1-L2- is -O-C(O)-O-L2.

33. The compound or salt of claim 32, wherein L2is ethylene or n-propylene.

34. The compound or salt of claim 33, wherein -L1-L2- is or. 35.T e compound or salt of any one of claims 1-34, wherein A is C6-10aryl.

36. The compound or salt of claim 35, wherei or. 37.und or salt of any one of claims 1-34, wherein A-L2is 5-10 membered heteroaryl.

38. The compound or salt of claim 37, wherei ,. 39.8, wherein R4is hydrogen, hydroxyl, halogen, C1-4alkyl or C1-4alkoxy. 10210938-WO01-SEC 40. The compound or salt of claim 39, wherein R4is fluorine.

41. The compound or salt of claim 1, wherein the compound is: Compound Compound Compound , , , ,10310938-WO01-SEC Compound Compound Compound , , ,10410938-WO01-SEC 42. A pharmaceutical composition comprising the compound or salt according to any one of claims 1-41 and a pharmaceutically acceptable excipient.

43. A compound or salt according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 for use as a medicament.

44. A compound or salt according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 for use in treating cancer.

45. A compound or salt according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 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.

46. The compound, salt or pharmaceutical composition for use of claim 44 or 45, 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.

47. A use of the compound or salt according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 in the preparation of a medicament for treating cancer.

48. A use of the compound or salt according to any one of claims 1-41 or the pharmaceutical composition according to claim 42 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.

49. The use according to claim 47 or 48, 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. 10510938-WO01-SEC 50. 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 1-41 or a pharmaceutical composition according to claim 42.

51. 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 1-41 or a pharmaceutical composition according to claim 42, wherein one or more cells of the cancer express a KRAS G12D, G12V, G12A, G12S, G12R, G13D, Q61H, Q61L, Q61R or G12C mutant protein.

52. The method according to claim 50 or 51, 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.

53. The method according to claim 50 or 51, 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.

54. The method according to claim 53, wherein the cancer is non-small cell lung cancer.

55. The method according to claim 53, wherein the cancer is colorectal cancer.

56. The method according to claim 53, wherein the cancer is pancreatic cancer.

57. The method according to anyone of claims 50-56, 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. 106

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