Heterocyclic compounds and methods of use

Abstract

The present disclosure provides compounds useful for the inhibition of KRAS. The compounds have a general Formula I: wherein the variables of Formula I are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, cancer.

Description

[Technical Field]

[0001] This disclosure provides compounds having activity as inhibitors of G12D mutant KRAS protein. This disclosure also provides pharmaceutical compositions comprising such compounds, uses and methods for treating certain disorders, such as cancers including, but not limited to, non-small cell lung cancer (NSCLC), colorectal cancer and / or pancreatic cancer. [Previous Technology]

[0002] Since being identified as one of the first human oncogenes in 1982 (Der et al., 1982), KRAS (a homolog of the Kirsten rat sarcoma virus oncogene) has been the focus of extensive academic and industrial research as a key node in the MAPK signaling pathway, a transforming factor in parallel-effect pathway networks (e.g., PI3K / AKT) (Vojtek et al., 1998), and a potential target for anticancer 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 MOK (Caunt et al., 2015)), historically, KRAS proteins have been shown to be resistant to direct inhibition.

[0003] KRAS is a G protein that combines extracellular mitotic signaling with intracellular proliferative responses. KRAS acts as an intracellular "on / off" switch. Mitogen stimulation induces GTP binding to KRAS, causing conformational changes that allow KRAS to interact with downstream effector proteins, leading to cell proliferation. Normally, proliferative signaling is regulated by GTPase activator proteins (GAPs) to restore KRAS to its GDP-bound non-proliferative state. Mutations in KRAS weaken the regulatory cycle between these GDP and GTP-bound states, leading to the accumulation of GTP-bound active states and dysregulated cell proliferation (Simanshu et al., 2017).

[0004] Attempts to develop inhibitors of mutant KRAS proteins have historically been hampered by the lack of druggable pockets on the protein surface (Cox et al., 2014). In 2013, Shokat and colleagues discovered a covalent inhibitor of the common oncogenic mutant KRAS, KRAS G12C (O'Bryan, 2019), which binds to a previously unrecognized allosteric pocket on GDP-KRASG12C and prevents its subsequent activation (Ostream et al., 2013). This discovery injected significant new energy into KRAS inhibitor research, which has recently reached a climax in the entry of KRAS inhibitors into human clinical trials.

[0005] Despite some progress in KRAS G12C inhibitors, there remains a sustained interest and effort in developing KRAS inhibitors, particularly inhibitors of other KRAS such as KRAS G12D, G12V, G12A, or G12S. Therefore, there is a need to develop new inhibitors of KRAS G12D, G12V, G12A, G12S, or G12C for the treatment of disorders such as cancer. [Summary of the Invention]

[0006] In one aspect, this application relates to compounds having formula (I): (I) or a pharmaceutically acceptable salt of said compound, wherein: --- is a single or double bond; W is C, CH or N, wherein when W is CH or N, --- is a single bond; X is O, S, S(O), S(O)(NR z) or S(O) 2; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; each R x is hydroxyl, halogen, oxy, cyano, -N(R z) 2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-7 heteroaryl, -TR y, or two R x with adjacent carbon atoms can together form a C 3-7 cycloalkyl or a 5-7 heterocycloalkyl, wherein each C 3-7 cycloalkyl or 5-7 heterocycloalkyl are further substituted by Ry appearing 0-3 times, or two Rx can form a bridging ring together, wherein the bridge is selected from one of the following: -C1-4 alkyl, -C1-4 alkyl-OC1-4 alkyl-, -O-, -S-, or -C1-4 alkyl-SC1-4 alkyl-, and wherein each C1-4 alkyl chain is further substituted by Ry appearing 0-2 times; L-series C1-6 alkyl, -OC1-6 alkyl, -SC1-6 alkyl, NRz, O, or S, wherein each C1-6 alkyl, -OC1-6 alkyl, and -SC1-6 alkyl chain is substituted by R2 appearing 0-2 times; R1 series hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl, or heterocycloalkyl substituted by R5 appearing 0-3 times; R2 series halogen, hydroxyl, C2 1-4 alkyl groups, or two R2 groups on the same or adjacent carbon atoms that can together form a C3-7 cycloalkyl group; R3 groups are aryl or heteroaryl groups substituted by R6 groups appearing 0-3 times; R4 groups are hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, or cyano groups; each R5 group is halogen, oxy group, hydroxyl group, amino group, cyano group, or C1-4 alkyl group; each R6 group is halogen, hydroxyl, cyano group, -N(R2)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C2-4 alkynyl, or C3-6 cycloalkyl group; T-groups are C1-4 alkyl groups, -S(O)2-, -C(O)-, -C 1-4 alkyl-C(O)-, C 1-4 alkyl-S(O) 2- or -S-; R y halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxy, cyano or -N(R z) 2; and R z hydrogen or C 1-4 alkyl.

[0007] In a second aspect, this document provides pharmaceutical compositions comprising a compound having Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0008] In a third aspect, this document provides compounds having Formula I, or pharmaceutically acceptable salts of said compounds, or pharmaceutical compositions as described herein for use in the treatment of cancer (e.g., NSCLC, colorectal cancer, or pancreatic cancer).

[0009] Reference will now be made in detail to embodiments disclosed herein. Although certain embodiments of this disclosure will be described, it will be understood that it is not intended to limit the embodiments of this disclosure to those described. Rather, references to embodiments of this disclosure are intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of embodiments of this disclosure as defined by the appended claims.

Implementation Method

[0011] Cross-reference to related applications

[0012] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 231,543, filed August 10, 2021, and U.S. Provisional Patent Application No. 63 / 289,576, filed December 14, 2021, each incorporated herein by reference in its entirety.

[0013] The system provided herein as Embodiment 1 comprises a compound having formula (I): (I) or a pharmaceutically acceptable salt of said compound, wherein: --- is a single or double bond; W is C, CH or N, wherein when W is CH or N, --- is a single bond; X is O, S, S(O), S(O)(NR z) or S(O) 2; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; each R x is a hydroxyl, halogen, oxy group, cyano group, -N(R z) 2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-7 heteroaryl, -TR y, or two R x with adjacent carbon atoms may together form a C 3-7 cycloalkyl or a 5-7 heterocycloalkyl, wherein each C 3-7 cycloalkyl or 5-7 heterocycloalkyl are further substituted by Ry appearing 0-3 times, or two Rx can form a bridging ring together, wherein the bridge is selected from one of the following: -C1-4 alkyl, -C1-4 alkyl-OC1-4 alkyl-, -O-, -S-, or -C1-4 alkyl-SC1-4 alkyl-, and wherein each C1-4 alkyl chain is further substituted by Ry appearing 0-2 times; L-series C1-6 alkyl, -OC1-6 alkyl, -SC1-6 alkyl, NRz, O, or S, wherein each C1-6 alkyl, -OC1-6 alkyl, and -SC1-6 alkyl chain is substituted by R2 appearing 0-2 times; R1 series hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl, or heterocycloalkyl substituted by R5 appearing 0-3 times; R2 series halogen, hydroxyl, C2 1-4 alkyl groups, or two R2 groups on the same or adjacent carbon atoms that can together form a C3-7 cycloalkyl group; R3 groups are aryl or heteroaryl groups substituted by R6 groups appearing 0-3 times; R4 groups are hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, or cyano groups; each R5 group is halogen, oxy group, hydroxyl group, amino group, cyano group, or C1-4 alkyl group; each R6 group is halogen, hydroxyl, cyano group, -N(R2)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C2-4 alkynyl, or C3-6 cycloalkyl group; T-groups are C1-4 alkyl groups, -S(O)2-, -C(O)-, -C 1-4 alkyl-C(O)-, C 1-4 alkyl-S(O) 2- or -S-; R y halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxy, cyano or -N(R z) 2; and R z hydrogen or C 1-4 alkyl.

[0014] The compound provided herein as Embodiment 2 is the compound described in Embodiment 1, wherein L is a C1-6 alkyl group (e.g., methylene or ethyl) substituted by R2 0-2 times. The compound provided herein as Embodiment 3 is the compound described in Embodiment 1, wherein L is a -OC1-6 alkyl group (e.g., -O-methylene-, -O-ethyl-, or -O-propylidene) substituted by R2 0-2 times. The compound provided herein as Embodiment 4 is the compound described in Embodiment 3, wherein L is a -O-ethylidene or -O-propylidene substituted by R2 0-2 times. The compound provided herein as Embodiment 5 is the compound described in Embodiment 4, wherein L is a -O-ethylidene substituted by R2 0 times.

[0015] The compound provided herein as Embodiment 6 is a compound as described in any one of Embodiments 1-5, wherein R1 is a heterocyclic alkyl group substituted with R5 appearing 0-3 times. The compound provided herein as Embodiment 7 is a compound as described in Embodiment 6, wherein R1 is a 7-(hexahydro-1H-pyrrole) substituted with R5 appearing 0-3 times. The compound provided herein as Embodiment 8 is a compound as described in Embodiment 7, wherein R1 is a 7-(hexahydro-1H-pyrrole) substituted with R5 appearing 0 times. The compound provided herein as Embodiment 9 is a compound as described in Embodiment 7, wherein R1 is a 7-(hexahydro-1H-pyrrole) substituted with R5 appearing 1 time. The compound provided herein as Embodiment 10 is a compound as described in Embodiment 9, wherein R5 is a halogen (e.g., fluorine).

[0016] The compound provided herein as Embodiment 11 is the compound described in Embodiment 6, wherein R1 is a 2-pyrrolidine or 3-pyrrolidine substituted with R5 appearing 0-3 times. The compound provided herein as Embodiment 12 is the compound described in Embodiment 11, wherein R1 is a 3-pyrrolidine substituted with R5 appearing once. The compound provided herein as Embodiment 13 is the compound described in Embodiment 12, wherein R5 is a cyano group.

[0017] The compound provided herein as Embodiment 14 is the compound described in Embodiment 11, wherein R1 is a 3-pyrrolidine substituted with R5 appearing twice. The compound provided herein as Embodiment 15 is the compound described in Embodiment 14, wherein one R5 is a methyl group and the other R5 is a cyano group.

[0018] The compound provided herein as Embodiment 16 is the compound described in Embodiment 11, wherein R1 is a 2-pyrrolidine substituted with R5 appearing twice. The compound provided herein as Embodiment 17 is the compound described in Embodiment 16, wherein R5 is a C1-4 alkyl (e.g., methyl), side-oxygen, cyano, or halogen (e.g., fluorine). The compound provided herein as Embodiment 18 is the compound described in Embodiment 17, wherein one R5 is methyl and the other R5 is fluorine. The compound provided herein as Embodiment 19 is the compound described in Embodiment 17, wherein one R5 is methyl and the other R5 is side-oxygen.

[0019] The compound provided herein as Embodiment 20 is the compound described in Embodiment 3, wherein L is a -O-n-propylidene group substituted by R2 appearing twice. The compound provided herein as Embodiment 21 is the compound described in Embodiment 20, wherein the two R2 groups together with the same carbon atom form a C3-7 cycloalkyl group (e.g., cyclopropyl). The compound provided herein as Embodiment 22 is the compound described in Embodiment 21, wherein R1 is a heterocyclic alkyl group substituted by R5 appearing 0-3 times (e.g., N-hydroxyl). The compound provided herein as Embodiment 23 is the compound described in Embodiment 21, wherein R1 is a hydroxyl group.

[0020] The compound provided herein as Embodiment 24 is a compound as described in any one of Embodiments 1-23, wherein -LR 1 is a compound of type 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 ...

[0021] The compound provided herein as Embodiment 25 is as described in Embodiment 24, wherein -LR 1 is a compound, ..., or ...

[0022] The compound provided herein as Embodiment 26 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 27 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 28 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 29 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 30 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 31 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 32 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 33 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 34 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 35 is the compound described in Embodiment 24, wherein -LR 1 is a compound. The compound provided herein as Embodiment 36 is the same as that described in Embodiment 24, wherein the -LR 1 group is present. The compound provided herein as Embodiment 37 is the same as that described in Embodiment 24, wherein the -LR 1 group is present.

[0023] The compound provided herein as Embodiment 38 is a compound as described in any one of Embodiments 1-37, wherein R3 is an aryl group (e.g., phenyl or naphthyl) substituted by R6 appearing 0-3 times.

[0024] The compound provided herein as Embodiment 39 is the compound described in Embodiment 38, wherein R3 is a naphthyl group substituted by R6 appearing once. The compound provided herein as Embodiment 40 is the compound described in Embodiment 39, wherein R6 is a halogen, amino group, C1-4 alkyl group (e.g., methyl), C1-4 haloalkyl group (e.g., trifluoromethyl or difluoromethyl), hydroxyl group, or C2-4 ynyl group (e.g., ethynyl). The compound provided herein as Embodiment 41 is the compound described in Embodiment 40, wherein R6 is a hydroxyl group.

[0025] The compound provided herein as Embodiment 42 is the compound described in Embodiment 40, wherein R3 is a naphthyl group substituted by R6 appearing twice. The compound provided herein as Embodiment 43 is the compound described in Embodiment 42, wherein R6 is a C1-4 alkyl, C2-4 ynyl, C3-6 cycloalkyl, halogen, hydroxyl, or -N(R2)2. The compound provided herein as Embodiment 44 is the compound described in Embodiment 43, wherein R6 is an ethyl, ethynyl, cyclopropyl, fluorine, chlorine, hydroxyl, or -NH2. The compound provided herein as Embodiment 45 is the compound described in Embodiment 42, wherein one R6 is an ethynyl group and the other R6 is a hydroxyl group. The compound provided herein as Embodiment 46 is the compound described in Embodiment 42, wherein one R6 is an ethyl group and the other R6 is a hydroxyl group. The compound provided herein as Embodiment 47 is the compound described in Embodiment 42, wherein one R6 is an ethyl group and the other R6 is a fluorine group. The compound provided herein as Embodiment 48 is the same as that described in Embodiment 42, wherein both R6 are fluorine. The compound provided herein as Embodiment 49 is the same as that described in Embodiment 42, wherein one R6 is cyclopropyl and the other R6 is hydroxyl. The compound provided herein as Embodiment 50 is the same as that described in Embodiment 42, wherein one R6 is fluorine and the other R6 is hydroxyl. The compound provided herein as Embodiment 51 is the same as that described in Embodiment 42, wherein one R6 is chlorine and the other R6 is -NH₂. The compound provided herein as Embodiment 52 is the same as that described in Embodiment 42, wherein one R6 is ethynyl and the other R6 is fluorine.

[0026] The compound provided herein as Embodiment 53 is the compound described in Embodiment 40, wherein R3 is a naphthyl group substituted by R6 appearing three times. The compound provided herein as Embodiment 54 is the compound described in Embodiment 53, wherein R6 is a C1-4 alkyl, C2-4 alkynyl, halogen, or hydroxyl group. The compound provided herein as Embodiment 55 is the compound described in Embodiment 54, wherein R6 is an ethyl, ethynyl, fluorine, or hydroxyl group. The compound provided herein as Embodiment 56 is the compound described in Embodiment 53, wherein one R6 is a hydroxyl group, another R6 is an ethyl group, and the last R6 is a fluorine group. The compound provided herein as Embodiment 57 is the compound described in Embodiment 53, wherein one R6 is a hydroxyl group, another R6 is an ethynyl group, and the last R6 is a fluorine group. The compound provided herein as Embodiment 58 is the compound described in Embodiment 53, wherein two R6 groups are halogens (e.g., fluorine or chlorine), and the other R6 group is a hydroxyl group.

[0027] The compound provided herein as Embodiment 59 is the compound described in Embodiment 38, wherein R3 is a phenyl group substituted by R6 appearing three times. The compound provided herein as Embodiment 60 is the compound described in Embodiment 59, wherein one R6 is a hydroxyl group, another R6 is a cyclopropyl group, and the last R6 is a chlorine group.

[0028] The compound provided herein as Embodiment 61 is a compound as described in any one of Embodiments 1-37, wherein R3 is a heteroaryl group (e.g., 4-(1H-indazole) or 4-benzo[d]thiazolyl) substituted with R6 0-3 times. The compound provided herein as Embodiment 62 is a compound as described in Embodiment 61, wherein R3 is a 4-(1H-indazole) substituted with R6 2 times. The compound provided herein as Embodiment 63 is a compound as described in Embodiment 62, wherein one R6 is methyl and the other R6 is chlorine. The compound provided herein as Embodiment 64 is a compound as described in Embodiment 61, wherein R3 is a 4-benzo[d]thiazolyl group substituted with R6 2 times. The compound provided herein as Embodiment 65 is a compound as described in Embodiment 64, wherein one R6 is fluorine and the other R6 is -NH2.

[0029] The compound provided herein as Embodiment 66 is a compound as described in any one of Embodiments 1-65, wherein R3 is a compound of type 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19, 19, 19, 19, 19,

[0030] The compound provided herein as Embodiment 67 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 68 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 69 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 70 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 71 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 72 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 73 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 74 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 75 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 76 is the compound described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 77 is the same as that described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 78 is the same as that described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 79 is the same as that described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 80 is the same as that described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 81 is the same as that described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 82 is the same as that described in Embodiment 66, wherein R is a 3-based compound. The compound provided herein as Embodiment 83 is the same as that described in Embodiment 66, wherein R is a 3-based compound.

[0031] The compound provided herein as Embodiment 84 is a compound as described in any one of Embodiments 1-83, wherein W is N and --- is a single bond.

[0032] The compound provided herein as Embodiment 85 is the same as that described in Embodiment 84, wherein X is S. The compound provided herein as Embodiment 86 is the same as that described in Embodiment 85, wherein n is 1 and m is 1. The compound provided herein as Embodiment 87 is the same as that described in Embodiment 86, wherein p is 0. The compound provided herein as Embodiment 88 is the same as that described in Embodiment 86, wherein p is 1. The compound provided herein as Embodiment 89 is the same as that described in Embodiment 88, wherein Rx is -TRy (e.g., CH2OH). The compound provided herein as Embodiment 90 is the same as that described in Embodiment 85, wherein n is 1 and m is 2, or m is 1 and n is 2. The compound provided herein as Embodiment 91 is the same as that described in Embodiment 90, wherein p is 0.

[0033] The compound provided herein as Embodiment 92 is the compound described in Embodiment 84, wherein X is S(O)2. The compound provided herein as Embodiment 93 is the compound described in Embodiment 92, wherein n is 1 and m is 1. The compound provided herein as Embodiment 94 is the compound described in Embodiment 92, wherein n is 1 and m is 2. The compound provided herein as Embodiment 95 is the compound described in Embodiment 92, wherein n is 2 and m is 0. The compound provided herein as Embodiment 96 is the compound described in Embodiments 93, 94 or 95, wherein p is 0.

[0034] The compound provided herein as Embodiment 97 is the compound described in Embodiment 93, wherein p is 2. The compound provided herein as Embodiment 98 is the compound described in Embodiment 97, wherein the two R x together form a bridging ring, wherein the bridging system is further substituted by -C1-4 alkyl groups (e.g., methylene or ethyl groups) with R y appearing 0-2 times. The compound provided herein as Embodiment 99 is the compound described in Embodiment 98, wherein the two R x together form a bridging ring, wherein the bridging system is further substituted by methylene or ethyl groups with R y appearing 0 times.

[0035] The compound provided herein as Embodiment 100 is the compound described in Embodiment 84, wherein X is S(O). The compound provided herein as Embodiment 101 is the compound described in Embodiment 100, wherein n is 1 and m is 1. The compound provided herein as Embodiment 102 is the compound described in Embodiment 100, wherein n is 1 and m is 2. The compound provided herein as Embodiment 103 is the compound described in Embodiment 101 or 102, wherein p is O.

[0036] The compound provided herein as Embodiment 104 is the compound described in Embodiment 84, wherein X is S(O)(NR z). The compound provided herein as Embodiment 105 is the compound described in Embodiment 104, wherein R z is hydrogen. The compound provided herein as Embodiment 106 is the compound described in Embodiment 105, wherein n is 1 and m is 1. The compound provided herein as Embodiment 107 is the compound described in Embodiment 105, wherein n is 1 and m is 2. The compound provided herein as Embodiment 108 is the compound described in Embodiments 106 or 107, wherein p is O.

[0037] The compound provided herein as Embodiment 109 is a compound as described in any one of Embodiments 1-83, wherein it is , , , , , , , , , , , or.

[0038] The compound provided herein as Embodiment 110 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 111 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 112 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 113 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 114 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 115 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 116 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 117 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 118 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 119 is the compound described in Embodiment 109, wherein it is […]. The compound provided herein as Embodiment 120 is as described in Embodiment 109, wherein the compound is...

[0039] The compound provided herein as Embodiment 121 is the compound described in Embodiment 84, wherein x is 0. The compound provided herein as Embodiment 122 is the compound described in Embodiment 121, wherein n is 1 and m is 1. The compound provided herein as Embodiment 123 is the compound described in Embodiment 122, wherein p is 0.

[0040] The compound provided herein as Embodiment 124 is the compound described in Embodiment 122, wherein p is a 1. The compound provided herein as Embodiment 125 is the compound described in Embodiment 124, wherein Rx is a C1-4 alkyl, C1-4 haloalkyl, side-oxygen, or -TRy. The compound provided herein as Embodiment 126 is the compound described in Embodiment 125, wherein -TRy is -CH2CN, CH2OH, -C(O)NH2, or -CH2OMe. The compound provided herein as Embodiment 127 is the compound described in Embodiment 125, wherein Rx is a methyl, difluoromethyl, -CH2CN, CH2OH, -C(O)NH2, or -CH2OMe.

[0041] The compound provided herein as Embodiment 128 is the compound described in Embodiment 122, wherein p is 2. The compound provided herein as Embodiment 129 is the compound described in Embodiment 128, wherein the two R x together form a bridging ring, wherein the bridge is selected from -C1-4 alkyl groups (e.g., methylene or ethyl) further substituted with R y 0-2 times. The compound provided herein as Embodiment 130 is the compound described in Embodiment 129, wherein the two R x together form a bridging ring, wherein the bridge is further substituted with methylene or ethyl with R y 0 times.

[0042] The compound provided herein as Embodiment 131 is the compound described in Embodiment 128, wherein the two Rx atoms together with adjacent carbon atoms form a C3-7 cycloalkyl group further substituted by Ry appearing 0-3 times. The compound provided herein as Embodiment 132 is the compound described in Embodiment 131, wherein the two Rx atoms together with adjacent carbon atoms form a cyclopropyl group further substituted by Ry appearing 0 times.

[0043] The compound provided herein as Embodiment 133 is the compound described in Embodiment 122, wherein p is a 3. The compound provided herein as Embodiment 134 is the compound described in Embodiment 133, wherein two Rx groups together form a bridging ring, wherein the bridge is selected from a -C1-4 alkyl group (e.g., -n-propylene-) further substituted with Ry 0-2 times. The compound provided herein as Embodiment 135 is the compound described in Embodiment 134, wherein two Rx groups together form a bridging ring, wherein the bridge is a n-propylene group further substituted with Ry once. The compound provided herein as Embodiment 136 is the compound described in Embodiment 135, wherein Ry is a cyano group.

[0044] The compound provided herein as Embodiment 137 is a compound as described in any one of Embodiments 1-83, wherein it is , , , , , , , , , , , or.

[0045] The compound provided herein as Embodiment 138 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 139 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 140 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 141 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 142 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 143 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 144 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 145 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 146 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 147 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 148 is the compound described in Embodiment 137, wherein... The compound provided herein as Embodiment 149 is the same as that described in Embodiment 137, wherein... The compound provided herein as Embodiment 150 is the same as that described in Embodiment 137, wherein... The compound provided herein as Embodiment 151 is the same as that described in Embodiment 137, wherein...

[0046] The compound provided herein as Embodiment 152 is the same as that described in Embodiment 121, wherein n is 1 and m is 2. The compound provided herein as Embodiment 153 is the same as that described in Embodiment 152, wherein p is 0. The compound provided herein as Embodiment 154 is the same as that described in Embodiment 152, wherein p is 1. The compound provided herein as Embodiment 155 is the same as that described in Embodiment 154, wherein Rx is a side-oxygen group, C1-4 alkyl group, C1-4 alkoxy group, hydroxyl group, halogen group, cyano group, or -TRy group. The compound provided herein as Embodiment 156 is the same as that described in Embodiment 155, wherein Rx is a methyl group, cyano group, side-oxygen group, hydroxyl group, methoxy group, -C(O)N(H)(Me), -C(O)NH2, -CH2OH, or -SO2NH2.

[0047] The compound provided herein as Embodiment 157 is the compound described in Embodiment 152, wherein p is 2. The compound provided herein as Embodiment 158 ​​is the compound described in Embodiment 157, wherein Rx is a hydroxyl, halogen, C1-4 alkyl, C2-4 ynyl, C3-6 cycloalkyl, or two Rx together form a bridging ring, wherein the bridging ring is a C1-4 alkyl group (e.g., methylene). The compound provided herein as Embodiment 159 is the compound described in Embodiment 158, wherein Rx is a hydroxyl, methyl, ethyl, fluorine, ethynyl, or cyclopropyl. The compound provided herein as Embodiment 160 is the compound described in Embodiment 158, wherein one Rx is a hydroxyl and the other Rx is a methyl or ethyl. The compound provided herein as Embodiment 161 is the compound described in Embodiment 158, wherein one Rx is a hydroxyl and the other Rx is a cyclopropyl. The compound provided herein as Embodiment 162 is the compound described in Embodiment 158, wherein one Rx is a hydroxyl and the other Rx is an ethynyl. The compound provided herein as Embodiment 163 is as described in Embodiment 158, wherein both R x are fluorine.

[0048] The compound provided herein as Embodiment 164 is the compound described in Embodiment 158, wherein two Rx groups together form a bridging ring, and the bridging system is further substituted with methylene groups by Ry appearing 0-2 times. The compound provided herein as Embodiment 165 is the compound described in Embodiment 164, wherein two Rx groups together form a bridging ring, and the bridging system is further substituted with methylene groups by Ry appearing 0 times. The compound provided herein as Embodiment 166 is the compound described in Embodiment 164, wherein two Rx groups together form a bridging ring, and the bridging system is further substituted with methylene groups by Ry appearing 1 time, wherein Ry is a hydroxyl group.

[0049] The compound provided herein as Embodiment 167 is the compound described in Embodiment 121, wherein n is 2 and m is 2. The compound provided herein as Embodiment 168 is the compound described in Embodiment 167, wherein p is 2. The compound provided herein as Embodiment 169 is the compound described in Embodiment 168, wherein two R x together form a bridging ring, wherein the bridging ring is -O- or -C1-4 alkyl, wherein the -C1-4 alkyl is further substituted by Ry appearing 0-2 times. The compound provided herein as Embodiment 170 is the compound described in Embodiment 169, wherein two R x together form a bridging ring, wherein the bridging ring is -O-. The compound provided herein as Embodiment 171 is the compound described in Embodiment 169, wherein two R x together form a bridging ring, wherein the bridging ring is further substituted by a methylene group of Ry appearing once. The compound provided herein as Embodiment 172 is the compound described in Embodiment 171, wherein Ry is a hydroxyl group.

[0050] The compound provided herein as Embodiment 173 is a compound as described in any one of Embodiments 1-83, wherein it is , ...

[0051] The compound provided herein as Embodiment 174 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 175 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 176 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 177 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 178 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 179 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 180 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 181 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 182 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 183 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 184 is the compound described in Embodiment 173, wherein... The compound provided herein as Embodiment 185 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 186 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 187 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 188 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 189 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 190 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 191 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 192 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 193 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 194 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 195 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 196 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 197 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 198 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 199 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 200 is the same as that described in Embodiment 173, wherein [the compound is...]. The compound provided herein as Embodiment 201 is the same as that described in Embodiment 173, wherein [the compound is...].The compound provided herein as Embodiment 202 is the same as that described in Embodiment 173, wherein... The compound provided herein as Embodiment 203 is the same as that described in Embodiment 173, wherein... The compound provided herein as Embodiment 204 is the same as that described in Embodiment 173, wherein... The compound provided herein as Embodiment 205 is the same as that described in Embodiment 173, wherein...

[0052] The compound provided herein as Embodiment 206 is a compound as described in any one of Embodiments 1-205, wherein R4 is a C1-4 alkyl, C1-4 alkoxy, hydroxyl, halogen, or C1-4 haloalkyl. The compound provided herein as Embodiment 207 is a compound as described in Embodiment 206, wherein R4 is a C1-4 alkyl, hydroxyl, or halogen. The compound provided herein as Embodiment 208 is a compound as described in Embodiment 207, wherein R4 is a C1-4 alkyl or halogen. The compound provided herein as Embodiment 209 is a compound as described in Embodiment 208, wherein R4 is a halogen (e.g., fluorine or chlorine). The compound provided herein as Embodiment 210 is a compound as described in Embodiment 209, wherein R4 is fluorine.

[0053] The compound provided herein as Embodiment 211 is the compound as described in Embodiment 1, wherein the compound is a compound having the formula (II): (II).

[0054] The compound provided herein as Embodiment 212 is the compound as described in Embodiment 1, wherein the compound is a compound having the formula (III): (III).

[0055] The compound provided herein as Embodiment 213 is the compound described in Embodiment 1, wherein the compound is a compound having the formula (IV): (IV).

[0056] The compound provided herein as Embodiment 214 is the compound described in Embodiment 1, wherein the compound is a compound having the formula (V): (V).

[0057] The compound provided herein as embodiment 215 is any one of embodiments 1-214, wherein when R is a 3-system, it is not , , , , , , , or.

[0058] The compound provided herein as embodiment 216 is any one of embodiments 1-214, wherein when R is a 3-system, it is not , , , , , , , , or.

[0059] The compound provided herein as Embodiment 217 is as described in any one of Embodiments 1-214, wherein when R is a 3-system, it is not or

[0060] The compound provided herein as Embodiment 218 is any one of Embodiments 1-214, wherein when R is a 3-system, it is not , , or .

[0061] The compound provided herein as Embodiment 219 is as described in any one of Embodiments 1-214, wherein when R is a 3-system, it is not or

[0062] The compound provided herein as Embodiment 220 is as described in any one of Embodiments 1-214, wherein when R is a 3-system, it is not or

[0063] The compound provided herein as Embodiment 221 is as described in any one of Embodiments 1-214, wherein when R is a 3-system, it is not or

[0064] The compound provided herein as Embodiment 222 is as described in any one of Embodiments 1-214, wherein when R is a 3-system, it is not.

[0065] The compound provided herein as Embodiment 223 is as described in any one of Embodiments 1-214, wherein when R is a 3-system, it is not.

[0066] The compound provided herein as Embodiment 224 is the compound described in Embodiment 1, wherein the compound is not: 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiaazacycloheptane; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiocyano; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiocyano; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; (4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-yl)methanol; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol; 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol; (S)-4-(8-fluoro-2-((l-methylpyrrolidin-2-yl)methoxy)-4-o-linopyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;(S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; (S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; 1-(4-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrolin-2-yl)methanesulfonamide; (4-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-2-yl)methanol; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-methylamine; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-(methanesulfonyl)-1,4-oxazacycloheptane; (4-(7-(8-ethylnaphth-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-yl)methanol; 4-(7-(8-ethylnaphth-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-((1-(pyrrolo-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol; 4-(7-(8-ethylnaphth-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazatecycloheptane;5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)-4-(l,4-thiazocycloheptan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)-1,4-oxazazocycloheptan-4-yl)pyrido[1,3d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; (S)-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; (R)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-bromo-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol; 5-bromo-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-chloro-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol;5-Chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(6-(hydroxymethyl)-6-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; (2R,6R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazacycloheptane-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(6-methoxy-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(2,2-dimethyl-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; or 4-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol.

[0067] The compound provided herein as Embodiment 225 is the compound described in Embodiment 1, wherein the compound is not: 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiaazacycloheptane; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiocyano; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiocyano; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; (4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-yl)methanol; 4-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol; 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol; (S)-4-(8-fluoro-2-((l-methylpyrrolidin-2-yl)methoxy)-4-o-linopyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;(S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; or (S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol.

[0068] The compound provided herein as Embodiment 226 is the compound described in Embodiment 1, wherein the compound is selected from one of the following compounds: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(( R)-6-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide;4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-thiazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2 S,4)-yl)-1-oxazetane-6-one; R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3- [d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-6-methoxy-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1- ... S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-carboxylonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol;Or (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol.

[0069] The compound provided herein as Embodiment 227 is the compound described in Embodiment 1, wherein the compound is selected from one of the following compounds: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(( R)-6-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide;Or 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-one.

[0070] The compound provided herein as Embodiment 228 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; [d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol; 5-Ethyl-4-(8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazetane-4-yl)-8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;6-Ethyl-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-6-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-oxazacycloheptan-6-one; H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-thiazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;5-Ethyl-6-fluoro-4-(8-fluoro-2-((1- ... 4-(4-(6-oxo-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxo-azabicycloheptan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylon (isomeric compound 2); 5-ethyl-4-(8-fluoro-2-((1-(1-(1-(1-oxoline-methyl)cyclopropyl)methoxy)-4-(1,4-oxa-azabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4) R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazonicycloheptan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolidin-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazonicycloheptan-6-methylamine (isomeric 2); or 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5H)-yl)methoxy)-4-pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol.

[0071] The compound provided herein as Embodiment 229 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; [d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol; 5-Ethyl-4-(8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazetane-4-yl)-8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;6-Ethyl-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol; or 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazacycloheptan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (isomer 2).

[0072] The compound provided herein as Embodiment 230 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-thio-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-thio-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; H)-yl)methoxy)-4-(1,4-thiazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-((1 R,5 S)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2 S,4 R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 S,4 R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;4-(4-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.2.1]oct-8-ol; 5-ethynyl-4-(8-fluoro-2-(((2 S,4 R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(8-fluoro-4-(1,4-oxazetane-4-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane; 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-((1- ... S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphth-2-ol;5-Ethyl-4-(8-fluoro-2-((1- ... 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-((1- ... (S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-pyrido-[4,3-d]pyrimidin-7-yl)naphth-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxo-azacycloheptan-6-ol; (R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxo-2-yl)heptan-6-ol; H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxa-nitroheptan-6-ol; 4-(4-((1R,5S)-6-oxa-3-azir-biscyclic[3.1.1]hept-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(4-((1S,4R)-2-oxa-5-azir-biscyclic[2.2.2]oct-5-yl)-8-fluoro-2-(((2 R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol;4-(4-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-4-(1,4-oxaazabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-methylpyrrolo-2-one; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-3-carboxylon; 5-ethyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3- [d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-carboxylonitrile; (S)-4-(7-(8-ethyl-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; ( S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thio-1-oxo-1-oxo-1-ylene-6-ol;4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6-thiocyanoline 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptane 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thioazacycloheptane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6,4-thioazacycloheptane 1-oxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6,4-thioazacycloheptane 1-oxide; S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thio-lino)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thio-lino)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-2-methamide (isomer 1);4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-2-carboxamide (Isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-6-carboxamide (Isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazetane-6-carboxamide (Isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-carboxamide (Isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-methylamine (Isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(2-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((S)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Isomer 2);4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-2-methylamine; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-2-methylpyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-2-methylpyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-2-(methoxymethyl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(( S)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(7-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3- [d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]non-9-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide;5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(2-(hydroxymethyl)pyridinoline)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-carboxylon; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-carboxylon S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-sulfonamide; 4-(4-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 2-(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrolin-2-yl)acetonitrile; 4-(4-((1R,6S)-2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-one;4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazacycloheptan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile (isomer 1); 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile (isomer 2); 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazabicycloheptane-6-ol; 6-Cyclopropyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol; 4-(4-(2-(difluoromethyl)olino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol; R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrolin-2-methylamine; or 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol.

[0073] The compound provided herein as Embodiment 231 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-thio-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-thio-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; H)-yl)methoxy)-4-(1,4-thiazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-((1 R,5 S)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2 S,4 R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 S,4 R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;4-(4-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.2.1]oct-8-ol; 5-ethynyl-4-(8-fluoro-2-(((2 S,4 R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(8-fluoro-4-(1,4-oxazetane-4-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane; 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-((1- ... S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphth-2-ol;5-Ethyl-4-(8-fluoro-2-((1- ... 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-((1- ... (S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-pyrido-[4,3-d]pyrimidin-7-yl)naphth-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxo-azacycloheptan-6-ol; (R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxo-2-yl)heptan-6-ol; H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxa-nitroheptan-6-ol; 4-(4-((1R,5S)-6-oxa-3-azir-biscyclic[3.1.1]hept-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(4-((1S,4R)-2-oxa-5-azir-biscyclic[2.2.2]oct-5-yl)-8-fluoro-2-(((2 R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol;4-(4-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-4-(1,4-oxaazabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-methylpyrrolo-2-one; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-3-carboxylon; 5-ethyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3- [d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-carboxylonitrile; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiocarbamoline 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6-thiocarbamoline 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptane 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptane 1,1-dioxide;4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6,4-thiazacycloheptan-1-oxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-6-methoxy-1,4-oxazacycloheptan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-6-methoxy-1,4-oxazacycloheptan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thio-lino)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7aR)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl) 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-2-methylamine (Isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-2-methylamine (Isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-2-methylamine H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-6-carboxamide (Isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-6-carboxamide (Isomer 2);4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-carboxamide (Isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-carboxamide (Isomer 2); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((S)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-2-methylamine; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-2-methylamine; R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-2-methylpyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-2-(methoxymethyl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(7-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]non-9-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]non-9-ol; H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)phosphono)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3- [d]pyrimidin-4-yl)-1,4-oxazetane-6-carboxylonitrile; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide;4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazabicycloheptane-6-sulfonamide; 4-(4-((1 R,5 S)-9-oxa-3-azabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol; 2-(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) pyroline-2-yl)acetonitrile; 4-(4-((1 R,6 S)-2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-one; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazacycloheptane-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile (isomer 1); 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile (isomeric 2);6-Ethyl-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; 6-Cyclopropyl-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; 4-(4-(2-(difluoromethyl)phosphono)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3- [d]pyrimidin-4-yl) pyrimidin-2-methylamine; or 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol.

[0074] The compound provided herein as Embodiment 232 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-thio-7a-linopyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-thiazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-yl) H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol;3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.2.1]oct-8-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolodin-2-yl)methoxy)-4-(1,4-oxazabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; 4-(8-fluoro-4-(1,4-oxazabicycloheptane-4-yl)-2-((tetrahydro-1H-1H-pyrrolo-7a(5H)-yl) H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane; 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(1-(1-(1-oxazetane-4-yl)cyclopropyl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole-7a(5 H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthyl-2-ol; 5-ethyl-4-(8-fluoro-2-((1-(1-(1-oxazacyclomethyl)cyclopropyl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol;4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-((1-(1-(1-oxoline-methyl)cyclopropyl)methoxy)-4-(1,4-oxazabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)phenol; S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-olinepyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; 4-(4-((1 R,5 S)-6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-8-fluoro-2-(((2 R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(4-((1S,4R)-2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(4-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H ...2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-2-yl)-8-fluoro-2-(((2R,7aS H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-methylpyrrolo-2-one; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthyl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolo-3-carboxylon;5-Ethyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-carboxylon; (S)-4-(7-(8-ethyl-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3- [d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptane-6-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3- 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiocyano-1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6-thiocyano-1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptane 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptane 1,1-dioxide;4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6,4-thiazacycloheptan-1-oxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(2-(hydroxymethyl)thio-lino)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-2-carboxamide (Isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-2-carboxamide (Isomer 2); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-2-methylamine; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-2-methylamine; R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-2-methylpyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-2-(methoxymethyl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(7-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]non-9-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]non-9-ol; H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)phosphono)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3- [d]pyrimidin-4-yl)-1,4-oxazetane-6-carboxylonitrile; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide;4-(4-((1 R,5 S)-9-oxa-3-azabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 2-(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrolin-2-yl)acetonitrile; 4-(4-((1 R,6 S)-2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxaazabicycloheptane-6-one; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazacycloheptan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile (isomer 1); 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile (isomer 1); 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile (isomer 2); 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazabicycloheptane-6-ol;6-Cyclopropyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol; 4-(4-(2-(difluoromethyl)oline)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphth-2-ol; R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrolin-2-methylamine; or 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol.

[0075] The compound provided herein as Embodiment 233 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-thio-7a-linopyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-thiazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-yl) H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol;3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.2.1]oct-8-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolodin-2-yl)methoxy)-4-(1,4-oxazabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; 4-(8-fluoro-4-(1,4-oxazabicycloheptane-4-yl)-2-((tetrahydro-1H-1H-pyrrolo-7a(5H)-yl) H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane; 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(1-(1-(1-oxazetane-4-yl)cyclopropyl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole-7a(5 H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthyl-2-ol; 5-ethyl-4-(8-fluoro-2-((1-(1-(1-oxazacyclomethyl)cyclopropyl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol;4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-((1-(1-(1-oxoline-methyl)cyclopropyl)methoxy)-4-(1,4-oxazabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)phenol; S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-olinepyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; 4-(4-((1 R,5 S)-6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-8-fluoro-2-(((2 R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(4-((1S,4R)-2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(4-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H ...2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-2-yl)-8-fluoro-2-(((2R,7aS H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-methylpyrrolo-2-one; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthyl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolo-3-carboxylon;5-Ethyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidin-3-carboxylon; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole-7a(5 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyridolo-[4,3-d]pyrimidin-4-yl)-1-imino-1λ6-thiocyano-1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thioazacycloheptane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6,4-thioazacycloheptane 1-oxide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thio-lino)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-2-methamide (isomer 1);4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazacycloheptane-2-methylamine (Isomer 2); 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-2-methylamine; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-2-methylpyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-2-methylpyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-2-(methoxymethyl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(( S)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(7-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]non-9-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(2-(hydroxymethyl)pyridinoline)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-carboxylon; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-carboxylon S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide; 4-(4-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 2-(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)oline-2-yl)acetonitrile; 4-(4-((1R,6S)-2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol;4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-one; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazacycloheptane-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile (isomer 1); 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile (isomer 2); 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1,4-oxaazabicycloheptane-6-ol; 6-cyclopropyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol; 4-(4-(2-(difluoromethyl)phosphono)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3- [d]pyrimidin-4-yl) pyrimidin-2-methylamine; or 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol.

[0076] The compound provided herein as Embodiment 234 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; [d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol; 5-Ethyl-4-(8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazetane-4-yl)-8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;6-Ethyl-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-6-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-oxazacycloheptan-6-one; H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-thiazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol;5-Ethyl-6-fluoro-4-(8-fluoro-2-((1- ... 4-(4-(6-oxo-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxo-azabicycloheptan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylon (isomeric compound 2); 5-ethyl-4-(8-fluoro-2-((1-(1-(1-(1-oxoline-methyl)cyclopropyl)methoxy)-4-(1,4-oxa-azabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4) R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazonicycloheptan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolidin-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazonicycloheptan-6-methylamine (isomeric 2); or 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5H)-yl)methoxy)-4-pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol.

[0077] The compound provided herein as Embodiment 235 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a R)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyridino[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(( R)-6-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide;4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-thiazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2 S,4)-yl)-1-oxazetane-6-one; R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3- [d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-6-methoxy-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1- ... S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-carboxylonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol;(S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazabicycloheptan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylon (isomer 2); 5-Ethyl-4-(8-fluoro-2-((1- ... [d]pyrimidin-4-yl)-N-methyl-1,4-oxazetane-6-methamide (isomeric compound 2); or 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-oxolinopyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol.

[0078] The compound provided herein as Embodiment 236 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol; [d]pyrimidin-4-yl)-6-methyl-1,4-oxazetane-6-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol; 5-ethyl-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol (isomer 2);3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-one; 5,6-difluoro-4-(8-fluoro-2-(((2 S,4 R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3- [d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1- ... S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylon (isomer 2);5-Ethyl-4-(8-fluoro-2-((1-(1-(1,4-oxazine-7-yl)cyclopropyl)methoxy)-4-(1,4-oxazine-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazine-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; or 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-1,4-oxazine-7-yl)pyrido[4,3- d]pyrimidin-7-yl)naphthyl-2-ol.

[0079] The compound provided herein as Embodiment 237 is the compound described in Embodiment 1, wherein the compound is selected from one of the following: 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-Difluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 6-Ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1 H-oxazetane-6-ol H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-one; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolo-2-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol;3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(1-(1-(1-oxazetane-methyl)cyclopropyl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)phenol; H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-carboxylon; 4-(4-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3- [d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylon (isomer 2); 5-ethyl-4-(8-fluoro-2-((1-(1-(1-oxoline-methyl)cyclopropyl)methoxy)-4-(1,4-oxa-azabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxa-azabicycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; or 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolo-7a(5H)-yl)methoxy)-4-pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol.

[0080] The compound provided herein as Embodiment 238 is the compound described in Embodiment 1, wherein the compound is not from Examples 42, 43, 49, 50, 63, 64, 74, 83, 111, 149, 195, 200, 201, 249, 269, 270, 271, 289, 291, 315, 321, 334, 342, 343, 345, 361, 386, 391, 400, 401, 419, 420, 457, 496, 497, 499, 501 or 522 of International Publication No. WO 2022 / 132200 (International Application No. PCT / US 2021 / 010065).

[0081] The compound provided herein as Embodiment 239 is the compound described in Embodiment 1, wherein the compound is not from Examples 42, 43, 49, 50, 63, 64, 74, 83, 111, 149, 195, 200 or 201 of International Publication No. WO 2022 / 132200 (International Application No. PCT / US2021 / 010065).

[0082] The foregoing only summarizes certain aspects of this disclosure and is not intended, nor should it be construed, as limiting this disclosure in any way. Preparations and Administration Methods

[0083] Although it is possible to administer the compounds disclosed herein alone for the purposes described herein, the compounds are typically administered as active ingredients in a pharmaceutical composition. Therefore, in one embodiment, a pharmaceutical composition is provided herein comprising the compounds disclosed herein in combination with one or more pharmaceutically acceptable excipients (such as diluents, carriers, adjuvants, etc.) and other active ingredients, if desired. See, for example, Remington: The Science and Practice of Pharmacy, Volumes I and II, 22nd ed., edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vols. 1–3), edited by Liberman et al., 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), 1st ed., edited by GD Tovey, Royal Society of Chemistry [Royal Society of Chemistry], 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the compound disclosed herein.

[0084] One or more compounds disclosed herein may be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and at a dose effective for the intended treatment. The compounds and compositions disclosed herein may be administered in dose units containing conventionally pharmaceutically acceptable excipients, for example, orally, via mucosae, topically, percutaneously, rectally, pulmonaryly, parenterally, intranasally, intravascularly, intravenously, intra-arterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by infusion techniques.

[0085] The pharmaceutical composition may be in the following forms: for example, tablets, chewable tablets, small tablets, capsules, pills, beads, hard capsules, soft capsules, gelatin capsules, granules, powders, lozenges, patches, creams, gels, sachets, microneedle arrays, syrups, flavored syrups, juices, drops, injectable solutions, emulsions, microemulsions, ointments, aerosols, aqueous suspensions, or oil suspensions. The pharmaceutical composition is typically prepared in dosage units containing a specific amount of the active ingredient.

[0086] The pharmaceutical composition provided herein as Embodiment 240 comprises a compound or tautomer thereof as described in any one of Embodiments 1-239, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, and a pharmaceutically acceptable excipient.

[0087] The compound or its tautomer as described in any one of Embodiments 1-239, or a pharmaceutically acceptable salt of said compound or its tautomer, or a pharmaceutical composition as described in Embodiment 240, provided herein as Embodiment 241, is intended for use as a medicament.

[0088] As discussed herein (see the section entitled "Definitions"), the compounds described herein should be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates of any of the foregoing substances. Therefore, the scope of the methods and uses provided in this disclosure should also be understood to cover methods and uses employing all such forms.

[0089] The compounds provided herein can be used not only for human treatment but also for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals and rodents. For example, the compounds provided herein can be used to treat animals including horses, dogs, and cats.

[0090] In one embodiment, this disclosure provides a method for treating diseases using the compounds or pharmaceutical compositions disclosed herein, including but not limited to diseases involving KRAS G12D, G12V, G12A, G12S, or G12C mutations (e.g., cancer). Such cancer types include non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary origin, ampullary cancer, gastric cancer, small bowel cancer, sinus cancer, cholangiocarcinoma, or melanoma.

[0091] KRAS G12D mutations occur with the alteration frequencies shown in the table below (TCGA dataset; 1-3). For example, the table shows that 32.4% of pancreatic cancer subjects had cancer in which one or more cells expressed the KRAS G12D mutant protein. Therefore, the compounds that bind to KRAS G12D as described herein (see the section titled "Biological Evaluation" below) may be used to treat subjects with cancer, including but not limited to the cancers listed in the table below. Cancer types Change frequency Pancreatic adenocarcinoma (PAAD) 32.4 Colorectal adenocarcinoma (COAD) 12.25 Rectal adenocarcinoma (READ) 8.03 Endometrial cancer of the uterine body (UCEC) 6.04 Lung adenocarcinoma (LUAD) 3.53 plasmacytoma 2.92 Gastric adenocarcinoma (STAD) 2.27 Bladder urothelial carcinoma (BLCA) 1.46 Cervical squamous cell carcinoma (CESC) 1.38 Renal adenocarcinoma 1.07 thymic carcinoma 0.81 Myeloid leukemia (LAML) 0.69 Hepatocellular carcinoma (LIHC) 0.55 Glioblastoma multiforme (GBM) 0.51 Skin melanoma (SKCM) 0.43 Bladder cancer 0.4 Prostate adenocarcinoma (PRAD) 0.2 Invasive breast cancer (BRCA) 0.1

[0092] The compound provided herein as Embodiment 242 is a pharmaceutically acceptable salt thereof, as described in any one of Embodiments 1-239, or a pharmaceutical composition as described in Embodiment 240, for use in the treatment of cancer.

[0093] The compound described herein as Embodiment 243 is a pharmaceutically acceptable salt thereof, as described in any one of Embodiments 1-239, or a pharmaceutical composition as described in Embodiment 240, for use in the treatment of cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S, or G12C mutant proteins.

[0094] The compound or pharmaceutical composition provided herein as Embodiment 244 is used in Embodiment 242 or 243, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendix cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelometaplasia / myeloproliferative tumor, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0095] The present invention provides for the use of any of the compounds described in Embodiments 1-239 or their pharmaceutically acceptable salts, or pharmaceutical compositions described in Embodiment 240, in the preparation of a medicament for treating cancer.

[0096] The present invention provides for the use of any of the compounds described in Embodiments 1-239 or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described in Embodiment 240, in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant proteins.

[0097] The embodiment 247 provided herein is used as described in embodiment 245 or 246, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, 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, myelometaplasia / myeloproliferative tumor, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0098] The method provided herein as Embodiment 248 is a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1-239.

[0099] The method of treating a subject with cancer as Embodiment 249 provided herein includes administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1-239, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant proteins.

[0100] The method provided herein as Embodiment 250 is as described in Embodiment 248 or 249, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelometaplasia / myeloproliferative tumor, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0101] The method provided herein as Embodiment 251 is the method described in Embodiment 248 or 249, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary origin, ampullary cancer, gastric cancer, small bowel cancer, sinus cancer, bile duct cancer, or melanoma.

[0102] The method provided herein as Embodiment 252 is the method described in Embodiment 251, wherein the cancer is non-small cell lung cancer.

[0103] The method provided herein as embodiment 253 is the method described in embodiment 251, wherein the cancer is colorectal cancer.

[0104] The method provided herein as Embodiment 254 is the method described in Embodiment 251, wherein the cancer is pancreatic cancer.

[0105] The method provided herein as Embodiment 255 is as described in any one of Embodiments 248-254, wherein the subject has cancer, and it is determined that the cancer has one or more cells expressing KRAS G12D, G12V, G12A, G12S, or G12C mutant proteins prior to administration of the compound or a pharmaceutically acceptable salt thereof. Combination therapy

[0106] This disclosure also provides methods for use in combination therapies, wherein an agent known to modulate other components of other or identical pathways, or even an overlapping set of target enzymes, is used in combination with a compound of the disclosure or a pharmaceutically acceptable salt thereof. In one aspect, such therapies include, but are not limited to, combinations of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide synergistic or additive therapeutic effects. See, for example, U.S. Patent No. 10,519,146 B2, published December 31, 2019; specifically, sections 201 (line 37) through 212 (line 46) and 219 (line 64) through 220 (line 39), which are incorporated herein by reference.

[0107] The method provided herein as Embodiment 256 is as described in any one of Embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an aurora kinase A inhibitor, AKT inhibitor, argininase inhibitor, CDK4 / 6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutamate 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 agents.

[0108] In one embodiment, the second compound is administered as a pharmaceutically acceptable salt. In another embodiment, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Aurora Kinase A Inhibitor

[0109] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an aurora kinase A inhibitor.

[0110] Exemplary aurora kinase A inhibitors used 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-methylpiperidin-4-carboxylic acid), and ENMD-2076 (6-(4-methylpiperidin-4-carboxylic acid)). 𠯤-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylvinyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylmethanephenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indol-7-methylamine), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradecano-1(14),3,6,8,10,12-hexen-13-yl] α-line), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthaloyl-1-amine), MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimidino[5,4-d][2]benzoza-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]amino) [-11-azatricyclo[6.2.1.02,7]undec-2(7),3,5-trien-11-yl]-2-sideoxyethyl]acetamide), SNS-314 (1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-1,3-thiazolyl-2-yl]urea), CYC116 (4-methyl-5-[2-(4-pyrimidin-4-ylaniline)pyrimidin-4-yl]-1,3-thiazolyl-2-ylamine), TAS-119, BI 811283, and TTP607. AKT inhibitors

[0111] This document provides a method as described in any of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0112] Exemplary AKT inhibitors used 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]tadalafil-6-methoxymethylamine), 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]naphthidium-3-one), SR13668 (indodo[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-tetraazatricyclo[7.4.0.02,6]tetrazol-1(9),5-dien-8-one), ARQ 751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-sideoxyquinazoline-2-yl)but-3-ynyl]-3-chloro-2-fluorobenzoamide), RX-0201, and LY2780301. Arginase inhibitors.

[0113] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

[0114] Exemplary arginase inhibitors used in the methods provided herein include, but are not limited to, numidargistat and CB 280. CDK4 / 6 inhibitors

[0115] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

[0116] As used herein, the term "CDK 4 / 6" refers to cyclin-dependent kinases ("CDK") 4 and 6, which are members of mammalian serine / threonine protein kinases.

[0117] As used herein, the term "CDK 4 / 6 inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the enzyme activity of CDK 4 and / or 6.

[0118] Exemplary CDK 4 / 6 inhibitors used 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-(methylsulfonylurea)-4-piperidinyl]amino]).

[0119] In one embodiment, the CDK4 / 6 inhibitor is palbociclib. (ErbB family inhibitor)

[0120] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

[0121] As used herein, the term “ErbB family” refers to members of the mammalian transmembrane protein tyrosine kinase family, which includes ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).

[0122] As used herein, the term "ErbB family inhibitor" means an agent, such as a compound or antibody, capable of negatively regulating or inhibiting all or part of the activity of at least one member of the ErbB family. Regulation or inhibition of one or more ErbB tyrosine kinases can be achieved by regulating or inhibiting the kinase activity of one or more ErbB family members or by blocking the homodimerization or heterodimerization of ErbB family members.

[0123] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, such as an anti-EGFR antibody. Exemplary anti-EGFR antibodies used in the methods provided herein include, but are not limited to: zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab. In one embodiment, the anti-EGFR antibody is cetuximab. In one embodiment, the anti-EGFR antibody is panitumumab.

[0124] In another embodiment, the ErbB family inhibitor is a HER2 inhibitor, such as an anti-HER2 antibody. Exemplary anti-HER-2 antibodies used in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.

[0125] In yet another embodiment, the ErbB family inhibitor is a HER3 inhibitor, such as an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).

[0126] In one embodiment, the ErbB family inhibitor is a combination of anti-EGFR antibody and anti-HER2 antibody.

[0127] In one embodiment, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors used 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-piperyl)-1-butyn-1-yl]-6-quinazolinyl]-2-acrylamide), PF 6274484 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-acrylamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinoline-6-yl]-4-(dimethylamino)but-2-enylamine).

[0128] In one embodiment, the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.

[0129] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors used 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-methylbutyramine), AEE788 ((S)-6-(4-((4-ethylpiperazine-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS 599626 ((3S)-3-oline-methyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]tris(oline-6-yl)-aminocarbamate), and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylutriylethylamino)methyl]-1,3-thiazolyl]quinazolin-4-amine).

[0130] In one embodiment, the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib. ERK inhibitor

[0131] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0132] Exemplary ERK inhibitors used 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-enylamine), LY3214996 (6,6-di Methyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-pyrolin-4-ylethyl)thieno[2,3-c]pyrrolo-4-one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187. FAK inhibitors

[0133] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0134] Exemplary FAK inhibitors used in the methods provided herein include, but are not limited to: GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-prop-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-sideoxy-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), VS-4718 (2-[[2-(2-methoxy-4-oline-4-ylaniline)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide), and APG-2449. FGFR inhibitors

[0135] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0136] Exemplary FGFR inhibitors used in the methods provided herein include, but are not limited to: futibatibatinib, 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-dimethylpiperazine-1-yl]benzamide), debio 1347 ([5-amino-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methyl ketone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)aminomethylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazine-1-yl)phenyl]prop-2-enylamine), ICP-105, CPL304110, HMPL-453, and HGS1036. Glutaminase inhibitors.

[0137] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a glutamate inhibitor.

[0138] Exemplary glutamate inhibitors used in the methods provided herein include, but are not limited to: telaglenastat, IPN60090, and OP 330. IGF-1R inhibitors

[0139] This document provides a method as described in any one of embodiments 234-241, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0140] Exemplary IGF-1R inhibitors used in the methods provided herein include, but are not limited to: cixutumab, dalotuzumab, linsitinib, ganytumab, robatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazole-3-) [-yl)amino]pyrrolo[2,1-f][1,2,4]tris(2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidin-2-methylamine), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazine-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)vinyl]phenyl]-3-methylthiophene-2-methylamine), PL225B, AVE1642, and BIIB022. KIF18A inhibitors

[0141] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0142] Exemplary KIF18A inhibitors used 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 incorporated herein by reference in its entirety. MCL-1 inhibitors

[0143] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0144] Exemplary MEK inhibitors used 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-(methiminomethylene)-14,20:26,23-dimethylene-10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxazonodithiadiazacyclohexadecane-32-carboxylic acid), MIK 665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperyl)ethoxy]phenyl]-6-(4-fluorophenyl)thiopheno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4-pyrimidinyl]methoxy]phenylpropionic acid), and ABBV-467.

[0145] In one embodiment, the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax. MEK inhibitor

[0146] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0147] Exemplary MEK inhibitors used in the methods provided herein include, but are not limited to: trametinib, cobimetinib, selumetinib, pimastetinib, remetinib, 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-sideoxypyridine-3-methylamine, GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-methylamine), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-sideoxyacetyl-2-yl)methyl]benzamide), TAK-7 33 (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), PD3180 88 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzylamine), PD98059 (2-(2-amino-3-methoxyphenyl)-4H-chromene-4-one), PD334581 (N-[5-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-1,3,4-diazol-2-yl]-4-oxolinylamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554.

[0148] In one embodiment, the MEK inhibitor is tramotinib. mTOR inhibitor

[0149] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0150] Exemplary mTOR inhibitors used 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, and Torin-1. (1-(4-(4-propylopyr-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthidin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylpyrolino)-7-(oxecyclobutane-3-yl)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)phenyl)urea), and VS-5584 (SB2343, (5-(8-methyl-2-pyrolin-4-yl-9-prop-2-ylpurine-6-yl)pyrimidin-2-amine).

[0151] In one embodiment, the mTOR inhibitor is everolimus. PD-1 inhibitor

[0152] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0153] Exemplary PD-1 inhibitors used 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 anti-PD-1 antibodies (such as US 10,640,504). B2 (“Anti-PD-1 Antibody A”, Column 66, Line 56 to Column 67, Line 24 and Column 67, Lines 54-57) is mentioned in this article by reference.

[0154] In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment, the PD-1 inhibitor is anti-PD-1 antibody A. PD-L1 inhibitor

[0155] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.

[0156] Exemplary PD-L1 inhibitors used 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.

[0157] In one embodiment, the PD-L1 inhibitor is atezolizumab. PI3K inhibitor

[0158] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0159] Exemplary PI3K inhibitors used in the methods provided herein include, but are not limited to: idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, tolisicosib, voxtalisib, sonolisib, tenalisib, s erabelisib, acalisib, CUDC-907 (N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-hydroxylin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidin-5-methamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]prop-2-yl]-4-(2-methylsulfonylinobenzimidazol-1-yl)-6-hydroxylin-4-yl-1,3,5 ... -tris(2-amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-sideoxy-2-phenylisoquinoline-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-methylamine), SF1126 ((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethyleneamino)-2-[[4-sideoxy-4-[[4-(4-sideoxy-8-yl)-8-yl)-2-[[4-sideoxy-4-[[4-(4-sideoxy-8-yl)-2 ... -Phenylacetin-2-yl)phospholin-4-on-4-yl]methoxy]butyryl]amino]pentyl]amino]acetyl]amino]propionyl]amino]-3-hydroxypropionate), XL147 (N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoline-2-yl]-4-methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinoline-6-yl)methylene]-1,3-thiazolidin-2,4-dione), and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinoline-3-yl)ethyl]-7H-purine-6-amine). Raf kinase inhibitors

[0160] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

[0161] As used herein, the term "RAF kinase" refers to a member of a mammalian serine / threonine kinase consisting of three isotypes (C-Raf, B-Raf and A-Raf), and includes homodimers of each isotype as well as heterodimers between isotypes (e.g., C-Raf / B-Raf heterodimer).

[0162] As used herein, the term "Raf kinase inhibitor" means a compound that can negatively regulate or inhibit all or part of the enzyme activity of one or more members of the Raf family of kinases, or that can disrupt the inhibitory activity of Raf homodimer or heterodimer formation.

[0163] In one embodiment, the Raf kinase inhibitor includes, 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- Fluoropyrrolidone-1-sulfenamide), Raf-709 (N-(2-methyl-5,-hydroxy-6'-((tetrahydro-2H-piperan-4-yl)oxy)-[3,3'-bipyridine]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6-hydroxy-6-hydroxy-6-hydroxy-6-pyridine-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isocyanamide), 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)acetamino)phenoxy)benzo[d]thiazolyl)cyclopropanemethylamine), CEP-32496 (1-(3-((6,7-dimethoxyquinazoline-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropyl-2-yl)iso (1-(3-(tributyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-sideoxy-3,4-dihydropyridino[2,3-b]pyridino-8-yl)oxy)phenyl)urea), and RO5126766 (N-[3-fluoro-4-[[4-methyl-2-sideoxy-7-(2-pyrimidinyloxy)-2H-1-benzopiperan-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfonamide).

[0164] In one embodiment, the Raf kinase inhibitor is encorafenib. In one embodiment, the Raf kinase inhibitor is sorafenib. In one embodiment, the Raf kinase inhibitor is lifirafenib. SHP2 inhibitor

[0165] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an SHP2 inhibitor.

[0166] Exemplary SHP2 inhibitors used in the methods provided herein include, but are not limited to: SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyridine-2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyridine-2-yl]methanol), TNO155, (3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4-yl)thioalkylpyridine-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine), and RMC-4630 (Revolution Pharmaceuticals). In one embodiment, the SHP inhibitor used in the methods provided herein is RMC-4630 (Revolution Pharmaceuticals).

[0167] In another embodiment, exemplary SHP2 inhibitors for 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-pyridinemethanol (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-pyridinemethanol (CAS 2172652-13 ...methoxy-8-methyl-2-methyl-2-pyridinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-methoxy-8-methyl-2-methyl-2-pyridinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-methoxy-8-methyl-2-methyl-2-pyridinemethanol (CAS 2172652-13-8), 3-[(3 S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1-azacyclobutyl)-4-pyridyl]thio]-5-methyl-2-pyridinemethanol (CAS 2172652-38-7), and 6-[(2-amino-3-chloro-4-pyridyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyridinemethanol (CAS 2172652-48-9).

[0168] In another embodiment, exemplary SHP2 inhibitors used in the methods provided herein include, but are not limited to: 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazo-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazo-8-yl]-8-azaspiro[4.5]dec-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazo-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (CAS 2240981-78-4). 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridyl)thio]pyrazolo[1,5-a]pyrazolo-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-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]pyrazolo-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]pyrazol-2-methanol (CAS 2240982-73-2), and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazol-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (CAS 2240982-77-6).

[0169] In one embodiment, the SHP inhibitor used in the method provided herein is (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyridine-8-yl]-8-azaspiro[4.5]dec-1-amine (CAS 2240981-78-4).

[0170] In another embodiment, exemplary SHP2 inhibitors for 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-pyridinol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinephenol (CAS 2238840-56-5). 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinylmethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridyl]-8-azaspiro[4.5]dec-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-pyridinylmethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridyl]-8-azaspiro[4.5]dec-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinephenol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[(2,3-dichlorophenyl)thio]-3-pyridinephenol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[(2,3-dichlorophenyl)thio]-3-pyridinephenol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-3-pyridinephenol]-2-[(2,3-dichlorophenyl)thio]-3-pyridinephenol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridyl]-8 ... 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinylmethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinylmethanol (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-pyridinylmethanol (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-pyridinylmethanol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridyl)thio]- ... 2238840-69-0), 6-[(2-amino-3-chloro-4-pyridyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyridinol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinol (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-pyridinol (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 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2 ...2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S) 2238840-75-8), and 2-[(2-amino-3-chloro-4-pyridinyl)thioalkyl]-5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(hydroxymethyl)pyridin-3-ol.

[0171] In one embodiment, the SHP inhibitor used in the method 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).

[0172] In one embodiment, the SHP2 inhibitor used 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, each of which is incorporated herein by reference in its entirety. SOS1 Inhibitor

[0173] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

[0174] Exemplary SOS1 inhibitors used 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)-oxacyclopentan-3-yl]oxyquinazoline-4-amine) and BI 1701963. Src kinase inhibitors

[0175] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.

[0176] As used herein, the term “Src kinase” refers to a member of the mammalian non-receptor tyrosine kinase family, which includes: Src, Yes, Fyn and Fgr (SrcA subfamily); Lck, Hck, Blk and Lyn (SrcB subfamily) and Frk subfamily.

[0177] As used herein, the term "Src kinase inhibitor" refers to a compound that can negatively regulate or inhibit the activity of all or part of one or more Src kinase members.

[0178] Exemplary Src kinase inhibitors used in the methods provided herein include, but are not limited to: dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2-hydroxyphenoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-sideoxy-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indololin-5-sulfonamide), PP 1 (1-(tributyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperyl-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate), and KX-01 (N-benzyl-2-(5-(4-(2-pyriminoethoxy)phenyl)pyridin-2-yl)acetamide).

[0179] In one embodiment, the Src kinase inhibitor is dasatinib. In one embodiment, the Src kinase inhibitor is salatinib. In one embodiment, the Src kinase inhibitor is panatinib. In one embodiment, the Src kinase inhibitor is vandetanib. In one embodiment, the Src kinase inhibitor is KX-01. Chemotherapy agents

[0180] This document provides a method as described in any one of embodiments 248-255, the method further comprising simultaneously, separately or sequentially administering an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agents.

[0181] Exemplary chemotherapeutic agents used in the methods provided herein include, but are not limited to, leucovorin calcium (leucovorin), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate. Definitions

[0182] The following definitions are provided to help understand the scope of this disclosure.

[0183] Unless otherwise stated, all figures representing amounts of ingredients, reaction conditions, etc., used in this specification and the claims should be understood to be modified by the term "about" in all cases. Therefore, unless indicated to the contrary, the numerical parameters presented in the following specification and the appended claims are approximate values, which may vary according to the standard deviation found in their respective test measurements.

[0184] As used herein, if any variable appears more than once in a chemical formula, its definition for each occurrence is independent of its definition for each subsequent occurrence. If a chemical structure and chemical name conflict, the chemical structure will determine the identity of the compound. Stereoisomers

[0185] The compounds disclosed herein may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with hindered rotation, and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), mirror-image isomers, non-mirror-image isomers, and restricted configuration isomers. Therefore, unless the stereochemistry is explicitly determined, the scope of this disclosure is to be understood to cover all possible stereoisomers of the compounds shown, including pure stereoisomers (e.g., pure geometric isomers, pure mirror-image isomers, pure non-mirror-image isomers, and pure restricted configuration isomers) and mixtures of stereoisomers (e.g., mixtures of geometric isomers, mirror-image isomers, non-mirror-image isomers, and restricted configuration isomers, or mixtures of any of the foregoing) of any chemical structure (all or part) disclosed herein.

[0186] If the stereochemistry of a structure or part thereof is not indicated by, for example, a thick or dashed line, then the structure or part thereof shall be interpreted as encompassing all its stereoisomers. If the stereochemistry of a structure or part thereof is indicated by, for example, a thick or dashed line, then the structure or part thereof shall be interpreted as encompassing only the stereoisomers shown. Bonds drawn with wavy lines indicate that both stereoisomers are encompassed. Do not confuse this with wavy lines drawn perpendicular to the bonds, indicating the attachment points of groups to the rest of the molecule.

[0187] As used herein, the term "stereoisomer" or "stereoisomer-pure" compound refers to a stereoisomer of the compound (e.g., a geometric isomer, mirror image isomer, non-mirror image isomer, and restricted configuration isomer) that substantially does not contain other stereoisomers of the compound. For example, a stereoisomer-pure compound having one chiral center will substantially not contain mirror image isomers of the compound, and a stereoisomer-pure compound having two chiral centers will substantially not contain other mirror image or non-mirror image isomers of the compound. A typical stereoisomer pure compound comprises, by weight, more than about 80% of the compound and other stereoisomers equal to or less than about 20% of the compound; more than about 90% of the compound and other stereoisomers equal to or less than about 10% of the compound; more than about 95% of the compound and other stereoisomers equal to or less than about 5% of the compound; or more than about 97% of the compound and other stereoisomers equal to or less than about 3% of the compound.

[0188] This disclosure also covers the use of pharmaceutical compositions comprising pure stereoisomers and pure stereoisomers of any compounds disclosed herein. Furthermore, this disclosure covers the use of pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein, and mixtures of said pharmaceutical compositions or stereoisomers. Such stereoisomers or mixtures thereof can be synthesized according to methods well known in the art and methods disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques such as chiral columns or chiral resolving agents. Additionally, this disclosure covers pharmaceutical compositions comprising mixtures of any compounds disclosed herein and one or more other other active pharmaceutical agents disclosed herein. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by Eliel, Univ. of Notre Dame Press, Notre Dame, Indiana, 1972). Tautomers

[0189] As is known to those skilled in the art, some of the compounds disclosed herein can exist in one or more tautomer forms. Because a chemical structure can only be used to represent one tautomer form, for convenience it should be understood that references to compounds having a given structural formula include other tautomers having said structural formula. Therefore, the scope of this disclosure should be understood to cover all tautomer forms of the compounds disclosed herein. Isotope-labeled compounds

[0190] Furthermore, the scope of this disclosure includes all pharmaceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds having Formula I, wherein one or more atoms are replaced by atoms having the same number of atoms but with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2H and 3H; isotopes of carbon, such as 11C, 13C, and 14C; isotopes of chlorine, such as 36CI; isotopes of fluorine, such as 18F; isotopes of iodine, such as 123I and 125I; isotopes of nitrogen, such as 13N and 15N; isotopes of oxygen, such as 15O, 17O, and 18O; isotopes of phosphorus, such as 32P; and isotopes of sulfur, such as 35S. Certain isotopically labeled compounds of Formula I (e.g., those incorporating radioisotopes) can be used in studies of drug and / or substrate tissue distribution. Radioisotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly suitable for this purpose due to their ease of incorporation and ready-to-use detection methods. Substitution with isotopes (such as deuterium, 2H, or D) can provide certain therapeutic advantages derived from higher metabolic stability (e.g., prolonged in vivo half-life or reduced dose requirements), and is therefore preferred in some cases. For example, substitution with positron emission isotopes (such as 11C, 18F, 15O, and 13N) can be used in positron emission tomography (PET) studies to examine target occupancy. The isotopically labeled compounds disclosed herein can generally be prepared using conventional techniques known to those skilled in the art, or by methods similar to those described in the appended general synthetic protocols and examples, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents. Solvates

[0191] As discussed above, the compounds disclosed herein, their stereoisomers, tautomers and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing, can exist in solvated or non-solvated forms.

[0192] As used herein, the term "solvent" means a molecular complex comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules in stoichiometric or non-stoichiometric amounts. If the solvent is water, the solvate is referred to as a "hydrate".

[0193] Therefore, the scope of this disclosure should be understood to cover all solvents of the compounds disclosed herein, as well as their stereoisomers, tautomers, and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing. Other definitions

[0194] This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0195] The term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in its ring moiety. Typically, aryl is a monocyclic, bicyclic, or tricyclic aryl group having 6-20 carbon atoms. Furthermore, as used herein, the term "aryl" refers to an aromatic substituent, which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl, each of which may be substituted with 1-4 substituents as desired, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxyl, alkoxy, acetyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S-nitro, cyano, carboxyl, alkyl-OC(O)--, aminomethyl, alkyl-S(O)-, sulfonylutri, sulfonyluamine, phenyl, and heterocyclic alkyl.

[0196] As used herein, the terms "C1-4 alkyl" and "C1-6 alkyl" refer to straight-chain or branched hydrocarbons containing 1 to 4 and 1 to 6 carbon atoms, respectively. Representative examples of C1-4 alkyl or C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

[0197] The terms "C1-4 alkylene" and "C1-6 alkylene" refer to straight-chain or branched divalent alkyl groups containing 1 to 4 and 1 to 6 carbon atoms, respectively, as defined herein. Representative examples of alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, secondary butylene, isobutylene, tertiary butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, and similar groups.

[0198] As used herein, the term "C 2-4 alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms and having at least one carbon-carbon double bond. Alkenyl groups include straight-chain and branched portions. Representative examples of C 2-4 alkenyl groups include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0199] As used herein, the term "C2-4 ynyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms and having at least one carbon-carbon triple bond. The term includes both straight-chain and branched portions. Representative examples of C3-6 ynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, and 3-butynyl.

[0200] As used herein, the terms "C1-4 alkoxy" or "C1-6 alkoxy" refer to -OR#, where R# as defined herein represents a C1-4 alkyl group or a C1-6 alkyl group, respectively. Representative examples of C1-4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Representative examples of C1-6 alkoxy groups include, but are not limited to, ethoxy, propoxy, isopropoxy, and butoxy.

[0201] As used herein, the term "C3-8 cycloalkyl" refers to a saturated carbocyclic molecule having a cyclic skeleton of 3 to 8 carbons. Representative examples of C3-8 cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.

[0202] As used herein, the term "deuterium-containing" as another term prefix for a chemical group refers to a modification of the chemical group in which one or more hydrogen atoms are replaced by deuterium ("D" or "2H"). For example, the term "C1-4 deuterium-containing alkyl" refers to a C1-4 alkyl group as defined herein, in which one or more hydrogen atoms are replaced by D. Representative examples of C1-4 deuterium-containing alkyl groups include, but are not limited to, -CH2D, -CHD2, -CD3, -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3).

[0203] As used herein, the term "halogen" refers to -F, -CI, -Br or -I.

[0204] As used herein, the term "halogenated" as another term prefix for a chemical group refers to a modification of a chemical group in which one or more hydrogen atoms are substituted with a halogen, as defined herein. The halogen is chosen independently each time it appears. For example, the term "C1-4 haloalkyl" as defined herein refers to a C1-4 alkyl group in which one or more hydrogen atoms are substituted with a halogen. Representative examples of C1-4 haloalkyl groups include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3).

[0205] As used herein, the term "heteroaryl" refers to a 5-20 member monocyclic, bicyclic, or tricyclic aromatic ring system having 1 to 8 heteroatoms selected from N, O, and S. In some preferred aspects, the heteroaryl system is a 5-10 member ring system (e.g., a 5-7 member monocyclic, an 8-10 member bicyclic, or an 11-14 member tricyclic) or a 5-7 member ring system. Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrroleyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-azololyl, 3-, 4- or 5-isoazololyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridinyl, 3- or 4-pyridyl, 3-, 4- or 5-pyridyl, 2-pyridyl, and 2-, 4- and 5-pyrimidinyl. Exemplary bicyclic heteroaryl groups include 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7- or 8-benzimidazolyl, and 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-indolyl.

[0206] The term "heteroaryl" also refers to a group in which a heteroaryl ring is fused with one or more aryl, alicyclic or heterocyclic alkyl rings.

[0207] As used herein, the terms "heterocycle," "heterocyclic alkyl," or "heterocyclo" refer to a saturated or unsaturated non-aromatic ring or cyclic system, for example, a 4, 5, 6, or 7-membered monocyclic system, a 7, 8, 9, 10, 11, or 12-membered bicyclic system, or a 10, 11, 12, 13, 14, or 15-membered tricyclic system, and contain at least one heteroatom selected from O, S, and N, wherein N and S may also be oxidized to various oxidation states as needed. Heterocyclic groups may be linked at heteroatoms or carbon atoms. Heterocyclic alkyl groups may include fused or bridged rings and spirocyclic rings. Examples of heterocycles include tetrahydrofuran, dihydrofuran, 1,4-dioxane, piperidine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazoline, pyrrolidine, tetrahydropiperidine, dihydropiperidine, oxothiocyclopentane, dithiopentane, 1,3-dioxane, 1,3-dioxane, oxathiophene, thiopiperidine, azacyclobutane, thiazoline, piperidine and similar groups.

[0208] As used herein, the term "pharmaceutically acceptable" means something that is generally accepted for use in subjects (particularly humans).

[0209] As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or acid addition salts formed with organic acids (such as 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-hydroxybenzoic acid)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.); or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions (such as alkali metal ions, alkaline earth metal ions, or aluminum ions); or salts formed by coordination with organic bases (such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, dicyclohexylamine, etc.). Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). See also Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2nd revised edition (2011).

[0210] As used herein, the term "pharmaceuticalally acceptable excipient" refers to a variety of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations. Typically, excipients include, but are not limited to, diluents, colorants, mediators, anti-adhesives, flow aids, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0211] As used herein, the term "subject" refers to humans and mammals, including but not limited to primates, cattle, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment, the subject is a human.

[0212] As used herein, the term "therapeuticly effective amount" means an amount of the compound disclosed herein that would elicit a biological or medical response in a tissue, system, or subject sought by an investigator, veterinarian, physician, or other clinician. General synthetic procedures

[0213] The compounds provided herein can be synthesized according to the procedures described in this section and the following sections. As will be understood by those skilled in the art, the synthetic methods described herein are merely exemplary, and the compounds disclosed herein can also be synthesized using alternative synthetic strategies via alternative routes. It should be understood that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed in any way as limiting the scope of this disclosure.

[0214] Generally, compounds having Formula I can be synthesized according to the following schemes. Unless otherwise stated, any variables used in the following schemes are variables defined for Formula I. All starting materials are commercially available (e.g., from Merck Sigma-Aldrich Inc., Fluorochem Ltd., and Enamine Ltd.); or are known in the art and can be synthesized using common techniques by known procedures. Starting materials can also be synthesized via the procedures disclosed herein. Suitable reaction conditions (e.g., solvents, reaction temperatures, and reagents) for the schemes discussed in this section can be found in the examples provided herein. Scheme I

[0215] A compound having formula (I) can be prepared according to scheme I. In step A, compound (I-1) is treated with an aliphatic alcohol (such as benzyl alcohol) and a base (such as hunig's base) or a metal alkoxide (such as potassium tributoxide) in a solvent (such as 1,4-dimethylamine) to give compound (I-2). In step B, in the presence of a base (such as hunig's base), compound (I-2) undergoes a SNAr reaction with a nucleophile having formula R1-LH in a solvent (such as acetonitrile) to give compound (I-3). In step C, compound (I-3) is coupled with an organometallic reagent or a borate (ester) to provide compound (I-4). This coupling reaction is carried out in a solvent or a mixture of solvents (such as 1,4-dimethylamine and water) and a catalyst (such as cataCXium A Pd G3) with or without a base (such as potassium phosphate). In step D, compound (I-4) is treated with a suitable set of reagents (e.g., Pd / C containing H₂) to remove the alkyl group R, giving compound (I-5). In step E, compound (I-5) is treated with a substituted cyclic amine in a solvent (e.g., DMA) in the presence of a coupling agent (e.g., HATU) and a base (e.g., juniper base) to give a compound having formula (I). In some cases, such R₃ will contain one or more protecting groups, which can be removed after step D or step E in the synthetic sequence. Scheme II

[0216] The compound having formula (I) can also be prepared according to scheme II. In step A, in a solvent (e.g., dichloromethane) and in the presence of a base (e.g., juniper), compound (1) undergoes an S NAr reaction with a substituted cyclic amine as desired to give compound (I-10). In step B, in the presence of a base (e.g., juniper), compound (I-10) undergoes an S NAr reaction with a nucleophile having formula R1-LH in a solvent (e.g., acetonitrile) to give compound (I-11). In step C, compound (I-11) is coupled with an organometallic reagent or a borate (ester) to provide the compound having formula (I). This coupling reaction is carried out in a solvent or solvent mixture (e.g., 1,4-dioxane and water) and a catalyst (e.g., cataCXium A Pd G3) with or without a base (e.g., potassium phosphate). In some cases, this type of R3 will contain one or more protecting groups, which can be removed after step C in the synthetic sequence. Example

[0217] This section provides specific examples of compounds having Formula I and their preparation methods. List of abbreviations [Table 1]. Ac Acetyl AcOH Acetic acid aq or aq. Water-based Bn benzyl B2pin2 Bis(yīn) diborone BOC or Boc Tertiary butoxycarbonyl cataCXium A Pd G2 Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) cataCXium A Pd G3 Methanesulfonate [(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) COD or cod 1,5-Cyclooctadiene DABCO 1,4-Diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-Dichloroethane DCM dichloromethane DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO dimethyl sulfoxide Dppf, DPPF, or dppf 1,1'-Bis(diphenylphosphine)ferrocene Dtbbpy 4,4'-Di-tert-butyl-2,2'-dipyridyl eq or eq. or equiv. equivalent ESI or ES Electrolysis and ionization Et Ethyl EtOAc Ethyl acetate G gram H Hour HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBpin 4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane HMPA Hexamethylphosphonamide HOAc Acetic acid HPLC High-pressure liquid chromatography iPr Isopropyl iPr2NEt or DIPEA N-Ethyldiisopropylamine (Hünig's base) KOAc Potassium acetate LAH Lithium aluminum hydride LC MS, LCMS, LC-MS or LC / MS Liquid chromatography-mass spectrometry LHMDS or LiHMDS Hexamethyldisilyllithium azide m / z mass-to-charge ratio mCPBA m-chloroperoxybenzoic acid Me methyl MeCN Acetonitrile MeOH methanol Mg mg Min minute mL milliliters MS mass spectrometry NMR Nuclear magnetic resonance Pd(dppf)Cl2·DCM, Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane Pd(dtbpf)Cl2 [1,1'-bis(di- and tri-butylphosphino)ferrocene]palladium(II) dichloride Pd(PPh3)4 Tetra(triphenylphosphine)palladium(0) Ph Phenyl PhMe Toluene PIFA (bis(trifluoroethoxy)iodide)benzene Pin Youpinhe PMB 4-Methoxybenzyl PMB-Cl 4-Methoxybenzyl chloride Rbf round-bottom flask RP-HPLC Reverse-phase high-pressure liquid chromatography RT or rt or rt room temperature sat. or satd. saturation SFC Supercritical fluid chromatography TBAF Tetra-n-butylammonium fluoride TBDPS Tertiary butyldiphenylsilyl TBDPSCl Tertiary butyldiphenylchlorosilane TBS Tertiary butyldimethylsilyl TBSCl Tertiary butyldimethylchlorosilane tBu Grade III Butyl TC Thiophene-2-carboxylate TEA or Et3N Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TIPS Triisopropylsilyl TMS Trimethylsilyl UV UV General analytical and purification methods

[0218] This section provides descriptions of general analytical and purification methods used to prepare the specific examples provided herein.

[0219] Chromatography: Unless otherwise stated, residues containing crude product are purified by passing the crude material or concentrate through a Biotage or ISCO brand silica gel column (pre-packaged with fast silica (SiO2)) and eluting the product off the column using the indicated solvent gradient.

[0220] Preparative HPLC Method: When indicated, the compounds described herein are purified by reverse-phase HPLC using a Waters FractionLynx or Gilson semi-preparative HPLC-MS system with one of the following two HPLC columns: (a) Phenomenex Gemini column (5 μm, C18, 150 x 30 mm) or (b) Waters X-select CSH column (5 μm, C18, 100 x 30 mm). Typical operation with this instrument involves elution 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 may be varied to achieve optimal separation.

[0221] Proton NMR Spectra: Unless otherwise stated, all 1H NMR spectra were collected at 300, 400, or 500 MHz on a Bruker NMR instrument. Internal solvent peaks were used as a reference, and all observed protons were reported in parts per million (ppm) in tetramethylsilane (TMS) under a low magnetic field. Some 1H signals may have been lost due to MeOD exchange with D or due to signal suppression.

[0222] Mass Spectrometry (MS): Unless otherwise stated, all mass spectrometry data for starting materials, intermediates, and / or exemplary compounds are reported as the mass / charge (m / z) of the [M+H]+ molecular ion. The reported molecular ion was obtained using a Waters Acquity UPLC / MS system by electrospray detection (commonly referred to as ESI MS). As understood by those skilled in the art, compounds having isotopic atoms (such as bromine) are typically reported based on the detected isotopic pattern. Preparation of Intermediates 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (Intermediate A)

[0223] Step 1: 4-(benzyloxy)-2,7-dichloro-8-fluoropyridano[4,3-d]pyrimidine. 1,4-dichloro-8-fluoropyridano[4,3-d]pyrimidine (48 mL), DIPEA (9.22 g, 12.5 mL, 71.3 mmol), benzyl alcohol (3.86 g, 3.7 mL, 35.7 mmol), and 2,4,7-trichloro-8-fluoropyridano[4,3-d]pyrimidine (6.00 g, 23.8 mmol) were added to a 250 mL round-bottom flask containing activated 3 Å molecular sieves. The mixture was stirred at 85°C for 2 h. The volatiles were removed under vacuum, and the residue was purified by column chromatography on silicone using a 0%–100% 3:1 EtOAc / EtOH mixture in heptane to yield 4-(benzyloxy)-2,7-dichloro-8-fluoropyridino[4,3-d]pyrimidine (3.30 g, 10.18 mmol, 43% yield). m / z (ESI): 325.9 (M+H)+.

[0224] Step 2: 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. Add ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methanol (1.78 g, 11.20 mmol) and DIPEA (5.26 g, 7.1 mL, 40.7 mmol) to a solution of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (3.30 g, 10.18 mmol) in acetonitrile (20 mL). Stir the reaction at 80°C for 1 h. The volatiles were removed under reduced pressure, and the mixture was purified by column chromatography on silicone using a 0%-100% 3:1 EtOAc / EtOH mixture in heptane (containing 2% triethylamine additive) to produce 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.60 g, 5.82 mmol, 57% yield). m / z (ESI): 447.0 (M+H)+.

[0225] Step 3: 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. Potassium phosphate (3.70 g, 17.45 mmol) and cataCXium A Pd G3 (0.85 g, 1.16 mmol) were added to a solution of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.60 g, 5.82 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane (3.14 g, 8.73 mmol) in tetrahydrofuran (17 mL) and water (1.7 mL). The reaction mixture was stirred at 70°C for 2 h. The reaction mixture was purified by column chromatography on silicone using a 0%–50% 3:1 EtOAc / EtOH mixture (containing 2% triethylamine additive) in heptane to yield 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.42 g, 3.75 mmol, 65% yield). m / z (ESI): 645.0 (M+H)+.

[0226] Step 4: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidinyl (2.42 g, 3.75 mmol) was dissolved in ethyl acetate (75 mL). Palladium (0.80 g, 0.75 mmol) was added to activated carbon, and the mixture was stirred overnight at room temperature under a H₂ atmosphere. The mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM:MeOH (2:1) until the filtrate was clear. The volatiles were removed under vacuum to produce 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol, which was a light brown foam and ready for use without further purification. m / z (ESI): 555.0 (M+H)+. 7-(8-Ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (intermediate B)

[0227] Step 1: 4-(Tributoxy)-2,7-dichloro-8-fluoropyridano[4,3-d]pyrimidine. Potassium tributoxide (1.0 M in THF, 14.9 mL, 14.85 mmol) was slowly added to a stirred mixture of 2,4,7-trichloro-8-fluoropyridano[4,3-d]pyrimidine (2.50 g, 9.90 mmol) in THF (3.5 mL) over a 0.5 h period at -40°C. After 1 h, additional potassium 2-methyl-2-propoxide (1.0 M solution in THF, 2.5 mL) was added. The resulting mixture was stirred at -40°C for 10 min and then poured into an ice-cold, saturated aqueous solution of ammonium hydroxide, followed by extraction with EtOAc. The combined organic matter was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient elution of 0%–20% EtOAc in heptane to give 4-(tert-butoxy)-2,7-dichloro-8-fluoropyridino[4,3-d]pyrimidine (1.12 g, 3.86 mmol, 39% yield). m / z (ESI): 234.0 (M- tBu+H)+.

[0228] Step 2: 4-(tributoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. A mixture of 4-(tributoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (0.58 g, 2.00 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methanol (0.45 g, 2.80 mmol), and 1,1'-dimethyltriethylamine (1.03 g, 1.4 mL, 8.00 mmol) in MeCN (6.0 mL) in a 10 mL microwave reaction vessel was microwave irradiated (at 75 °C for 16 h). The volatiles were removed under reduced pressure, and the crude mixture was purified by column chromatography on silica gel using a gradient elution of 0%–50% (20% MeOH in DCM) to give 4-(tributoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.66 g, 1.60 mmol, 80% yield) as a grayish-white solid. m / z (ESI): 413.2 (M+H)+.

[0229] Step 3: 4-(tributoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. In a 5 mL microwave reaction vessel, 4-(tributoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.66 g, 1.60 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (0.92 g, 2.56 mmol), cataCXium A Pd G3 (0.23 g, 0.32 mmol), and tripotassium phosphate (0.85 g, 4.00 mmol) were placed, followed by the addition of 1,4-dioxane (10 mL) and water (1.8 mL). The resulting mixture was purged with nitrogen for 10 min, then sealed and irradiated at 85°C under microwave for 3 h. Volatile substances were removed under reduced pressure, and the crude residue was purified by column chromatography on silica gel using a gradient elution of 0%–50% (20% MeOH in DCM) to give 4-(tributoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.84 g, 1.38 mmol, 86% yield) as a colorless film. m / z (ESI): 611.2 (M+H)+.

[0230] Step 4: 7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. At room temperature, a 4.0 M solution (12 mL, 48.1 mmol) of HCl in dimethyl methoxy (2 R,7aS)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.84 g, 1.38 mmol) in MeCN (2.0 mL) with stirring was added. The resulting mixture was stirred at room temperature for 0.5 h. Volatile substances were removed under reduced pressure. The crude residue was dissolved in MeOH / DCM, cooled in an ice bath, neutralized with ammonium hydroxide, and then loaded onto a silica gel pre-column. Purification was performed by column chromatography on silica gel using a gradient elution of 0%–50% (20% MeOH in DCM) to give 7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.39 g, 0.76 mmol, 56% yield) as a grayish-white solid. m / z (ESI): 511.0 (M+H)+. N-Methyl-1,4-oxazetane-2-methylamine hydrochloride (intermediate C1)

[0231] Step 1: Tributyl 2-(methylaminomethyl)-1,4-oxazetane-4-carboxylate. 4-[(tributoxy)carbonyl]-1,4-oxazetane-6-carboxylic acid (0.20 g, 0.82 mmol, AA Blocks), methylamine hydrochloride (0.10 g, 3.26 mmol, Spectrum Chemicals), DIPEA (0.43 mL, 2.45 mmol), and HATU (0.37 g, 0.98 mmol) were dissolved in DMF (4.0 mL). The reaction was stirred at room temperature for 16 h. After completion, the mixture was loaded onto a reverse-phase column and purified by reverse-phase HPLC to produce tributyl 2-(methylaminomethoxy)-1,4-oxazetane-4-carboxylate as a colorless oil (0.21 g, 0.82 mmol, 100% yield).

[0232] Step 2: N-Methyl-1,4-oxazacycloheptane-2-methylamine hydrochloride. Tributyl 2-(methylaminomethyl)-1,4-oxazacycloheptane-4-carboxylate (0.21 g, 0.82 mmol) was dissolved in 2.0 mL of MeCN and HCl (4.0 M in dimethyl ether, 0.61 mL, 2.45 mmol). The reaction was stirred at room temperature for 30 min. After completion, the mixture was concentrated to give N-methyl-1,4-oxazacycloheptane-2-methylamine (0.13 g, 0.82 mmol, 100% yield) as a white solid, which was used directly in the next step without purification. m / z (ESI): 159.1 (M+H)+. [Table 2]. Intermediates C2 to C4 were prepared in a manner similar to that of intermediate C1. Intermediate number Chemical structure name reagents MS m / z(ESI) (M+H) + C2 1,4-Oxazine-2-methylamine hydrochloride 4-(tert-butoxycarbonyl)-1,4-oxazetane-2-carboxylic acid (CAS#: 1141669-61-5, Compibrco) and NH4Cl 145.1 C3 1,4-Oxazetane-6-methylamine hydrochloride 1,4-oxazetane-6-methylamine (CAS#: 1269755-58-9, AA Blocks) and NH4Cl 145.1 C4 N-Methyl-1,4-oxazine-6-methylamine hydrochloride 4-[(tributoxy)carbonyl]-1,4-oxazetane-6-carboxylic acid (CAS#: 1269755-58-9, AA Blocks) 159.2 (1,4-Oxazonyl-2-yl)methanol hydrochloride (intermediate D1)

[0233] Step 1: 4-(Tributyl)-2-methyl-1,4-oxazetane-2,4-dicarboxylate. Add 4-(tributoxycarbonyl)-1,4-oxazetane-2-carboxylic acid (0.50 g, 2.04 mmol, Enermi), toluene (10 mL), and DBU (0.31 g, 0.31 mL, 2.04 mmol) to a 100 mL round-bottom flask. Add MeI (0.38 mL, 6.12 mmol) to the mixture and stir the reaction at room temperature for 16 h. After completion, the reaction was concentrated under reduced pressure and purified by column chromatography on silica gel using a gradient elution of 0%–100% EtOAc in heptane to give 4-(tert-butyl)-2-methyl-1,4-oxazacycloheptan-2,4-dicarboxylate as a yellow oil (0.48 g, 1.86 mmol, 91% yield). ¹H NMR (400 MHz, chloroform-d): δ ppm 4.07–4.38 (m, 3H), 3.79 (m, 4H), 3.55–3.72 (m, 1H), 3.07–3.36 (m, 2H), 1.86–2.06 (m, 2H), 1.49 (s, 9H).

[0234] Step 2: (1,4-oxazacycloheptan-2-yl)methanol hydrochloride. Add 4-(tert-butyl)-2-methyl-1,4-oxazacycloheptan-2,4-dicarboxylate (0.48 g, 1.86 mmol), THF (9.0 mL), and lithium aluminum hydride (2.0 M in THF, 1.88 mL, 3.77 mmol) to a 100 mL round-bottom flask. Stir the mixture at room temperature for 2 h. After completion, quench the mixture with a saturated Roschöll salt solution (0.5 mL) and stir for another 1 h. Filter the reaction mixture through diatomaceous earth and wash with EtOAc. Concentrate the filtrate under reduced pressure. Redissolve the residue in DCE (5 mL) and HCl (4.0 M in dimethyl ether, 1.39 mL, 5.56 mmol). Stir the reaction at room temperature for 2 h. After completion, the reaction was concentrated to give a white solid (1,4-oxazacycloheptan-2-yl)methanol hydrochloride (0.24 g, 1.85 mmol, 99% yield), which was ready for use in the next step without further purification. m / z (ESI): 132.2 (M+H)+. (1,4-oxazacycloheptan-6-yl)methanol hydrochloride (intermediate D2)

[0235] Synthesized using 4-(tributoxycarbonyl)-1,4-oxazacycloheptane-6-carboxylic acid (CAS#: 1269755-58-9, Enimex), in a manner similar to intermediate D1. Thio-2-ylmethanol hydrochloride (intermediate E)

[0236] Add 4-(tributyl)-2-ethylthiocyano-2,4-dicarboxylate (0.50 g, 1.82 mmol, Accela), THF (9.0 mL), and lithium aluminum hydride (2.0 M in THF, 1.82 mL, 3.63 mmol) to a 100 mL round-bottom flask. Stir the mixture at room temperature for 2 h. After this, quench the mixture with a saturated Roschöll salt solution (0.5 mL) and stir for another 1 h. Filter the reaction mixture through diatomaceous earth and wash with EtOAc. Concentrate the filtrate under reduced pressure. Redissolve the residue in DCE (5 mL) and HCl (4.0 M in dichloroisocyanuric acid, 1.36 mL, 5.45 mmol). Stir the reaction at room temperature for 2 h. After completion, the reaction was concentrated to give a white solid, thiocyano-2-ylmethanol (0.24 g, 1.80 mmol, 99% yield), which was used for the next step without further purification. ¹H NMR (400 MHz, methanol-d⁴): δ ppm 3.73–3.82 (m, ¹H), 3.64–3.73 (m, ²H), 3.53–3.61 (m, ¹H), 3.17–3.26 (m, ²H), 3.14–3.30 (m, ¹H), 2.92–3.05 (m, ²H). 3-Oxa-7-azabicyclo[3.3.1]nonyl-9-ol (intermediate F)

[0237] Add tributyl-9-hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate (0.20 g, 0.82 mmol, Ambeed), DCM (4.0 mL), and HCl solution (4.0 M in dimethyl ether, 0.62 mL, 2.47 mmol) to a 25 mL round-bottom flask. Stir the mixture at room temperature for 4 h. After completion, concentrate the reaction to give 3-oxa-7-azabicyclo[3.3.1]non-9-ol (0.12 g, 0.82 mmol, 100% yield), which can be used for the next step without further purification. m / z(ESI): 144.1 (M+H)+. 2-(((tributyldimethylsilyl)oxy)methyl) α-line (intermediate G)

[0238] 2-O-2-ylmethanol (0.38 g, 3.21 mmol, Compibrco) was dissolved in dichloromethane (16 mL). Triethylamine (0.49 g, 0.67 mL, 4.82 mmol) was added, and the solution was cooled to 0°C. Tributylchlorodimethylsilane (0.53 g, 3.53 mmol) was added in a single addition, and the mixture was heated to room temperature and stirred overnight. The crude mixture was loaded directly onto silica gel and purified by column chromatography on silica gel using a gradient elution of 0%–35% MeOH in DCM to produce 2-(((tributyldimethylsilyl)oxy)methyl)oline (0.45 mg, 1.94 mmol, 60% yield). m / z (ESI): 232.2 (M+H)+. 1,4-Oxazetane-6-carboxynitrile (intermediate H)

[0239] Step 1: Tributyl-6-aminomethylformyl-1,4-oxazacycloheptane-4-carboxylate. 4-[(tributoxy)carbonyl]-1,4-oxazacycloheptane-6-carboxylic acid (0.20 g, 0.82 mmol), ammonium chloride (0.40 g, 7.48 mmol), DIPEA (0.32 g, 0.43 mL, 2.45 mmol), and HATU (0.37 g, 0.98 mmol) were dissolved in N,N-dimethylformamide (4.0 mL). The reaction was stirred overnight at room temperature. The mixture was loaded onto a reverse-phase column and purified by reverse-phase chromatography (10%–100% MeCN / H₂O + 0.01% TFA) to produce a colorless oily tertiary butyl 6-aminomethoxy-1,4-oxazacycloheptane-4-carboxylate (0.16 g, 0.64 mmol, 78% yield). m / z (ESI): 267.2 (M+H)⁺.

[0240] Step 2: 1,4-Oxazepine-6-carboxynitrile. Tertiary butyl 6-aminomethyl 1,4-oxazepine-4-carboxylate (0.15 g, 0.61 mmol) was dissolved in pyridine (1.5 mL), and 1 H-imidazolium (84 mg, 1.23 mmol) was added. The mixture was cooled to -30°C, and phosphorus oxychloride (0.38 g, 0.23 mL, 2.46 mmol) was slowly added dropwise. The mixture was stirred at the same room temperature for 1 h. Saturated NH4Cl (2 mL) was added to quench the reaction. The aqueous layer was extracted with EtOAc (3 × 2 mL), and the combined organic layers were dried over Na2SO4. The volatiles were removed under vacuum, and the crude residue was purified by column chromatography on silica gel using a gradient elution of 0%–20% MeOH in DCM to produce a colorless oily tertiary butyl 6-cyano-1,4-oxazetane-6-carboxylate (94 mg, 0.42 mmol, 68% yield), which was then dissolved in DCM (2 mL) and TFA (200 μL). The mixture was stirred at room temperature for 1 h. The volatiles were removed under vacuum, and the residue was purified by column chromatography on silica gel using a gradient elution of 0%–30% MeOH in DCM (containing 0.5% 2N NH3 in MeOH) to produce a colorless oily 1,4-oxazetane-6-carboxynitrile (45 mg, 0.36 mmol, 58% yield). m / z(ESI): 127.2 (M+H) +. 8-Oxa-3-azabicyclo[3.2.1]octane-6-carboxylonite hydrochloride (intermediate I)

[0241] Synthesized using 3-[(tert-butoxy)carbonyl]-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylic acid (CAS#: 1251010-77-1, Enerminium), in a manner similar to intermediate H. m / z(ESI): 151.2 (M+H)+. 6-Methyl-1,4-oxazabicycloheptane-6-ol hydrochloride isomer 1 (intermediate J1) and isomer 2 (intermediate J2).

[0242] Step 1: 4-(4-methoxybenzyl)-1,4-oxazetane-6-one. Add 1,4-oxazetane-6-one hydrochloride (0.30 g, 1.98 mmol, AA Blocks), 4-methoxybenzyl chloride (0.37 g, 0.32 mL, 2.38 mmol, TCI), DIPEA (0.77 g, 1.0 mL, 5.94 mmol, Sigma-Aldrich), and DCM (10 mL) to a 20 mL vial. Stir the reaction overnight at room temperature. The crude material was purified by column chromatography on silica gel using a gradient elution of 0%–80% EtOAc / EtOH (containing 1% TEA) in heptane to provide a colorless oily product, 4-(4-methoxybenzyl)-1,4-oxazacycloheptan-6-one (0.43 g, 1.83 mmol, 92% yield). m / z (ESI): 236.2 (M+H)+.

[0243] Step 2: 4-(4-Methoxybenzyl)-6-methyl-1,4-oxazetane-6-ol. Add 0.87 g (3.70 mmol) of 4-(4-methoxybenzyl)-1,4-oxazetane-6-one in 15 mL of THF to a 100 mL round-bottom flask. Cool the mixture to 0°C and then add a solution of methyl magnesium bromide (3 M in Et 2O, 3.7 mL, 11.09 mmol, Sigma-Aldrich). Stir the reaction for 1 h. Dilute the reaction mixture with saturated NH 4Cl (15 mL) and extract with EtOAc (2 × 15 mL). Wash the organic extract with saturated NaCl (15 mL) and dry over MgSO 4. Filter the solution and concentrate under vacuum to give the crude substance. The crude material was purified by column chromatography on silica gel using a gradient elution of 0%–50% EtOAc / EtOH in heptane to provide a yellow oily product, 4-(4-methoxybenzyl)-6-methyl-1,4-oxazacycloheptan-6-ol (0.65 g, 2.59 mmol, 70% yield). m / z (ESI): 252.1 (M+H)+.

[0244] Step 3: Chiral separation. 4-(4-methoxybenzyl)-6-methyl-1,4-oxazacycloheptan-6-ol (0.65 g, 2.59 mmol) was purified by SFC using a Chiralpak AD column (30 × 150 mm 5 μm column, mobile phase 20% methanol (containing 0.2% triethylamine), flow rate 200 mL / min) to produce peak 1 at 246 mg (where ee > 99%) and peak 2 at 292 mg (where ee > 99%).

[0245] Step 4: 6-Methyl-1,4-oxazacycloheptane-6-ol hydrochloride. 4-(4-methoxybenzyl)-6-methyl-1,4-oxazacycloheptane-6-ol (0.24 g, 0.96 mmol, peak 1) was dissolved in ethanol (5.8 mL). Palladium on activated carbon (0.25 g, 0.23 mmol, Sigma-Aldrich) and an aqueous solution of HCl (2 N, 0.7 mL, 1.33 mmol, Sigma-Aldrich) were added, and the mixture was stirred at room temperature for 5 h under a H₂ atmosphere. The catalyst was removed, and the solution was concentrated to provide 6-methyl-1,4-oxazacycloheptane-6-ol hydrochloride (quantitative yield, isomer 1, intermediate J1). Isomer 2, intermediate J2, was obtained by the same method. 6-((trimethylsilyl)ethynyl)-1,4-oxazetane-6-ol hydrochloride (intermediate K)

[0246] Step 1: Tributyl-6-hydroxy-6-((trimethylsilyl)ethynyl)-1,4-oxazetane-4-carboxylate. Add (trimethylsilyl)ethynylene (0.27 g, 0.27 mL, 2.79 mmol, Compibrco) in THF (3.7 mL) to a 50 mL round-bottom flask. Cool the mixture to -78°C, then add a solution of n-butyllithium in hexane (2.5 M, 0.9 mL, 2.32 mmol, Sigma-Aldrich). Stir the reaction for 15 min, then heat to 0°C and add tributyl-6-hydroxy-1,4-oxazetane-4-carboxylate (0.20 g, 0.2 mL, 0.93 mmol, Compibrco). Stir the reaction at this temperature for 2 h. The reaction mixture was diluted with saturated NH₄Cl (10 mL) and extracted with EtOAc (2 × 15 mL). The organic extract was washed with saturated NaCl (15 mL) and dried over MgSO₄. The solution was filtered and concentrated under vacuum to give crude material. The crude material was purified by column chromatography on silica gel using a gradient elution of 0%–80% 3:1 EtOAc / EtOH in heptane to give tert-butyl-6-hydroxy-6-((trimethylsilyl)ethynyl)-1,4-oxazetane-4-carboxylate as a yellow oil (0.24 g, 0.77 mmol, 82% yield).

[0247] Step 2: 6-((trimethylsilyl)ethynyl)-1,4-oxazetane-6-ol hydrochloride. Tertiary butyl 6-hydroxy-6-((trimethylsilyl)ethynyl)-1,4-oxazetane-4-carboxylate (0.12 g, 0.38 mmol) was dissolved in 2 mL of DCM and 0.5 mL of TFA. The reaction was stirred for 1 h. The mixture was then concentrated under vacuum. 0.6 mL of 1 N HCl aqueous solution was added to the residue, and the mixture was lyophilized to provide 6-((trimethylsilyl)ethynyl)-1,4-oxazetane-6-ol hydrochloride (quantitative yield). m / z (ESI): 214.2 (M+H)+. 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane (intermediate L)

[0248] Step 1: 4-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane. At -40°C, 1,4-oxazacycloheptane hydrochloride (14 g, 0.10 mol) was added in portions to a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidin (33 g, 0.13 mol, LabNetwork) and DIPEA (42 g, 57 mL, 0.33 mol) in MeCN (500 mL). The mixture was stirred at -40°C for 1 h. The reaction mixture was diluted with H₂O (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (250 mL × 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography on silica gel by elution with petroleum ether at a ratio of 5:1 to 3:1 (EtOAc) to give 4-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (22 g, 70 mmol, 53% yield, 91% purity) as a yellow solid. m / z (ESI): 317.1 (M+H)⁺.

[0249] Step 2: 4-(7-chloro-2,8-difluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane. KF (59 g, 1.01 mol) was added to a solution of 4-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (32 g, 0.10 mol) in DMSO (330 mL). The mixture was stirred at 80°C for 12 h. The reaction mixture was diluted with H₂O (700 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (350 mL × 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography on silica gel by elution with petroleum ether / EtOAc at a ratio of 3:1 to 1:1 to give 4-(7-chloro-2,8-difluoro-pyridano[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (20 g, 67 mmol, 66% yield) as a yellow solid. m / z(ESI): 301.2 (M+H)+.

[0250] Step 3: 4-(7-chloro-8-fluoro-2-methylthioalkyl-pyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane. At 0°C, NaSMe (20% purity in H₂O, 33 mL, 0.10 mol) was added dropwise to a solution of 4-(7-chloro-2,8-difluoro-pyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (31 g, 0.10 mol) in THF (310 mL). The mixture was stirred at 20°C for 2 h to give a yellow suspension. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The filtrate was concentrated under reduced pressure to give the residue, and the filter cake was milled at 20°C for 30 min with 8:1 petroleum ether / EtOAc (250 mL). The suspension was filtered, and the filter cake was washed with 8:1 petroleum ether / EtOAc (100 mL × 3) and concentrated under reduced pressure to give 4-(7-chloro-8-fluoro-2-methylthioalkyl-pyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (37 g, 0.10 mol, 98% yield, 90% purity) as a yellow solid. m / z (ESI): 329.0 (M+H)+.

[0251] Step 4: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylthioalkyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane. Under N2, cataCXium A Pd G2 (2.0 g, 3.04 mmol) was added to a solution of 4-(7-chloro-8-fluoro-2-methylthioalkyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (10 g, 30 mmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (14 g, 40 mmol, PharmaBlock), Cs2CO3 (9.9 g, 30 mmol) in toluene (200 mL) and H2O (25 mL). The mixture was stirred at 100°C for 12 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (150 mL × 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography on silica gel by elution with petroleum ether / EtOAc at a ratio of 2:1 to 0:1 to give 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylthioalkyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (11 g, 17 mmol, 57% yield, 91% purity), as a yellow solid. m / z (ESI): 527.3 (M+H)⁺.

[0252] Step 5: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane. At 0°C, m-CPBA (4.4 g, 22 mmol, 85% purity) was added in portions to a solution of 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylthioalkyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (11 g, 22 mmol) in DCM (400 mL). The mixture was then stirred at 0°C for 1 h. The reaction mixture was quenched at 25°C by adding 1000 mL of aqueous Na₂S₂O₃ solution, diluted with 600 mL of H₂O, and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography on silica gel by elution with 100% EtOAc to a 10:1 EtOAc / MeOH solution to give 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (6.5 g, 11 mmol, 52% yield, 95% purity) as a yellow solid. m / z(ESI): 543.1 (M+H)+. 6-Methyl-1,4-oxazetane-6-ol hydrochloride isomer 1 (intermediate M1) and isomer 2 (intermediate M2).

[0253] Step 1: 6-Ethyl-1,4-oxazetane-6-ol 2,2,2-trifluoroacetate. At 0°C, tributyl 6-sidekoxy-1,4-oxazetane-4-carboxylate (0.55 g, 2.56 mmol, Compibrco) in 2-MeTHF (10 mL) was added to a 100 mL round-bottom flask. A 1.0 M solution of ethyl magnesium bromide in tetrahydrofuran (6.4 mL, 6.40 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, then diluted with saturated NH₄Cl solution (15 mL) and extracted with EtOAc (2 × 15 mL). The organic extract was washed with saturated NaCl solution (15 mL) and dried over MgSO₄. The solution was filtered and concentrated under vacuum to give the crude product.

[0254] At 0°C, TFA (2 mL) was added dropwise to the above substance dissolved in 10 mL of DCM. After stirring at 0°C to room temperature for 2 h, the reaction mixture was completely concentrated and used for the next step without further purification.

[0255] Step 2. 6-Ethyl-4-(4-methoxybenzyl)-1,4-oxazacycloheptane-6-ol. Add 6-ethyl-1,4-oxazacycloheptane-6-ol 2,2,2-trifluoroacetate (0.66 g, 2.56 mmol), 4-methoxybenzyl chloride (0.48 g, 0.42 mL, 3.07 mmol), and N,N-diisopropylethylamine (0.99 g, 1.34 mL, 7.68 mmol) from DCM (10 mL) to a 100 mL round-bottom flask. After stirring overnight at room temperature, the crude material was adsorbed onto a silicone stopper and purified by column chromatography on silicone using a gradient elution of 0%–80% EtOAc / EtOH (containing 1% TEA) in heptane, yielding 6-ethyl-4-(4-methoxybenzyl)-1,4-oxazacycloheptane-6-ol (0.40 g, 1.51 mmol, 59% yield). m / z (ESI): 266.2 (M+H)+.

[0256] Step 3: Chiral separation. 6-Ethyl-4-(4-methoxybenzyl)-1,4-oxazacycloheptane-6-ol (0.4 g, 1.5 mmol) was purified via SFC using a Chiralpak AZ (20 × 250 mm 5 μm column, mobile phase 15% methanol, flow rate 80 mL / min) to produce peak 1 at 163 mg (where ee is 99%) and peak 2 at 163 mg (where ee is 99%).

[0257] Step 4: 6-Ethyl-1,4-oxazetane-6-ol hydrochloride. 6-Ethyl-4-(4-methoxybenzyl)-1,4-oxazetane-6-ol (0.16 g, 0.61 mmol, peak 1) was dissolved in ethanol (3.1 mL). Palladium (0.13 g, 0.12 mmol) on activated carbon and an aqueous solution of HCl (2 N, 0.35 mL, 0.7 mmol) were added, and the mixture was stirred at room temperature under a H₂ atmosphere for 5 h. The catalyst was removed, and the solution was concentrated to provide 6-Ethyl-1,4-oxazetane-6-ol hydrochloride (quantitative yield, isomer 1, intermediate M1). Isomer 2, intermediate M2, was obtained by the same method. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol (Example 1)

[0258] Step 1: 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane. At -40°C, 1,4-oxazacycloheptane (0.80 g, 7.92 mmol) was added to a suspension of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.00 g, 7.92 mmol) in dichloromethane (31.7 mL), followed by the addition of DIPEA (3.07 g, 4.2 mL, 23.77 mmol). The reaction mixture was stirred at -40°C for 1 h. The reaction mixture was diluted with DCM, washed with aqueous citric acid, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated to provide 4-(2,7-dichloro-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (2.73 g, 8.61 mmol, 109% yield, 87% purity). The isolated product was used in the next reaction without further purification. m / z (ESI): 317.1 (M+H)+.

[0259] Step 2: 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazheptanane. DIEA (1.53 g, 2.1 mL, 11.82 mmol) was added to a suspension of 4-(2,7-dichloro-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (1.25 g, 3.94 mmol) and ((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methanol (0.75 g, 4.73 mmol) in acetonitrile (15.8 mL). The reaction was stirred overnight at 75°C. The reaction mixture was concentrated, and the crude product was purified by column chromatography on silica gel by elution with a 0%-100% 3:1 EtOAc / EtOH mixture (containing 2% triethylamine additive) in heptane to provide 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (0.67 g, 1.51 mmol, 38% yield) as a pale yellow powder. m / z(ESI): 440.2 (M+H)+.

[0260] Step 3: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazheptanane. Potassium phosphate (0.17 g, 0.82 mmol) and cataCXium A Pd G3 (40 mg, 0.055 mmol) were added to a solution of 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptanane (0.12 g, 0.27 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (0.15 g, 0.41 mmol) in tetrahydrofuran (2.5 mL) and water (0.2 mL). The reaction mixture was sprayed with argon, capped, and stirred at 70°C for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was concentrated. The crude product was purified by column chromatography on silica gel by elution with a 0%–100% 3:1 EtOAc / EtOH mixture (containing 2% triethylamine additive) in heptane to provide 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (0.17 g, 0.26 mmol, 95% yield). m / z (ESI): 638.1 (M+H)+.

[0261] Step 4: 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol. A solution of hydrogen chloride (4.0 M in dimethyl methoxy) was added to a solution of 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane (0.17 g, 0.26 mmol) in acetonitrile (5.2 mL). The reaction was stirred at ambient temperature for 30 min. The reaction mixture was concentrated, and the crude product was purified by reverse-phase HPLC to provide 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol (0.12 g, 0.14 mmol, 55% yield) as its TFA salt, as a pale yellow powder. m / z(ESI): 594.1 (M+H)+. 1H NMR (400 MHz, DMSO- d 6) δ ppm 10.61 - 10.84 (br s, 1 H) 9.78 - 10.08 (br s, 1 H) 9.24 (s, 1 H) 7.78 (dd, J=8.99, 6.06 Hz, 1 H) 7.26 - 7.44 (m, 2 H) 7.02 (d, J=2.51 Hz, 1 H) 5.45 - 5.71 (m, 1 H) 4.50 - 4.67 (m, 2 H) 4.11 - 4.30 (m, 4 H) 3.68 - 4.01 (m, 7 H) 3.68 - 3.80 (m, 4 H) 3.32 (br s, 1 H) 1.90 - 2.43 (m, 10 H) 0.74 (t, J=7.32 Hz, 3 H). [Table 3]. Examples 2 to 33 and 78-80 were prepared in a similar manner to Example 1. Instance number Chemical structure name Salt form reagents Method Change 2 5-Ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol Bis(2,2,2-trifluoroacetate) Step 3: 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (CAS#: 2621932-60-1, Lanbo Company) 3 5,6-Difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol dihydrochloride Step 3: 2-(7,8-difluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (CAS#: 2621935-35-9, Lanbo Company) 4 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-thio-linopyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Bis(2,2,2-trifluoroacetate) Step 1: Thio-phosphoroline (CAS#: 123-90-0, Compibrco) Step 3: Use Pd(dppf)Cl2 5 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-thiazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Bis(2,2,2-trifluoroacetate) Step 1: 1,4-Thiazacycloheptane hydrochloride (CAS#: 108724-14-7, Synthonix) 6 4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol 2,2,2-Trifluoroacetate Step 1: 3-oxa-8-azabicyclo[3.2.1]octane (CAS#: 280-07-9, Compibrco) 7 4-(4-(6,6-difluoro-1,4-oxazacycloheptan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol 2,2,2-Trifluoroacetate Step 1: 6,6-Difluoro-1,4-oxazetane heptane hydrochloride (CAS#: 1341039-23-3, Enimi Company) Step 3: 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (CAS#: 2621932-60-1, Lanbo Company) Step 2: Use DBACO (0.2 equivalents) and Cs2CO3 (3 equivalents). 8 5,6-Difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Bis(2,2,2-trifluoroacetate) Step 2: ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (CAS#: 2206737-78-0, eNovation) Step 3: 2-(7,8-difluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (CAS#: 2621935-35-9, Lanbo Company) 9 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Bis(2,2,2-trifluoroacetate) Step 2: ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (CAS#: 2206737-78-0, Energia) 10 4-(4-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol 2,2,2-Trifluoroacetate Step 1: 6-oxa-3-azabicyclo[3.2.1]octane hydrochloride (CAS#: 1461708-41-7, Enermi Corporation) Step 3: 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (CAS#: 2621932-60-1, Lanbo Company) Step 2: Use DABCO (0.2 equivalents) and Cs2CO3 (3 equivalents). 11 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.2.1]oct-8-ol 2,2,2-Trifluoroacetate Step 1: (1R,5R,8R)-rel-6-oxa-3-azabicyclo[3.2.1]oct-8-ol (CAS#: 1408076-41-4, Pharmaceutical Company) 12 5-Ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol 2,2,2-Trifluoroacetate Step 2: ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (CAS#: 2206737-78-0, Energia) Step 3: Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)naphth-1-yl)ethynyl)silane (CAS#: 2621932-42-9, Lanbo Company) Step 3: Use Pd(PPh3)4 and Cs2CO3. The following are the additional steps following step 4. Details are as follows. 13 4-(8-fluoro-4-(1,4-oxazacycloheptan-4-yl)-2-((tetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Free base Step 2: (Tetrahydro-1H-pyrrolo-7a(5H)-yl)methanol (CAS#: 78449-72-6, Enimi Company) Step 3: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaneborane-2-yl)-2-naphthol (CAS#: 2043962-01-0, ChemBridge) Step 3: Use Pd(PPh3)4 and Cs2CO3. 14 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol 2,2,2-Trifluoroacetate Step 3: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaneborane-2-yl)-2-naphthol (CAS#: 2043962-01-0, ChemBridge) Step 3: Use Pd(PPh3)4 and Cs2CO3. 15 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane 2,2,2-Trifluoroacetate Step 3: 6-Chloro-5-methyl-1-(tetrahydro-2H-piperan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-indazole (CAS#: 2374152-83-5, Pharmaron) Step 3: Use Pd(dtbpf)Cl2. 16 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol 2,2,2-Trifluoroacetate Step 2: ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (CAS#: 2206737-78-0, Energia) Step 3: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaneborane-2-yl)-2-naphthol (CAS#: 2043962-01-0, ChemBridge) Step 3: Use Pd(PPh3)4 and Cs2CO3. 17 5-Ethyl-6-fluoro-4-(8-fluoro-2-((1- ... Bis(2,2,2-trifluoroacetate) Step 2: (1-(1-(1-linomethyl)cyclopropyl)methanol (CAS#: 1267956-65-9, Compibrco) Step 2: Use DBACO (0.2 equivalents) and Cs2CO3 (3 equivalents). 18 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)phenol Free base Step 3: 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (CAS#: 2621936-26-1, Lanbo Company) 19 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthyl-2-ol Bis(2,2,2-trifluoroacetate) Step 1: 3,9-dioxa-7-azabicyclo[3.3.1]nonane hydrochloride (CAS#: 1803587-96-3, Enermy Laboratories) Step 3: 2-(7,8-difluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (CAS#: 2621935-35-9, Lanbo Company) Step 2: Use DABCO (0.2 equivalents) and Cs2CO3 (3 equivalents). 20 5-Ethyl-4-(8-fluoro-2-((1- ... Bis(2,2,2-trifluoroacetate) Step 2: (1-(1-(1-linomethyl)cyclopropyl)methanol (CAS#: 1267956-65-9, Compibrco) Step 3: 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (CAS#: 2621932-60-1, Lanbo Company) Step 2: Use DABCO (0.2 equivalents) and Cs2CO3 (3 equivalents). twenty one 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol Bis(2,2,2-trifluoroacetate) Step 1: 3,9-dioxa-7-azabicyclo[3.3.1]nonane hydrochloride (CAS#: 1803587-96-3, Enermy Laboratories) Step 2: Use DABCO (0.2 equivalents) and Cs2CO3 (3 equivalents). twenty two 3-Chloro-4-cyclopropyl-5-(8-fluoro-2-((1- ... Bis(2,2,2-trifluoroacetate) Step 2: (1-(1-(1-linomethyl)cyclopropyl)methanol (CAS#: 1267956-65-9, Compibrco) Step 3: 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (CAS#: 2621936-26-1, Lanbo Company) Step 2: Use DABCO (0.2 equivalents) and Cs2CO3 (3 equivalents). twenty three 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-ol Bis(2,2,2-trifluoroacetate) Step 1: 3,9-dioxa-7-azabicyclo[3.3.1]nonane hydrochloride (CAS#: 1803587-96-3, Enermy Laboratories) Step 3: 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (CAS#: 2621932-60-1, Lanbo Company) Step 2: Use DABCO (0.2 equivalents) and Cs2CO3 (3 equivalents). twenty four 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-olinepyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol 2,2,2-Trifluoroacetate Step 1: α-O-line (CAS#: 110-91-8, Sigma-Aldrich) Step 2: Use DABCO (0.2 equivalents) and Cs2CO3 (3 equivalents). 25 (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol 2,2,2-Trifluoroacetate Step 1: (S)-1,4-oxazetane-6-ol (CAS#: 1373232-31-5, J&W Pharmlab) 26 (R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol 2,2,2-Trifluoroacetate Step 1: (R)-1,4-oxazetane-6-ol (CAS#: 1022915-33-8, Jedavit Pharmaceuticals Ltd.) 27 4-(4-((1R,5S)-6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol 2,2,2-Trifluoroacetate Step 1: 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride (CAS#: 1414958-33-0, Compibrco) Step 2: Use DABCO (0.2 equivalents) and Cs2CO3 (3 equivalents). 28 4-(4-((1S,4R)-2-oxa-5-azabicyclo[2.2.2]oct-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol 2,2,2-Trifluoroacetate Step 1: 2-oxa-5-azabicyclo[2.2.2]octane hemioxalate (CAS#: 1523606-41-8, Advanced ChemBlocks, Inc.) 29 4-(4-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol 2,2,2-Trifluoroacetate Step 1: 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride (CAS#: 1860028-23-4, Angel Pharmatech Ltd.) none 30 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-methylpyrrolidin-2-one 2,2,2-Trifluoroacetate Step 2: 5-(hydroxymethyl)-5-methylpyrrolidone-2-one (CAS#: 1159991-46-4, Enimi Company) Step 2: Use NaH and THF. 31 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidin-3-carboxynitrile Bis(2,2,2-trifluoroethyl acetate) Step 2: Tertiary butyl 3-cyano-3-(hydroxymethyl)pyrrolidone-1-carboxylate (CAS#: 1374656-61-7, Pharmaceutical Company) Step 2: Use NaH and THF. 32 5-Ethyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Free base Step 2: ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (CAS#: 2206737-78-0, Energia) Step 3: 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (CAS#: 2621932-60-1, Lanbo Company) After step 4, the fraction is washed with NaHCO3 aqueous solution to alkalize the product. 33 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidone-3-carboxynitrile Bis(2,2,2-trifluoroethyl acetate) Step 1: 1,4-Oxazetane (CAS#: 5638-60-8, Oakwood Products, Inc.) Step 2: Tertiary butyl 3-cyano-3-(hydroxymethyl)pyrrolidone-1-carboxylate (CAS#: 1374656-61-7, Pharmaceutical Company) The following are the additional steps following step 4. Details are as follows. 78 (S)-4-(7-(8-ethyl-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol 2,2,2-Trifluoroacetate Step 1: Intermediate J1 79 (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol 2,2,2-Trifluoroacetate Step 1: Intermediate M1 Steps 1 and 2 are performed in one pot. 80 (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol 2,2,2-Trifluoroacetate Step 1: 6-Methyl-1,4-oxazacycloheptane-6-ol hydrochloride (CAS#: 1823315-50-9, Pharmaron) and 2,4,7,8-tetrachloropyrido[4,3-d]pyrimidine (CAS#: 2454396-63-3, Lambert). Chiral separation after step 1 (column: ChiralPak AD, 2 x 25 cm 5 µm) Mobile phase: 45% MeOH w / 0.2% TEA Flow rate: 65 mL / min. Yield: A 475 mg peak 1 (where ee > 99%) and a 456 mg peak 2 (where ee > 99%) were generated from a 1082 mg sample. (Using peak 1) Step 2: At 30 o At C, the reaction proceeds with cesium carbonate and DBACO in a mixture of THF and DMF. Additional steps in Example 12

[0262] Add 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-ol (14 mg, 0.02 mmol) in DMF (0.2 mL) to a 10 mL round-bottom flask. At 0°C, add cesium fluoride (15 mg, 0.10 mmol, Sigma-Aldrich). Stir the reaction overnight. The crude mixture was purified by reverse-phase HPLC to produce 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (4.0 mg, 6.1 μmol, 30% yield) as a brown solid, 2,2,2-trifluoroacetate. Further steps in Example 33

[0263] At 0°C, 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidone-3-carboxylonitrile (34 mg, 0.06 mmol) and 37% formaldehyde solution (58 mg, 53 µL, 0.72 mmol, Sigma-Aldrich) were added to a vial in dichloromethane (0.3 mL). One drop of acetic acid was added to the reaction mixture, and the reaction was stirred at 0°C for 10 min. Then, sodium triacetoxyborohydride (38 mg, 0.18 mmol, Sigma-Aldrich) was added at 0°C, and the reaction was stirred at room temperature for 2 h. After completion, the solution was transferred to a separatory funnel and extracted three times with ethyl acetate. The combined organic layers were dried over Na₂SO₄. The resulting solution was filtered and concentrated under vacuum to give a crude product. The crude product was purified by reverse-phase HPLC to provide 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-4-(1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidone-3-carboxylonitrile (15 mg, 0.02 mmol, 31% yield) as a bis(2,2,2-trifluoroacetate) and pale yellow solid. [Table 4]. Analytical data for Examples 2 to 33 and 78-80. Instance number MS m / z(ESI) (M+H) + 1 1H NMR 2 576.2 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.22 (s, 1 H) 7.59 - 7.72 (m, 1 H) 7.36 - 7.43 (m, 1 H) 7.33 (d, J = 2.72 Hz, 1 H) 7.19 (d, J = 6.69 Hz, 1 H) 7.02 - 7.08 (m, 1 H) 5.46 - 5.70 (m, 1 H) 4.63 - 4.78 (m, 2 H) 4.26 - 4.36 (m, 4 H) 4.05 - 4.10 (m, 2 H) 3.84 - 4.02 (m, 5 H) 3.42 - 3.59 (m, 1 H) 2.54 - 2.82 (m, 2 H) 2.11 - 2.50 (m, 8 H) 0.92 (td, J = 7.42, 1.46 Hz, 3 H). 3 584.0 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.38 (s, 1 H) 7.64 - 7.76 (m, 1 H) 7.37 - 7.58 (m, 3 H) 5.50 - 5.75 (m, 1 H) 4.89 (d, J = 9.41 Hz, 2 H) 4.40 - 4.53 (m, 4 H) 3.83 - 4.19 (m, 7 H) 3.43 - 3.56 (m, 1 H) 2.59 - 2.86 (m, 2 H) 2.46 - 2.57 (m, 1 H) 2.18 - 2.46 (m, 5 H). 4 596.2 11H NMR (400 MHz, DMSO-d6): δ ppm 9.12 (s, 1 H), 7.78 (dd, J = 9.1, 6.0 Hz, 1 H), 7.32 - 7.40 (m, 2 H), 7.02 (d, J = 2.7 Hz, 1 H), 5.46 - 5.69 (m, 1 H), 4.54 - 4.68 (m, 2 H), 4.17 - 4.35 (m, 4 H), 3.69 - 3.96 (m, 5 H), 3.25 - 3.38 (m, 2 H), 2.94 - 3.00 (m, 3 H), 2.34 (br dd, J = 3.8, 1.9 Hz, 2 H), 2.01 - 2.27 (m, 5 H), 0.74 (t, J = 7.4 Hz, 3 H). 5 610.3<00Q1069>(这里推测原文有误,应为 ,按照正确的保留) 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.23 (s, 1 H), 7.70 (dd, J = 9.1, 5.7 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.27 (t, J = 9.4 Hz, 1 H), 7.09 (d, J = 2.7 Hz, 1 H), 5.46 - 5.71 (m, 1 H), 4.71 (dd, J = 14.0, 4.2 Hz, 2 H), 4.25 - 4.48 (m, 4 H), 3.80 - 4.12 (m, 3 H), 3.43 - 3.56 (m, 1 H), 3.18 (t, J = 5.7 Hz, 2 H), 2.54 - 2.85 (m, 4 H), 2.29 - 2.53 (m, 6 H), 2.11 - 2.27 (m, 2 H), 0.82 (t, J = 7.2 Hz, 3 H). 6 606.0 11H NMR (400 MHz, methanol-d4) δ ppm 9.18 (s, 1 H) 7.66 - 7.75 (m, 1 H) 7.34 (d, J = 2.72 Hz, 1 H) 7.23 - 7.31 (m, 1 H) 7.05 - 7.10 (m, 1 H) 5.40 - 5.73 (m, 1 H) 5.15 - 5.27 (m, 2 H) 4.63 - 4.73 (m, 2 H) 3.89 (s, 7 H) 3.45 - 3.56 (m, 1 H) 2.54 - 2.82 (m, 2 H) 2.32 - 2.54 (m, 4 H) 2.10 - 2.30 (m, 6 H) 0.82 (s, 3 H). 7 612.2 1 1H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (br s, 1 H) 9.78 - 10.00 (br s, 1 H) 9.26 (s, 1 H) 7.64 - 7.74 (m, 1 H) 7.34 - 7.45 (m, 1 H) 7.31 (d, J = 2.72 Hz, 1 H) 7.15 (d, J = 6.90 Hz, 1 H) 6.94 - 7.02 (m, 1 H) 5.48 - 5.71 (m, 1 H) 4.56 - 4.92 (m, 4 H) 4.17 - 4.37 (m, 4 H) 4.02 - 4.17 (m, 2 H) 3.75 - 3.94 (m, 4 H) 3.27 - 3.39 (m, 1 H) 1.95 - 2.42 (m, 7 H) 0.83 (t, J = 7.42 Hz, 3 H). 8 558.1 11H NMR (400 MHz, methanol-d4) δ ppm 9.24 (s, 1 H) 7.61 - 7.70 (m, 1 H) 7.34 - 7.47 (m, 2 H) 7.28 (d, J = 2.30 Hz, 1 H) 5.42 - 5.61 (m, 1 H) 4.95 - 5.06 (m, 1 H) 4.70 - 4.79 (m, 1 H) 4.24 - 4.38 (m, 5 H) 4.04 - 4.10 (m, 1 H) 3.98 - 4.16 (m, 2 H) 3.83 - 3.92 (m, 2 H) 3.61 - 3.77 (m, 1 H) 3.21 (s, 3 H) 2.63 - 2.77 (m, 1 H) 2.33 - 2.55 (m, 1 H) 2.17 - 2.28 (m, 2 H). 9 568.1 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.24 (s, 1 H) 7.66 - 7.75 (m, 1 H) 7.23 - 7.38 (m, 2 H) 7.08 (d, J = 2.51 Hz, 1 H) 5.40 - 5.61 (m, 1 H) 4.94 - 5.04 (m, 1 H) 4.70 - 4.78 (m, 1 H) 4.25 - 4.35 (m, 5 H) 3.98 - 4.18 (m, 3 H) 3.89 (t, J = 5.23 Hz, 2 H) 3.63 - 3.78 (m, 1 H) 3.20 (s, 3 H) 2.62 - 2.78 (m, 1 H) 2.34 - 2.56 (m, 2 H) 2.16 - 2.28 (m, 3 H) 0.83 (t, J = 7.32 Hz, 3 H). 10 588.2 1H NMR (400 MHz, DMSO-d6) δ ppm 10.59 - 10.81 (br s, 1 H) 9.73 - 10.00 (br s, 1 H) 9.25 (s, 1 H) 7.68 (d,J=7.94 Hz, 1 H) 7.34 - 7.43 (m, 1 H) 7.26 - 7.32 (m, 1 H) 7.10 - 7.18 (m, 1 H) 6.93 - 7.01 (m, 1 H) 5.46 - 5.71 (m, 1 H) 4.70 - 4.82 (m, 1 H) 4.55 - 4.67 (m, 2 H) 4.40 - 4.49 (m, 2 H) 3.64 - 3.89 (m, 5 H) 3.27 - 3.39 (m, 1 H) 2.55 (s, 2 H) 1.89 - 2.40 (m, 9 H) 0.83 (t,J=7.42 Hz, 3 H)。 11 622.1 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.63 - 10.85 (m, 1 H) 9.33 (s, 1 H) 7.73 - 7.83 (m, 1 H) 7.30 - 7.40 (m, 2 H) 6.99 - 7.05 (m, 1 H) 5.47 - 5.69 (m, 1 H) 4.53 - 4.70 (m, 3 H) 4.33 - 4.44 (m, 1 H) 4.27 (t,J=5.33 Hz, 1 H) 4.00 - 4.13 (m, 2 H) 3.80 - 3.98 (m, 7 H) 3.27 - 3.38 (m, 2 H) 1.97 - 2.46 (m, 7 H) 0.74 (t,J=7.32 Hz, 3 H)。 12 545.6 11H NMR (400 MHz, methanol-d4) δ ppm 9.18 (s, 1 H), 7.85 (d, J=8.2 Hz, 1 H), 7.54 (d, J=6.9 Hz, 1 H), 7.35 - 7.45 (m, 2 H), 7.20 (dd, J=2.6, 0.9 Hz, 1 H), 5.54 - 5.61 (m, 1 H), 4.99 (dt, J=13.2, 2.5 Hz, 1 H), 4.75 (ddd, J=13.2, 5.9, 2.9 Hz, 1 H), 4.20 - 4.40 (m, 5 H), 3.99 - 4.16 (m, 3 H), 3.82 - 3.96 (m, 2 H), 3.59 - 3.79 (m, 1 H), 3.20 (s, 3 H), 3.11 (s, 1 H), 2.68 - 2.76 (m, 1 H), 2.21 - 2.26 (m, 3 H). 13 530.2 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.22 (s, 1 H), 7.73 - 7.90 (m, 1 H), 7.50 - 7.62 (m, 1 H), 7.37 - 7.50 (m, 1 H), 7.07 - 7.37 (m, 3 H), 4.21 - 4.44 (m, 6 H), 4.00 - 4.15 (m, 2 H), 3.79 - 3.96 (m, 2 H), 3.10 - 3.25 (m, 2 H), 2.60 - 2.91 (m, 2 H), 1.68 - 2.32 (m, 10 H). 14 548.6 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.29 (s, 1 H), 7.78 (s, 1 H), 7.40 - 7.61 (m, 2 H), 7.10 - 7.35 (m, 3 H), 5.31 - 5.90 (m, 1 H), 4.71 (d, J=18.2 Hz, 2 H), 4.32 (s, 4 H), 3.77 - 4.13 (m, 7 H), 3.42 - 3.58 (m, 1 H), 2.52 - 2.84 (m, 2 H), 2.30 - 2.52 (m, 3 H), 2.13 - 2.29 (m, 3 H). 15 572.2 1 H NMR (400 MHz, methanol-d4) δ ppm 9.32 (s, 1 H), 7.59 - 7.92 (m, 2 H), 5.52 - 5.94 (m, 1H), 4.68-4.73 (m, 2 H), 4.20 - 4.52 (m, 4 H), 3.73 - 4.12 (m, 7 H), 3.40 - 3.56 (m, 1 H), 2.29 - 2.92 (m, 8 H), 2.11 - 2.26 (m, 3 H). 16 522.2 1 H NMR (400 MHz, methanol-d4) δ ppm 8.87 - 9.43 (m, 1 H), 7.66 - 8.02 (m, 1 H), 7.51 - 7.61 (m, 1 H), 7.37 - 7.51 (m, 1 H), 7.01 - 7.37 (m, 3 H), 5.30 - 5.93 (m, 1 H), 4.94 - 5.11 (m, 1 H), 4.62 - 4.82 (m, 1 H), 4.29 (br dd, J=9.1, 5.2 Hz, 5 H), 4.07 (br d, J=5.0 Hz, 3 H), 3.87 (s, 2 H), 3.54 - 3.78 (m, 1 H), 3.21 (s, 3 H), 2.62 - 2.80 (m, 1 H), 2.30 - 2.59 (m, 1 H), 2.04 - 2.30 (m, 2 H). 17 606.0 1¹H NMR (400 MHz, methanol-d₄) δ ppm 9.15 - 9.23 (m, 1 H), 7.64 - 7.73 (m, 1 H), 7.31 - 7.34 (m, 1 H), 7.22 - 7.29 (m, 1 H), 7.04 - 7.08 (m, 1 H), 4.44 - 4.55 (m, 2 H), 4.21 - 4.33 (m, 4 H), 3.61 - 4.13 (m, 11 H), 3.35 - 3.40 (m, 2 H), 3.06 - 3.25 (m, 1 H), 2.40 - 2.56 (m, 1 H), 2.11 - 2.30 (m, 3 H), 0.98 - 1.04 (m, 2 H), 0.86 - 0.93 (m, 2 H), 0.77 - 0.84 (m, 3 H). 18 572.2 1 ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.26 (s, 1 H), 7.09 (d, J = 2.5 Hz, 1 H), 6.92 (d, J = 2.5 Hz, 1 H), 5.34 - 5.54 (m, 1 H), 4.32 - 4.45 (m, 6 H), 4.15 (dd, J = 5.5, 4.1 Hz, 2 H), 3.94 - 4.00 (m, 2 H), 3.27 - 3.39 (m, 3 H), 3.15 (s, 1 H), 2.22 - 2.49 (m, 5 H), 2.05 - 2.22 (m, 2 H), 1.94 - 2.04 (m, 2 H), 0.75 (br d, J = 7.9 Hz, 2 H), 0.20 (br d, J = 4.8 Hz, 2 H). 19 612.1 11H NMR (400 MHz, methanol-d4) δ ppm 9.18 - 9.23 (m, 1 H), 7.60 - 7.66 (m, 1 H), 7.37 - 7.44 (m, 1 H), 7.33 - 7.36 (m, 1 H), 7.25 - 7.28 (m, 1 H), 5.48 - 5.66 (m, 1 H), 4.96 - 5.04 (m, 2 H), 4.69 (br s, 2 H), 3.83 - 4.16 (m, 11 H), 3.43 - 3.53 (m, 1 H), 2.66 - 2.79 (m, 1 H), 2.53 - 2.64 (m, 1 H), 2.29 - 2.48 (m, 3 H), 2.10 - 2.24 (m, 1 H). 20 588.1 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.18 (s, 1 H), 7.62 - 7.67 (m, 1 H), 7.34 - 7.40 (m, 1 H), 7.29 - 7.33 (m, 1 H), 7.15 - 7.20 (m, 1 H), 7.01 - 7.05 (m, 1 H), 4.46 - 4.51 (m, 2 H), 4.22 - 4.32 (m, 4 H), 3.63 - 4.15 (m, 11 H), 3.35 - 3.39 (m, 2 H), 2.14 - 2.43 (m, 4 H), 0.86 - 1.02 (m, 8 H). 21 622.3 ​1H NMR (400 MHz, methanol-d4) δ ppm 9.16 - 9.25 (m, 1 H), 7.64 - 7.73 (m, 1 H), 7.31 - 7.34 (m, 1 H), 7.22 - 7.29 (m, 1 H), 7.06 - 7.09 (m, 1 H), 5.47 - 5.68 (m, 1 H), 4.93 - 5.04 (m, 2 H), 4.63 - 4.70 (m, 1 H), 3.85 - 4.20 (m, 11 H), 3.42 - 3.54 (m, 1 H), 2.67 - 2.80 (m, 1 H), 2.65 (br s, 6 H), 2.10 - 2.27 (m, 2 H), 0.80 (br d, J = 1.5 Hz, 3 H). 22 584.1[[ID=⑤]] [[ID=⑥]] 1 [[ID=⑦]]1H NMR (400 MHz, methanol-d4) δ ppm 9.19 (s, 1 H), 6.99 (s, 1 H), 6.80 - 6.82 (m, 1 H), 4.46 - 4.55 (m, 2 H), 4.21 - 4.33 (m, 5 H), 3.74 (br s, 11 H), 3.38 (s, 2 H), 2.13 - 2.27 (m, 2 H), 1.79 - 1.93 (m, 1 H), 0.96 - 1.06 (m, 2 H), 0.86 - 0.93 (m, 2 H), 0.58 - 0.70 (m, 2 H), 0.01 - 0.18 (m, 2 H).[[ID=⑧]] [[ID=⑨]]23[[ID=⑩]] [[ID=⑪]]604.2[[ID=⑫]] [[ID=⑬]] 1 It should be noted that the tags , , , , , , 1 , 1 are preserved as they are according to the requirement. Also, the "br s" in the NMR data is translated as "broad singlet" which is a common way to represent such signal characteristics in NMR spectroscopy. The "m" is translated as "multiplet" which is used to describe a complex signal pattern. The "s" is translated as "singlet" which represents a single peak in the NMR spectrum. And the chemical shift values in ppm are left unchanged as they are standard units in NMR spectroscopy. The coupling constant "J" is also left as it is.1H NMR (400 MHz, methanol-d4) δ ppm 9.15 - 9.20 (m, 1 H), 7.61 - 7.67 (m, 1 H), 7.33 - 7.40 (m, 1 H), 7.29 - 7.32 (m, 1 H), 7.14 - 7.20 (m, 1 H), 7.01 - 7.05 (m, 1 H), 5.48 - 5.67 (m, 1 H), 4.94 - 5.04 (m, 2 H), 4.69 (br s, 2 H), 3.86 - 4.17 (m, 11 H), 3.43 - 3.53 (m, 1 H), 2.66 - 2.79 (m, 1 H), 2.53 - 2.64 (m, 1 H), 2.10 - 2.49 (m, 6 H), 0.84 - 0.94 (m, 3 H). 24 580.3 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.15 - 9.21 (m, 1 H), 7.70 (dd,J=9.1, 5.7 Hz, 1 H), 7.34 (d,J=2.7 Hz, 1 H), 7.25 - 7.30 (m, 1 H), 7.07 (d,J=2.7 Hz, 1 H), 5.47 - 5.73 (m, 1 H), 4.63 - 4.73 (m, 2 H), 4.18 - 4.26 (m, 4 H), 3.82 - 4.10 (m, 7 H), 3.45 - 3.56 (m, 1 H), 2.54 - 2.81 (m, 2 H), 2.33 - 2.53 (m, 4 H), 2.10 - 2.30 (m, 2 H), 0.82 (t,J=7.0 Hz, 3 H), 0.54 - 0.55 (m, 1 H). 25 610.2 11H NMR (400 MHz, methanol-d4) δ ppm 8.53 - 8.68 (m, 1 H), 6.77 - 6.94 (m, 1 H), 6.44 - 6.57 (m, 2 H), 6.15 - 6.27 (m, 1 H), 4.71 - 4.92 (m, 1 H), 3.43 (br d, J = 6.1 Hz, 4 H), 3.26 - 3.33 (m, 2 H), 3.02 - 3.20 (m, 6 H), 2.65 - 2.74 (m, 2 H), 1.50 - 1.73 (m, 6 H), 1.39 (br dd, J = 4.3, 2.2 Hz, 3 H), -0.04 - 0.06 (m, 3 H). 26 610.2 1 1H NMR (400 MHz, methanol-d4) δ ppm 8.51 - 8.74 (m, 1 H), 6.82 - 6.95 (m, 1 H), 6.53 (br d, J = 2.5 Hz, 2 H), 6.18 - 6.31 (m, 1 H), 4.69 - 4.84 (m, 1 H), 3.36 - 3.68 (m, 5 H), 2.82 - 3.35 (m, 7 H), 2.63 - 2.76 (m, 1 H), 1.86 (s, 4 H), 1.25 - 1.71 (m, 6 H), -0.19 - 0.07 (m, 3 H). 27 592.2 11H NMR (400 MHz, methanol-d4) δ ppm 9.54 (s, 1 H), 7.71 (dd, J = 9.0, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.28 (t, J = 9.4 Hz, 1 H), 7.08 (d, J = 2.7 Hz, 1 H), 5.46 - 5.70 (m, 1 H), 4.87 (br d, J = 6.5 Hz, 2 H), 4.66 - 4.73 (m, 2 H), 4.46 - 4.56 (m, 2 H), 4.26 - 4.45 (m, 2 H), 3.83 - 4.16 (m, 3 H), 3.45 - 3.56 (m, 1 H), 3.35 - 3.43 (m, 1 H), 2.68 - 2.83 (m, 1 H), 2.30 - 2.63 (m, 5 H), 2.21 (td, J = 7.2, 3.0 Hz, 2 H), 2.03 (d, J = 9.2 Hz, 1 H), 0.82 (t, J = 6.9 Hz, 3 H). 28 606.3 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.26 - 9.40 (m, 1 H), 7.70 (dd, J = 9.0, 5.9 Hz, 1 H), 7.34 (d, J = 2.5 Hz, 1 H), 7.28 (t, J = 9.4 Hz, H), 7.02 - 7.11 (m, 1 H), 5.50 - 5.69 (m, 1 H), 5.16 (br s, 1 H), 4.60 - 4.69 (m, 2 H), 4.14 - 4.39 (m, 4 H), 3.92 (br s, 3 H), 3.50 (br s, 1 H), 2.71 - 2.81 (m, 1 H), 2.10 - 2.65 (m, 11 H), 1.83 - 1.98 (m, 1 H), 0.76 - 0.88 (m, 3 H). 29 592.3 11H NMR (400 MHz, methanol-d4) δ ppm 9.01 (s, 1 H), 7.70 (dd, J = 9.1, 6.0 Hz, 1 H), 7.34 (d, J = 2.5 Hz, 1 H), 7.27 (t, J = 9.4 Hz, 1 H), 7.07 (d, J = 2.5 Hz, 1 H), 5.48 - 5.71 (m, 1 H), 4.83 - 4.92 (m, 1 H), 4.59 - 4.77 (m, 4 H), 3.81 - 4.25 (m, 6 H), 3.44 - 3.56 (m, 1 H), 3.03 - 3.15 (m, 1 H), 2.68 - 2.85 (m, 1 H), 2.52 - 2.65 (m, 1 H), 2.30 - 2.51 (m, 4 H), 2.10 - 2.28 (m, 3 H), 0.81 (t, J = 7.3 Hz, 3 H). 30 564.1 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.18 - 9.23 (m, 1 H), 7.64 - 7.73 (m, 1 H), 7.31 - 7.35 (m, 1 H), 7.22 - 7.30 (m, 1 H), 7.05 - 7.12 (m, 1 H), 4.43 - 4.52 (m, 2 H), 4.26 - 4.36 (m, 4 H), 4.03 - 4.12 (m, 2 H), 3.83 - 3.92 (m, 2 H), 2.15 - 2.64 (m, 7 H), 1.91 - 2.07 (m, 1 H), 1.43 (s, 3 H), 1.34 - 1.40 (m, 1 H), 0.76 - 0.88 (m, 3 H). 31 561.1 11H NMR (400 MHz, methanol-d4) δ ppm 9.21 (s, 1 H), 7.65 - 7.73 (m, 1 H), 7.30 - 7.34 (m, 1 H), 7.22 - 7.29 (m, 1 H), 7.03 - 7.09 (m, 1 H), 4.81 - 4.85 (m, 1 H), 4.75 (br s, 2 H), 4.26 - 4.35 (m, 4 H), 4.04 - 4.11 (m, 2 H), 3.85 - 3.93 (m, 3 H), 3.73 - 3.78 (m, 1 H), 3.56 - 3.70 (m, 2 H), 2.66 - 2.75 (m, 1 H), 2.42 - 2.58 (m, 2 H), 2.14 - 2.26 (m, 3 H), 0.81 (s, 3 H). 32 550.1 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.15 (s, 1 H) 7.60 - 7.69 (m, 1 H) 7.34 - 7.42 (m, 1 H) 7.31 (d,J=2.51 Hz, 1 H) 7.18 (d,J=6.90 Hz, 1 H) 7.02 - 7.07 (m, 1 H) 5.10 - 5.33 (m, 1 H) 4.56 (d,J=5.02 Hz, 2 H) 4.21 - 4.32 (m, 4 H) 4.03 - 4.11 (m, 2 H) 3.82 - 3.92 (m, 2 H) 3.47 - 3.71 (m, 2 H) 3.17 - 3.27 (m, 1 H) 2.65 - 2.79 (m, 1 H) 2.60 (s, 3 H) 2.16 - 2.44 (m, 5 H) 1.96 - 2.15 (m, 1 H) 1.25 - 1.35 (m, 3 H). 33 575.2 11H NMR (400 MHz, methanol-d4) δ ppm 9.11 - 9.26 (m, 1 H), 7.61 - 7.73 (m, 1 H), 7.30 - 7.40 (m, 1 H), 7.22 - 7.29 (m, 1 H), 7.03 - 7.11 (m, 1 H), 4.71 (s, 1 H), 4.21 - 4.37 (m, 4 H), 3.82 - 4.10 (m, 6 H), 3.57 - 3.79 (m, 2 H), 3.05 - 3.10 (m, 3 H), 2.73 - 2.87 (m, 1 H), 2.58 - 2.70 (m, 2 H), 2.42 - 2.56 (m, 1 H), 2.14 - 2.30 (m, 3 H), 0.78 - 0.85 (m, 3 H). 78 605.9 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.56 - 9.77 (m, 1 H), 7.62 - 7.74 (m, 1 H), 7.30 - 7.43 (m, 2 H), 7.17 - 7.23 (m, 1 H), 7.01 - 7.10 (m, 1 H), 5.49 - 5.75 (m, 1 H), 4.55 - 4.73 (m, 4 H), 4.16 - 4.29 (m, 1 H), 3.82 - 4.12 (m, 6 H), 3.65 - 3.75 (m, 2 H), 3.43 - 3.55 (m, 1 H), 2.53 - 2.87 (m, 2 H), 2.14 - 2.49 (m, 6 H), 1.31 (d, J=1.3 Hz, 3 H), 0.82 - 1.01 (m, 3 H). 79 638.2 11H NMR (400 MHz, methanol-d4) δ ppm 9.53 - 9.79 (m, 1 H), 7.61 - 7.87 (m, 1 H), 7.24 - 7.43 (m, 2 H), 6.94 - 7.17 (m, 1 H), 5.37 - 5.81 (m, 1 H), 4.53 - 4.82 (m, 4 H), 4.18 - 4.30 (m, 1 H), 3.63 - 4.10 (m, 7 H), 3.42 - 3.57 (m, 1 H), 2.31 - 2.79 (m, 6 H), 2.10 - 2.29 (m, 2 H), 1.46 - 1.79 (m, 2 H), 1.07 (s, 3 H), 0.68 - 0.91 (m, 3 H). 80 640.0 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.72 - 9.86 (m, 1 H), 7.65 - 7.75 (m, 1 H), 7.31 - 7.34 (m, 1 H), 7.24 - 7.31 (m, 1 H), 6.98 - 7.09 (m, 1 H), 5.47 - 5.71 (m, 1 H), 4.68 - 4.81 (m, 2 H), 4.48 - 4.67 (m, 2 H), 4.18 - 4.28 (m, 1 H), 4.01 - 4.15 (m, 2 H), 3.85 - 4.00 (m, 4 H), 3.64 - 3.78 (m, 2 H), 3.45 - 3.56 (m, 1 H), 2.55 - 2.81 (m, 2 H), 2.43 - 2.53 (m, 1 H), 2.25 - 2.42 (m, 4 H), 2.08 - 2.24 (m, 1 H), 1.30 (d,J=1.2 Hz, 3 H), 0.86 (s, 3 H). 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thio-1-oxide (Example 34)

[0264] Step 1: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thio-1-oxide. Add 0.10 g (0.16 mmol) and 3.1 mL of DCM to a 20 mL vial. Add mCPBA (70.1 mg, 0.31 mmol) to the resulting solution and stir the reaction mixture at room temperature for 1 h. After completion, the reaction was concentrated under reduced pressure, and the residue was purified by column chromatography on silicone using a 0%-100% 3:1 EtOAc / EtOH mixture in heptane (containing 2% triethylamine additive) to give a yellow solid 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiocyano-1-oxide (21 mg, 0.031 mmol, 20% yield). m / z(ESI): 656.2 (M+H)+.

[0265] Step 2: 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thio-linolenic acid 1-oxide. Synthesized in a manner similar to Example 1. The product was isolated as a TFA salt. m / z(ESI): 612.2 (M+H)+. 1H NMR (400 MHz, DMSO- d 6): δ ppm 9.21 (s, 1 H), 7.78 (dd, J=9.1, 6.0 Hz, 1 H), 7.31 - 7.41 (m, 2 H), 7.02 (d, J=2.7 Hz, 1 H), 5.47 - 5.71 (m, 1 H), 4.51 - 4.70 (m, 4 H), 4.20 - 4.32 (m, 2 H), 3.68 - 3.93 (m, 4 H), 2.97 - 3.30 (m, 6 H), 2.08 - 2.40 (m, 7 H), 0.74 (t, J=7.4 Hz, 3 H). 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6-thiocyano-1-oxide (Example 35)

[0266] Step 1: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ6-thiocyano-1-oxide. Add 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiocarbamate (0.10 g, 0.16 mmol) and methanol (3.1 mL) to an 8 mL vial. Add ammonium carbamate (24 mg, 0.31 mmol) and iodobenzene diacetate (0.13 g, 0.39 mmol) to the resulting solution and stir the mixture at room temperature for 2 h. After completion, the reaction was concentrated under reduced pressure and purified by column chromatography on silicone using a 0%–100% 3:1 EtOAc / EtOH mixture (containing 2% triethylamine additive) in heptane to give a yellow solid 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-1-imino-1λ6-thiocyanoline 1-oxide (77 mg, 0.115 mmol, 73% yield). m / z (ESI): 671.25 (M+H)+.

[0267] Step 2: 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ6-thiocyano-1-oxide. Synthesized in a manner similar to that of Example 1. The product was isolated as a TFA salt. m / z(ESI): 627.20 (M+H)+. 1H NMR (400 MHz, DMSO- d 6): δ ppm 9.21 (s, 1 H), 7.78 (dd, J=9.0, 6.1 Hz, 1 H), 7.31 - 7.41 (m, 2 H), 7.02 (d, J=2.5 Hz, 1 H), 5.48 - 5.70 (m, 1 H), 4.60 - 4.72 (m, 2 H), 4.44 - 4.57 (m, 2 H), 4.08 - 4.26 (m, 3 H), 3.82 - 3.84 (m, 2 H), 3.26 - 3.55 (m, 7 H), 1.96 - 2.40 (m, 8 H), 0.74 (t, J=7.3 Hz, 3 H). 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazidecycloheptane 1-oxide (Example 36) and 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazidecycloheptane 1,1-dioxide (Example 37)

[0268] Step 1: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptan-1-oxide and 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4- Thiazinesepane 1,1-dioxide. Add 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazenecycloheptane (54 mg, 0.083 mmol), tetrahydrofuran (6.3 mL), and water (0.06 mL) to a 20 mL vial. Cool the resulting solution to 0°C, add OXONE®, persulfate (51 mg, 0.083 mmol), and stir the reaction mixture at 0°C. After 45 min, heat the reaction mixture to 23°C. After another 19 h, add 3 mL of 10% Na 2S 2O 3 aqueous solution and stir the mixture vigorously for 5 min. The aqueous layer was extracted with CH₂Cl₂ (2 × 5 mL), and the combined organic matter was dried over anhydrous Na₂SO₄ and concentrated to dryness to give 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptan-1-oxide and 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptan-1-oxide. A crude mixture of 1,1-dioxides of pyrimidin-4-yl)-1,4-thiazacycloheptanane. m / z (ESI): 670.2, 686.1 (M+H)+.

[0269] Step 2: 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptane 1-oxide and 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptane 1,1-dioxide. Synthesized in a manner similar to Example 1. The product was isolated as a TFA salt. 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptane 1-oxide. m / z (ESI, +ve ion): 626.1 (M+H)+. 1H NMR (400 MHz, methanol-d 4) δ ppm 9.29 (s, 1 H), 7.70 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 (dd, , 3.34 - 3.58 (m, 4H), 2.83 - 3.00 (m, 2 H), 2.13 - 2.81 (m, 10 H), 0.71 - 0.91 (m, 3 H). 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazacycloheptane 1,1-dioxide. m / z(ESI): 642.0 (M+H)+.1H NMR (400 MHz, methanol-d 4) δ ppm 9.27 (s, 1 H), 7.71 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.08 (d, J=2.7 Hz, 1 H), 5.46 - 5.73 (m, 1 H), 4.61 - 4.75 (m, 2 H), 4.31 - 4.52 (m, 4 H), 3.84 - 4.14 (m, 3 H), 3.76 (t, J=5.5 Hz, 2 H), 3.37 - 3.57 (m, 3 H), 2.29 - 2.83 (m, 8 H), 2.22 (ddd, J=14.0, 7.0, 4.0 Hz, 2 H), 0.76 - 0.88 (m, 3 H). 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1 λ 6,4-thiazacycloheptane 1-oxide (Example 38) Example 38.

[0270] Synthesized in a manner similar to that of Example 35. The product as a TFA salt was isolated. m / z(ESI): 641.1 (M+H)+. 1H NMR (400 MHz, methanol-d 4) δ ppm 9.27 (s, 1 H), 7.71 (dd, J=9.0, 5.9 Hz, 1 H), 7.34 (d, J=2.5 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.07 (d, J=2.3 Hz, 1 H), 5.49 - 5.78 (m, 1 H), 4.79 - 4.98 (m, 1 H), 3.67 - 4.61 (m, 12 H), 3.41 - 3.56 (m, 1 H), 2.32 - 2.72 (m, 8 H), 2.11 - 2.28 (m, 2 H), 0.81 (t, J=7.3 Hz, 3 H). 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-6-methoxy-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Example 39)

[0271] At 0°C, (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol (31 mg, 0.05 mmol, synthesized via the route of Example 25) and sodium hydride (5.8 mg, 0.14 mmol, TCI, USA) were added to a 20 mL vial in tetrahydrofuran (1.0 mL). The reaction was stirred at 0°C for 20 min. Iodomethane (14 mg, 6.0 µL, 0.10 mmol, Sigma-Aldrich) was then added, and the reaction was heated to room temperature. After 1 h, the reaction mixture was diluted with water and extracted with CH₂Cl₂. The organic extract was dried over MgSO₄. The solution was filtered and concentrated under vacuum to give a crude substance as a pale yellow solid, which was added to a 20 mL vial. HCl (4 M, 0.3 mL, 1.20 mmol, Sigma-Aldrich) and acetonitrile (0.9 mL) in diethyl sulfoxide were added at 0°C. After 30 min, the solvent was removed under reduced pressure. The crude material was purified by reverse-phase HPLC to provide 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol as a pale yellow solid (14 mg, 0.02 mmol, 40% yield). m / z (ESI): 624.3 (M+H)+.1H NMR (400 MHz, methanol-d 4) δ ppm 9.35 - 9.43 (m, 1 H), 7.70 (dd, J=9.2, 5.9 Hz, 1 H), 7.34 (d, J=2.7 Hz, 1 H), 7.24 - 7.31 (m, 1 H), 7.08 (s, 1 H), 5.46 - 5.71 (m, 1 H), 4.72 (dd, J=9.2, 2.1 Hz, 2 H), 4.32 - 4.48 (m, 3 H), 3.97 - 4.27 (m, 4 H), 3.82 - 3.96 (m, 5 H), 3.49 (d, J=4.6 Hz, 3 H), 2.69 - 2.81 (m, 1 H), 2.31 - 2.67 (m, 6 H), 2.13 - 2.28 (m, 2 H), 0.75 - 0.87 (m, 3 H). 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thio-lino)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Example 40).

[0272] Step 1: (4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiocarbamo-2-yl)methanol. Add 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin (0.46 g, 1.80 mmol, Lambert), thiocarbamo-2-ylmethanol (0.24 g, 1.80 mmol, intermediate E) and acetonitrile (7.0 mL) to a 40 mL vial. Cool the resulting suspension to -40°C and add DIPEA (1.16 g, 1.6 mL, 9.01 mmol, Aldrich). The resulting mixture was heated to 23°C over 30 min. After completion, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methanol (0.57 g, 3.60 mmol, Lambert) was added, and the mixture was heated to 80°C for 16 h. The mixture was purified by column chromatography on silica gel with a gradient elution of 0%–30% MeOH in DCM to give (4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thio-2-yl)methanol (0.85 g, 1.79 mmol, 99% yield) as an orange solid. m / z(ESI): 472.2 (M+H) +.

[0273] Step 2: (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thio-2-yl)methanol. Add (4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiolin-2-yl)methanol (0.30 g, 0.64 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (0.34 g, 0.95 mmol, Lambert), potassium phosphate (0.41 g, 1.91 mmol, Sigma-Aldrich), and cataCXium A Pd G3 (93 mg, 0.13 mmol, Sigma-Aldrich) to a 1 dallan vial. The vial was purged with nitrogen, and the reactants were suspended in degassed tetrahydrofuran (5.8 mL) and water (0.6 mL). The reaction mixture was then sealed and heated to 70°C. After stirring overnight, the reaction was cooled to room temperature and concentrated under reduced pressure to give a crude black oil. The oil was then purified by column chromatography on silica gel using a gradient elution of 0%–30% MeOH in DCM to provide an orange oil of (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)thio-2-yl)methanol. Yield not determined. m / z(ESI): 670.3 (M+H) +.

[0274] Step 3: 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thio-lino)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol. The above-mentioned (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiolin-2-yl)methanol was dissolved in MeCN (3.0 mL), and HCl (4 M, 4.0 mL, 15.89 mmol, Sigma-Aldrich) in 1,4-dimethylamine was added. The reaction was then stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and purified by reverse-phase HPLC to provide 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thio-lino)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol bis(2,2,2-trifluoroacetate) as a pale yellow solid (0.13 g, 0.16 mmol, 24% yield). m / z (ESI, +ve ion): 626.1 (M+H)+. 1H NMR (400 MHz, DMSO- d 6): δ ppm 10.58 - 10.90 (m, 1 H), 9.20 (d, J=1.3 Hz, 1 H), 7.78 (dd, J=9.0, 6.1 Hz, 1 H), 7.31 - 7.41 (m, 2 H), 7.03 (dd, J=5.9, 2.7 Hz, 1 H), 5.49 - 5.67 (m, 1 H), 4.34 - 4.79 (m, 8 H), 4.03 (br dd, J=13.6, 7.9 Hz, 1 H), 3.75 - 3.95 (m, 4 H), 3.50 - 3.68 (m, 2 H), 3.18 - 3.37 (m, 2 H), 2.89 - 3.10 (m, 2 H), 2.53 - 2.70 (m, 1 H), 2.31 - 2.42 (m, 2 H), 2.02 - 2.24 (m, 4 H), 0.74 (t, J=7.3 Hz, 3 H).[Table 5]. Examples 41 to 53 were prepared in a manner similar to that of Example 40. Instance number structure name Salt code reagents Method Change 41 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazetane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol 2,2,2-Trifluoroacetate Step 1: ((2R,7aR)-2-fluorohexahydro-1H-pyrrolo-7a-yl)methanol hydrochloride (CAS#: 2454490-66-3, WuXi AppTec Co. Ltd.) Step 3: Use MeOH. 42 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazetane-2-methylamine Isomer 1 Bis(2,2,2-trifluoroacetate) Step 1: N-methyl-1,4-oxazacycloheptane-2-methamide (intermediate C1) Chiral separation following step 1. Details are as follows. 43 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazetane-2-methylamine Isomer 2 Bis(2,2,2-trifluoroacetate) Step 1: N-methyl-1,4-oxazacycloheptane-2-methamide (intermediate C1) Chiral separation following step 1. Details are as follows. 44 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazetane-6-methylamine Isomer 1 Bis(2,2,2-trifluoroacetate) Step 1: N-methyl-1,4-oxazacycloheptane-6-methamide (intermediate C4) Chiral separation following step 1. Details are as follows. 45 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazetane-6-methylamine Isomer 2 Bis(2,2,2-trifluoroacetate) Step 1: N-methyl-1,4-oxazacycloheptane-6-methamide (intermediate C4) Chiral separation following step 1. Details are as follows. 46 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-methylamine Isomer 1 Bis(2,2,2-trifluoroacetate) Step 1: 1,4-oxazetane-6-methamide (intermediate C3) Chiral separation following step 1. Details are as follows. 47 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-methylamine Isomer 2 Bis(2,2,2-trifluoroacetate) Step 1: 1,4-oxazetane-6-methamide (intermediate C3) Chiral separation following step 1. Details are as follows. 48 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Isomer 1 Bis(2,2,2-trifluoroacetate) Step 1: (1,4-oxazine-2-yl)methanol (intermediate D1) Chiral separation following step 1. Details are as follows. 49 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((S)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Isomer 1 Bis(2,2,2-trifluoroacetate) Step 1: (1,4-oxazineheptan-6-yl)methanol (intermediate D2) Chiral separation following step 1. Details are as follows. 50 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Isomer 2 Bis(2,2,2-trifluoroacetate) Step 1: (1,4-oxazineheptan-6-yl)methanol (intermediate D2) Chiral separation following step 1. Details are as follows. 51 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-2-methylamine Bis(2,2,2-trifluoroacetate) Step 1: 1,4-oxazetane-2-methamide (intermediate C2) 52 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-2-methylpyridinolino)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol Free base Step 1: (R)-2-methyltrimonium phosphate hydrochloride (CAS#: 168038-14-0, Advanced Chemical Company) After step 3, the product is washed with an aqueous solution of NaHCO3 to achieve free alkalization. 53 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-2-(methoxymethyl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol Free base Step 1: (S)-3-(methoxymethyl) α-linolenic acid hydrochloride (CAS#: 218594-76-4, Ark Pharma) Step 1: Use DBACO (0.2 equivalents) and Cs2CO3 (3 equivalents). After step 3, the product is washed with an aqueous solution of NaHCO3 to achieve free alkalization. [Table 6]. SFC conditions for chiral separation. Separation condition Peak and Instance Number Column: Chiralcel OX (21 x 150 mm 5 μm) Mobile phase: 50% iPrOH w / 0.2% TEA Flow rate: 120 mL / min. Yield: Using a 600 mg sample, peak 1 (where ee > 99%) and peak 2 (where ee > 99%) were generated at 112.9 mg. Peak 1: Example 42 Peak 2: Example 43 Column: ChiralPak IF (2 x 25 cm 5 µm) Mobile phase: 40% iPrOH w / 0.2% TEA, flow rate: 80 mL / min. Yield: A sample of 550 mg was used to generate peak 1 of 71.1 mg (with ee of 99%) and peak 2 of 70.8 mg (with ee of 97%). Peak 1: Example 44 Peak 2: Example 45 Column: (S,S) Whelk-O1 (21 x 250 mm 5μm) Mobile phase: 45% MeOH w / 0.2% TEA, flow rate: 80 mL / min Yield: A 600 mg sample was used to generate peak 1 of 215.7 mg (where ee > 99%) and peak 2 of 72.8 mg (where ee > 96%). Peak 1: Example 46 Peak 2: Example 47 Column: Chiralcel OD (2 x 25 cm 5 µm) Mobile phase: 30% MeOH w / 0.2% DEA, flow rate: 80 mL / min. Yield: Using 1200 mg of substrate, peak 1 of 259 mg (with ee of 99%) and peak 2 of 409 mg (with ee of 95%) were generated. Peak 2: Example 48 column: ChiralPak IF (2 x 25 cm 5 µm), mobile phase: 40% MeOH w / 0.2% DEA, flow rate: 80 mL / min. Yield: A sample of 730 mg was used to generate peak 1 of 109 mg (with ee of 93%) and peak 2 of 170.8 mg (with ee of 90%). Peak 1: Example 49 Peak 2: Example 50 [Table 7]. Analysis data for Examples 41 to 53. Instance number MS m / z(ESI): (M+H) + 1 H NMR 41 594.0 11H NMR (400 MHz, methanol-d4) δ ppm 9.23 (s, 1 H), 7.66 - 7.77 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.23 - 7.31 (m, 1 H), 7.06 - 7.11 (m, 1 H), 5.45 - 5.63 (m, 1 H), 4.71 - 4.76 (m, 1 H), 4.24 - 4.36 (m, 4 H), 3.99 - 4.12 (m, 3 H), 3.85 - 3.92 (m, 2 H), 3.67 - 3.79 (m, 1 H), 3.53 - 3.61 (m, 1 H), 3.44 - 3.52 (m, 2 H), 2.64 - 2.80 (m, 1 H), 2.38 - 2.57 (m, 3 H), 2.22 (br s, 6 H), 0.79 - 0.88 (m, 3 H). 42 651.1 1 1H NMR (400 MHz, methanol-d4): δ ppm 9.27 (s, 1 H), 7.69 (dd,J=9.0, 5.7 Hz, 1 H), 7.32 (d,J=2.5 Hz, 1 H), 7.26 (t,J=9.3 Hz, 1 H), 7.05 (dd,J=9.7, 2.5 Hz, 1 H), 5.50 - 5.71 (m, 1 H), 4.88 - 5.07 (m, 2 H), 4.70 (d,J=12.6 Hz, 1 H), 4.32 - 4.49 (m, 2 H), 4.17 - 4.31 (m, 2 H), 3.86 - 4.13 (m, 4 H), 3.63 - 3.79 (m, 1 H), 3.43 - 3.56 (m, 1 H), 2.78 (d,J=2.1 Hz, 3 H), 2.09 - 2.72 (m, 10 H), 0.80 (dt,J=17.8, 7.5 Hz, 3 H). 43 651.1 11H NMR (400 MHz, methanol-d4) δ ppm 9.27 (s, 1 H), 7.69 (dd, J = 8.9, 5.8 Hz, 1 H), 7.32 (d, J = 2.5 Hz, 1 H), 7.26 (t, J = 9.3 Hz, 1 H), 7.05 (dd, J = 12.2, 2.5 Hz, 1 H), 5.47 - 5.70 (m, 1 H), 4.99 (ddd, J = 19.7, 14.6, 2.2 Hz, 1 H), 4.73 - 4.83 (m, 2 H), 4.33 - 4.48 (m, 2 H), 4.16 - 4.31 (m, 2 H), 3.85 - 4.13 (m, 4 H), 3.70 (dt, J = 17.8, 11.1 Hz, 1 H), 3.43 - 3.55 (m, 1 H), 2.58 - 2.83 (m, 5 H), 2.13 - 2.52 (m, 8 H), 0.80 (dt, J = 11.4, 7.4 Hz, 3 H). 44 651.1 1 1H NMR (400 MHz, methanol-d4): δ ppm 9.21 - 9.31 (m, 1 H), 7.71 (dd, J = 8.9, 5.8 Hz, 1 H), 7.34 (d, J = 2.5 Hz, 1 H), 7.28 (t, J = 9.4 Hz, 1 H), 7.08 (dd, J = 5.7, 2.4 Hz, 1 H), 5.48 - 5.71 (m, 1 H), 4.63 - 4.79 (m, 3 H), 3.85 - 4.46 (m, 10 H), 3.46 - 3.59 (m, 1 H), �.20 (dt, J = 8.6, 4.5 Hz, 1 H), 2.78 (s, 3 H), 2.12 - 2.71 (m, 8 H), 0.82 (dt, J = 13.0, 7.3 Hz, 3 H). 45 651.1 1 It should be noted that there seems to be a typo in the original text where "�.20" is likely a mistake. It is translated as "3.20" here for the sake of translation consistency.1H NMR (400 MHz, methanol-d4): δ ppm 9.24 (d, J = 2.1 Hz, 1 H), 7.71 (dd, J = 9.0, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.28 (t, J = 9.3 Hz, 1 H), 7.08 (dd, J = 5.1, 2.8 Hz, 1 H), 5.50 - 5.72 (m, 1 H), 4.61 - 4.78 (m, 3 H), 4.33 - 4.47 (m, 1 H), 3.98 - 4.32 (m, 6 H), 3.82 - 3.97 (m, 3 H), 3.44 - 3.56 (m, 1 H), 3.13 - 3.25 (m, 1 H), 2.56 - 2.83 (m, 5 H), 2.32 - 2.53 (m, 4 H), 2.12 - 2.29 (m, 2 H), 0.82 (dt, J = 18.0, 7.5 Hz, 3 H). 46 637.1 1H NMR (400 MHz, methanol-d4): δ ppm 9.25 (d, J = 3.1 Hz, 1 H), 7.71 (dd, J = 9.0, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.28 (t, J = 9.4 Hz, 1 H), 7.08 (dd, J = 6.6, 2.5 Hz, 1 H), 5.49 - 5.70 (m, 1 H), 4.64 - 4.80 (m, 3 H), 4.32 - 4.46 (m, 1 H), 3.84 - 4.30 (m, 9 H), 3.44 - 3.57 (m, 1 H), 3.17 - 3.29 (m, 1 H), 2.15 - 2.80 (m, 8 H), 0.75 - 0.89 (m, 3 H). 47 637.1 11H NMR (400 MHz, methanol-d4): δ ppm 9.23 - 9.33 (m, 1 H), 7.71 (dd, J = 9.0, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 任1 H), 7.28 (t, J = 9.3 Hz, 1 H), 7.0 (m, 1 H), 5.46 - 5.69 (m, 1 H), 3.76 - 4.82 (m, 13 H), 3.45 - 3.57 (m, 1 H), 3.19 - 3.31 (m, 1 H), 2.35 - 2.86 (m, 6 H), 2.11 - 2.30 (m, 2 H), 0.73 - 0.90 (m, 3 H). 48 624.1 1 1H NMR (400 MHz, methanol-d4): δ ppm 9.27 (d, J = 1.7 Hz, 1 H), 7.70 (dd, J = 9.0, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.28 (t, J = 9.4 Hz, 1 H), 7.08 (dd, J = 8.2, 2.5 Hz, 1 H), 5.49 - 5.71 (m, 1 H), 4.65 - 4.75 (m, 3 H), 3.64 - 4.43 (m, 11 H), 3.45 - 3.56 (m, 1 H), 2.34 - 2.81 (m, 7 H), 2.13 - 2.27 (m, 3 H), 0.83 (dt, J = 11.8, 7.4 Hz, 3 H). 49 624.1 1H NMR (400 MHz, methanol-d4): δ ppm 9.24 - 9.34 (m, 1 H), 7.70 (dd, J = 9.0, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.28 (t, J = 9.4 Hz, 1 H), 7.08 (dd, J = 9.0, 2.5 Hz, 1 H), 5.48 - 5.73 (m, 1 H), 4.75 (s, 2 H), 4.40 - 4.54 (m, 1 H), 3.85 - 4.22 (m, 8 H), 3.44 - 3.71 (m, 4 H), 1.95 - 2.82 (m, 10 H), 0.82 (dt, J = 12.4, 7.4 Hz, 3 H). 50 624.1 1 1H NMR (400 MHz, methanol-d4): δ ppm 9.29 (d, J = 2.1 Hz, 1 H), 7.70 (dd, J = 9.0, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.28 (t, J = 9.3 Hz, 1 H), 7.08 (dd, J = 7.6, 2.4 Hz, 1 H), 5.50 - 5.71 (m, 1 H), 4.62 - 4.74 (m, 2 H), 4.36 - 4.56 (m, 1 H), 3.39 - 4.27 (m, 12 H), 1.99 - 2.81 (m, 10 H), 0.76 - 0.89 (m, 3 H). 51 637.1 11H NMR (400 MHz, methanol-d4): δ ppm 8.92 - 9.32 (m, 1 H), 7.66 - 7.75 (m, 1 H), 7.32 - 7.37 (m, 1 H), 7.24 - 7.31 (m, 1 H), 7.01 - 7.11 (m, 1 H), 5.44 - 5.74 (m, 1 H), 4.79 - 5.04 (m, 3 H), 3.66 - 4.45 (m, 8 H), 3.42 - 3.57 (m, 1 H), 2.11 - 2.89 (m, 10 H), 1.80 - 2.01 (m, 1 H), 0.74 - 0.89 (m, 3 H). 52 594.3 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (s, 1 H), 9.15 (s, 1 H), 7.77 (dd,J=9.1, 6.0 Hz, 1 H), 7.28 - 7.40 (m, 2 H), 7.03 (d,J=2.3 Hz, 1 H), 5.15 - 5.44 (m, 1 H), 4.37 - 4.54 (m, 2 H), 4.12 - 4.22 (m, 1 H), 4.04 - 4.12 (m, 1 H), 3.98 (br d,J=11.9 Hz, 1 H), 3.67 - 3.85 (m, 2 H), 3.44 - 3.60 (m, 1 H), 2.93 - 3.25 (m, 4 H), 2.78 - 2.89 (m, 1 H), 2.28 - 2.43 (m, 1 H), 1.96 - 2.23 (m, 4 H), 1.71 - 1.91 (m, 3 H), 1.20 (dd,J=6.2, 2.8 Hz, 3 H), 0.74 (t,J=7.3 Hz, 3 H). 53 624.3 1H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (s, 1 H), 9.14 (s, 1 H), 7.76 (dd,J=9.0, 6.1 Hz, 1 H), 7.29 - 7.40 (m, 2 H), 7.03 (d,J=2.5 Hz, 1 H), 5.17 - 5.42 (m, 1 H), 4.35 - 4.51 (m, 2 H), 4.19 (dd,J=10.5, 5.9 Hz, 1 H), 4.09 (dd,J=10.6, 2.0 Hz, 1 H), 3.95 - 4.05 (m, 1 H), 3.86 (br dd,J=6.6, 3.7 Hz, 1 H), 3.75 (td,J=11.3, 2.2 Hz, 1 H), 3.43 - 3.62 (m, 3 H), 3.33 - 3.42 (m, 1 H), 3.31 (d,J=1.0 Hz, 3 H), 2.98 - 3.17 (m, 3 H), 2.80 - 2.89 (m, 1 H), 2.27 - 2.41 (m, 1 H), 2.11 - 2.25 (m, 2 H), 2.05 - 2.11 (m, 1 H), 1.95 - 2.05 (m, 1 H), 1.71 - 1.93 (m, 3 H), 0.74 (t,J=7.4 Hz, 3 H). 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazadicycloheptan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (Example 54)

[0275] Step 1: (R)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methyl-1,4-oxazetane. DIPEA (21 mg, 0.03 mL, 0.16 mmol, Sigma-Aldrich) and HATU (49 mg, 0.13 mmol, Compibrco) were added to a stirred solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (18 mg, 0.03 mmol, intermediate A) in N,N-dimethylacetamide (0.20 mL). The resulting mixture was stirred at room temperature for 5 min. (R)-5-methyl-1,4-oxazacycloheptane hydrochloride (7.4 mg, 0.05 mmol, Enimex) was added to N,N-dimethylacetamide (0.20 mL), and the reaction was stirred at room temperature for 1 h. The reaction mixture was purified by reverse-phase HPLC to give (R)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methyl-1,4-oxazacycloheptane (11 mg, 0.02 mmol, 52% yield) as a yellow solid, which was used directly in the next step. m / z (ESI, +ve ion): 652.2 (M+H)+.

[0276] Step 2: 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol. (R)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-5-methyl-1,4-oxazacycloheptane (11 mg, 0.02 mmol) was dissolved in acetonitrile (0.50 mL). HCl solution (4.0 M in dimethyl ether, 0.04 mL, 0.17 mmol, Sigma-Aldrich) was added, and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was purified by reverse-phase HPLC to give 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol as a yellow solid (11 mg, 0.01 mmol, 79% yield). m / z (ESI): 608.0 (M+H)+. 1H NMR (400 MHz, methanol-d 4) δ ppm 9.11 (d, J=5.4 Hz, 1 H), 7.71 (dd, J=9.2, 5.9 Hz, 1 H), 7.25 - 7.35 (m, 2 H), 7.07 (dd, J=17.1, 2.5 Hz, 1 H), 5.47 - 5.70 (m, 1 H), 4.88 - 4.99 (m, 1 H), 4.71 - 4.76 (m, 1 H), 4.54 - 4.69 (m, 2 H), 4.18 (br t, J=10.0 Hz, 1 H), 3.89 - 4.07 (m, 5 H), 3.76 - 3.86 (m, 1 H), 3.41 - 3.54 (m, 2 H), 2.11 - 2.79 (m, 10 H), 1.59 (d, J=6.3 Hz, 3 H), 0.83 (q, J=7.1 Hz, 3 H).[Table 8]: Examples 55 to 72 were prepared in a manner similar to that of Example 54. Instance number structure name Salt form reagents Method Change 55 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-((S)-5-methyl-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol 2,2,2-Trifluoroacetate Step 1: (S)-5-methyl-1,4-oxazetane heptane hydrochloride (CAS#: 2694057-41-3, Enimi Company) 56 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Bis(2,2,2-trifluoroacetate) Step 1: (1,4-oxazacycloheptan-2-yl)methanol (CAS#: 1207254-23-6, Aurum Pharmatech) 57 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(7-(hydroxymethyl)-1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol Bis(2,2,2-trifluoroacetate) Step 1: (1,4-oxazacycloheptan-7-yl)methanol (CAS#: 627860-89-3, Oram Pharmaceutical Technologies) 58 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]non-9-ol Bis(2,2,2-trifluoroacetate) Step 1: 3-oxa-7-azabicyclo[3.3.1]non-9-ol (intermediate F) 59 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide Bis(2,2,2-trifluoroacetate) Step 1: 2-Thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide (CAS#: 1312812-72-8, Ambeed) 60 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)pyridino-[4,3-d]pyrimidin-7-yl)naphth-2-ol 2,2,2-Trifluoroacetate Step 1: 2-(((tributyldimethylsilyl)oxy)methyl)carbamoline (intermediate G) Before step 2, use TBAF / THF (1 M) to remove the TBS group. 61 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-carboxynitrile Free base Step 1: 1,4-oxazetane-6-carboxynitrile (intermediate H) Purification was performed using 0.1% formic acid and MeCN in H2O as the mobile phase on an XSelect column (19 × 100 mm, 5 μm). 62 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide 2,2,2-Trifluoroacetate Step 1: 1-λ6,3- Thiamethane-1,1-dione hydrochloride (CAS#: 2059999-55-0, AiniMi Company) 63 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-sulfonamide 2,2,2-Trifluoroacetate Step 1: 1,4-oxazetane-6-sulfonamide hydrochloride (CAS#: 2694729-07-0, Chemspace) 64 4-(4-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol Formate Step 1: 9-oxa-3-azabicyclo[3.3.1]nonane hydrochloride (CAS#: 1947317-74-9, Enermy Laboratories) 65 2-(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl) pyrolin-2-yl)acetonitrile Formate Step 1: 2-(α-lin-2-yl)acetonitrile hydrochloride (CAS#: 1242465-38-8, WuXi AppTec) 66 4-(4-((1R,6S)-2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol 2,2,2-Trifluoroacetate Step 1: 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride (CAS#: 1354952-28-5, Enermi Corporation) 67 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-one 2,2,2-Trifluoroacetate Step 1: 1,4-oxazetane-6-one hydrochloride (CAS#: 2306265-53-0, AA Blocks) 68 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol Isomer 1 2,2,2-Trifluoroacetate Step 1: 6-Methyl-1,4-oxazetane-6-ol hydrochloride (intermediate J1) 69 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazacycloheptan-6-ol Isomer 2 2,2,2-Trifluoroacetate Step 1: 6-Methyl-1,4-oxazetane-6-ol hydrochloride (intermediate J2) 70 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazacycloheptan-6-ol 2,2,2-Trifluoroacetate Step 1: 6-((trimethylsilyl)ethynyl)-1,4-oxazetane-6-ol hydrochloride (intermediate K) The following are the additional steps following step 2. The procedure includes the following. 71 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile Isomer 1 2,2,2-Trifluoroacetate Step 1: 8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonite hydrochloride (intermediate I) 72 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonitrile Isomer 2 2,2,2-Trifluoroacetate Step 1: 8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylonite hydrochloride (intermediate I) Additional steps in Example 70

[0277] 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-((trimethylsilyl)ethynyl)-1,4-oxazacycloheptan-6-ol (64 mg, 0.09 mmol) was dissolved in methanol and treated with potassium carbonate (25 mg, 0.18 mmol, Sigma-Aldrich) in water (1.0 mL). The reaction was stirred for 3 h. The substance was purified by reverse-phase HPLC to give 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazacycloheptane-6-ol (8 mg, 11 μmol, 12% yield) as a 2,2,2-trifluoroacetate. [Table 9]: Analytical data for Examples 55 to 72. Instance number MS m / z(ESI): (M+H) + 1 H NMR 55 608.0 11H NMR (400 MHz, methanol-d4) δ ppm 9.11 (d, J = 5.2 Hz, 1 H), 7.70 (dd, J = 9.2, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.28 (t, J = 9.3 Hz, 1 H), 7.08 (dd, J = 17.6, 2.5 Hz, 1 H), 5.47 - 5.73 (m, 1 H), 4.84 - 4.97 (m, 1 H), 4.68 - 4.73 (m, 2 H), 4.54 - 4.64 (m, 1 H), 4.13 - 4.21 (m, 1 H), 3.88 - 4.11 (m, 5 H), 3.75 - 3.86 (m, 1 H), 3.43 - 3.53 (m, 2 H), 2.60 - 2.88 (m, 2 H), 2.33 - 2.57 (m, 5 H), 2.07 - 2.29 (m, 3 H), 1.59 (d, J = 6.3 Hz, 3 H), 0.82 (dt, J = 10.5, 7.5 Hz, 3 H). 56 624.3 1 1H NMR (400 MHz, methanol-d4): δ ppm 9.27 (d, J = 1.7 Hz, 1 H), 7.70 (dd, J = 9.2, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.28 (t, J = 9.4 Hz, 1 H), 7.08 (dd, J = 7.8, 2.6 Hz, 1 H), 5.42 - 5.74 (m, 1 H), 4.63 - 4.77 (m, 3 H), 3.55 - 4.43 (m, 11 H), 3.42 - 3.53 (m, 1 H), 2.14 - 2.84 (m, 10 H), 0.74 - 0.92 (m, 3 H). [[ID=⑨]]57 624.3 1 It should be noted that there is a mislabeling in your original text where "" is written as "[[ID=⑨]]", which is corrected in the translation. Also, the " " tags are used to mark the end of each relevant text segment in a way that might be specific to a certain document structure. If there are any further specific requirements or if this doesn't match your expectations, please provide more context.1H NMR (400 MHz, methanol-d4): δ ppm 8.98 - 9.32 (m, 1 H), 7.70 (dd, J = 9.1, 5.7 Hz, 1 H), 7.34 (d, J = 2.5 Hz, 1 H), 7.28 (t, J = 9.4 Hz, 1 H), 7.08 (dd, J = 6.3, 2.5 Hz, 1 H), 5.46 - 5.78 (m, 1 H), 4.63 - 4.76 (m, 2 H), 3.63 - 4.59 (m, 10 H), 3.41 - 3.61 (m, 3 H), 1.87 - 2.78 (m, 10 H), 0.70 - 0.91 (m, 3 H). 58 636.1 1 1H NMR (400 MHz, DMSO-d6): δ ppm 10.64 - 10.80 (m, 1 H), 9.70 - 10.11 (m, 1 H), 9.19 - 9.30 (m, 1 H), 7.77 (dd, J = 9.1, 6.2 Hz, 1 H), 7.30 - 7.40 (m, 2 H), 7.05 (d, J = 2.3 Hz, 1 H), 5.48 - 5.72 (m, 1 H), 4.70 - 5.10 (m, 2 H), 4.60 (s, 2 H), 4.00 (br d, J = 8.2 Hz, 6 H), 3.57 - 3.71 (m, 5 H), 3.33 (br dd, J = 4.9, 2.8 Hz, 1 H), 2.07 - 2.43 (m, 7 H), 1.78 - 1.93 (m, 2 H), 0.73 (t, J = 7.4 Hz, 3 H). 59 640.2 11H NMR (400 MHz, DMSO-d6): δ ppm 10.58 - 10.81 (m, 1 H), 9.75 - 10.14 (m, 1 H), 9.29 (br s, 1 H), 7.78 (dd, J = 8.9, 6.0 Hz, 1 H), 7.33 - 7.40 (m, 2 H), 7.03 (d, J = 2.5 Hz, 1 H), 5.43 - 5.72 (m, 2 H), 4.61 - 4.70 (m, 2 H), 4.25 - 4.43 (m, 2 H), 3.77 - 3.96 (m, 4 H), 3.24 - 3.38 (m, 2 H), 2.52 - 2.75 (m, 3 H), 1.96 - 2.42 (m, 7 H), 0.74 (dt, J = 12.0, 7.4 Hz, 3 H). 60 610.0 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.20 (s, 1 H), 7.70 (dd, J = 9.2, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.27 (t, J = 9.3 Hz, 1 H), 7.07 (d, J = 2.5 Hz, 1 H), 5.51 - 5.68 (m, 1 H), 4.70 (br s, 3 H), 4.09 - 4.17 (m, 1 H), 3.64 - 4.01 (m, 8 H), 3.51 (br d, J = 5.6 Hz, 2 H), 3.11 - 3.19 (m, 2 H), 2.55 - 2.80 (m, 2 H), 2.33 - 2.53 (m, 4 H), 2.16 - 2.29 (m, 2 H), 0.82 (t, J = 7.4 Hz, 3 H). 61 619.2 11H NMR (400 MHz, methanol-d4) δ ppm 9.24 (s, 1 H), 7.70 (dd, J = 9.1, 5.7 Hz, 1 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.27 (t, J = 9.4 Hz, 1 H), 7.08 (dd, J = 9.1, 2.6 Hz, 1 H), 5.34 - 5.54 (m, 1 H), 4.56 (s, 5 H), 4.28 - 4.38 (m, 2 H), 3.98 - 4.26 (m, 4 H), 3.55 (br s, 4 H), 3.17 - 3.26 (m, 1 H), 2.32 - 2.60 (m, 3 H), 2.01 - 2.31 (m, 5 H), 0.82 (br s, 3 H). 62 628.3 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.25 (s, 1 H), 7.71 (dd, J = 9.0, 5.9 Hz, 1 H), 7.34 (d, J = 2.7 Hz, 1 H), 7.28 (t, J = 9.4 Hz, 1 H), 7.09 (d, J = 2.� Hz, 1 H), 5.50 - 5.71 (m, 1 H), 5.47 (br s, 2 H), 4.65 - 4.76 (m, 2 H), 4.24 - 4.42 (m, 2 H), 3.93 (br d, J = 15.9 Hz, 3 H), 3.50 (br t, J = 5.7 Hz, 3 H), 2.71 - 2.90 (m, 1 H), 2.70 (s, 1 H), 2.68 - 2.76 (m, 1 H), 2.54 - 2.70 (m, 1 H), 2.30 - 2.54 (m, 4 H), 2.28 - 2.33 (m, 1 H), 2.13 - 2.27 (m, 2 H), 0.81 (t, J = 7.3 Hz, 3 H). 63 673.0 11H NMR (400 MHz, methanol-d4) δ ppm 9.03 - 9.30 (m, 1 H), 7.66 - 7.74 (m, 1 H), 7.32 - 7.36 (m, 1 H), 7.24 - 7.31 (m, 1 H), 7.01 - 7.11 (m, 1 H), 5.50 - 5.74 (m, 1 H), 5.10 - 5.44 (m, 1 H), 4.83 - 5.00 (m, 1 H), 4.60 - 4.74 (m, 1 H), 4.35 - 4.49 (m, 1 H), 3.75 - 4.33 (m, 8 H), 3.43 - 3.58 (m, 1 H), 3.09 - 3.28 (m, 1 H), 2.06 - 2.86 (m, 8 H), 0.74 - 0.93 (m, 3 H). 64 620.2 1 1H NMR (500 MHz, DMSO-d6) δ ppm 10.42 - 10.74 (m, 1 H), 9.21 - 9.24 (m, 1 H), 7.78 (dd,J=9.1, 6.1 Hz, 1 H), 7.33 - 7.38 (m, 2 H), 7.03 (d,J=2.3 Hz, 1 H), 5.49 - 5.66 (m, 1 H), 4.57 - 4.71 (m, 4 H), 4.03 - 4.15 (m, 2 H), 3.70 - 4.01 (m, 6 H), 3.27 - 3.36 (m, 1 H), 2.30 - 2.40 (m, 2 H), 2.11 - 2.24 (m, 3 H), 1.90 - 2.11 (m, 3 H), 1.73 - 1.88 (m, 3 H), 1.46 - 1.58 (m, 1 H), 0.70 - 0.75 (m, 3 H). 65 619.2 11H NMR (500 MHz, DMSO-d6) δ ppm 8.15 (s, 1 H), 7.77 (dd, J = 9.1, 6.1 Hz, 1 H), 7.31 - 7.37 (m, 2 H), 7.00 - 7.02 (m, 1 H), 5.18 - 5.41 (m, 1 H), 4.51 (br d, J = 13.1 Hz, 1 H), 4.37 - 4.44 (m, 1 H), 4.17 (ddd, J = 10.4, 6.4, 4.0 Hz, 1 H), 3.95 - 4.10 (m, 3 H), 3.79 - 3.88 (m, 1 H), 3.47 - 3.57 (m, 1 H), 3.22 - 3.43 (m, 1 H), 2.98 - 3.17 (m, 4 H), 2.80 - 2.98 (m, 2 H), 2.31 - 2.40 (m, 1 H), 1.97 - 2.18 (m, 4 H), 1.74 - 1.91 (m, 3 H), 0.73 (t, J = 7.3 Hz, 3 H). 66 592.3 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.81 - 9.98 (m, 1 H), 7.64 - 7.80 (m, 1 H), 7.35 (d, J = 2.7 Hz, 1 H), 7.26 - 7.31 (m, 1 H), 7.18 - 7.18 (m, 1 H), 7.09 (d, J = 2.5 Hz, 1 H), 6.88 - 6.88 (m, 1 H), 5.46 - 5.74 (m, 1 H), 4.64 - 4.72 (m, 2 H), 4.20 - 4.30 (m, 1 H), 4.09 - 4.14 (m, 1 H), 3.89 - 3.95 (m, 2 H), 3.68 - 3.76 (m, 1 H), 3.49 - 3.54 (m, 1 H), 2.32 - 2.52 (m, 6 H), 2.16 - 2.28 (m, 3 H), 1.30 - 1.43 (m, 2 H), 1.18 (br d, J = 3.1 Hz, 1 H), 0.82 (br d, J = 2.1 Hz, 3 H). 67 608.2 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.25 - 9.65 (m, 1 H), 7.49 - 7.89 (m, 1 H), 7.21 - 7.47 (m, 2 H), 7.00 - 7.14 (m, 1 H), 5.43 - 5.85 (m, 1 H), 4.46 - 4.74 (m, 5 H), 4.17 - 4.38 (m, 2 H), 3.97 - 4.17 (m, 3 H), 3.65 - 3.97 (m, 3 H), 3.40 - 3.56 (m, 1 H), 2.31 - 2.86 (m, 6 H), 2.12 - 2.27 (m, 2 H), 0.57 - 0.97 (m, 3 H). 68 624.2 1 1H NMR (400 MHz, methanol-d4) δ ppm 9.52 - 9.91 (m, 1 H), 7.57 - 7.81 (m, 1 H), 7.18 - 7.45 (m, 2 H), 6.92 - 7.16 (m, 1 H), 5.50 - 5.83 (m, 1 H), 4.55 - 4.72 (m, 3 H), 4.17 - 4.30 (m, 1 H), 3.86 - 4.11 (m, 6 H), 3.60 - 3.79 (m, 2 H), 3.44 - 3.57 (m, 1 H), 2.11 - 2.88 (m, 8 H), 1.18 - 1.55 (m, 3 H), 0.50 - 0.94 (m, 3 H). 69 624.2 11H NMR (400 MHz, methanol-d4) δ ppm 9.50 - 9.81 (m, 1 H), 7.55 - 7.94 (m, 1 H), 7.18 - 7.43 (m, 2 H), 6.90 - 7.14 (m, 1 H), 5.43 - 5.93 (m, 1 H), 4.47 - 4.75 (m, 4 H), 3.88 - 4.31 (m, 7 H), 3.61 - 3.78 (m, 2 H), 3.40 - 3.56 (m, 1 H), 2.13 - 2.87 (m, 8 H), 1.31 (d, J=1.9 Hz, 3 H), 0.39 - 0.90 (m, 3 H). 70 634.2 1 [[ID=⑦]]1H NMR (400 MHz, methanol-d4) δ ppm 9.35 - 9.81 (m, 1 H), 7.70 (dd,J=9.0, 5.9 Hz, 1 H), 7.23 - 7.50 (m, 2 H), 7.02 - 7.12 (m, 1 H), 5.27 - 5.82 (m, 1 H), 4.64 - 4.75 (m, 2 H), 4.33 - 4.56 (m, 2 H), 3.78 - 4.32 (m, 8 H), 3.43 - 3.62 (m, 1 H), 3.04 - 3.12 (m, 1 H), 2.02 - 2.83 (m, 8 H), 1.87 - 1.99 (m, 1 H), 0.61 - 0.97 (m, 3 H). 71 631.0 1 It should be noted that in the original text, the "⑦" in "[[ID=⑦]]" is likely a mislabeling. It should probably be "". This translation is based on the best understanding of the text with the given rules.H NMR (400 MHz, methanol-d4) δ ppm 9.17 (s, 1 H) 7.65 - 7.74 (m, 1 H) 7.34 (d,J=2.72 Hz, 1 H) 7.24 - 7.31 (m, 1 H) 7.05 (s, 1 H) 5.41 - 5.73 (m, 1 H) 4.80 - 4.83 (m, 1 H) 4.65 - 4.76 (m, 4 H) 4.47 - 4.63 (m, 1 H) 3.76 - 4.12 (m, 5 H) 3.45 - 3.56 (m, 1 H) 3.36 - 3.44 (m, 1 H) 2.55 - 2.84 (m, 2H) 2.39 (br d,J=5.43 Hz, 6 H) 2.14 - 2.26 (m, 2 H) 0.74 - 0.86 (m, 3 H). 72 631.0 1 H NMR (400 MHz, methanol-d4) δ ppm 9.17 - 9.28 (m, 1 H) 7.69 (dd,J=9.09, 5.54 Hz, 1 H) 7.34 (d,J=2.72 Hz, 1 H) 7.21 - 7.30 (m, 1 H) 7.03 - 7.12 (m, 1 H) 5.49 - 5.69 (m, 1 H) 4.83 (s, 2 H) 4.64 - 4.76 (m, 4 H) 3.72 - 4.24 (m, 5 H) 3.35 - 3.56 (m, 2 H) 2.52 - 2.84 (m, 3 H) 2.30 - 2.52 (m, 4H) 2.02 - 2.28 (m, 3 H) 0.74 - 0.86 (m, 3 H). 6-Ethyl-4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazadicycloheptan-6-ol (Example 73)

[0278] Add 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-one (20 mg, 0.03 mmol, synthesized via the route of Example 67) in THF (0.6 mL) to a 10 mL round-bottom flask. Cool the reaction to 0°C, then add ethyl magnesium bromide (1 M in THF, 0.09 mL, 0.09 mmol, Sigma-Aldrich). Stir the reaction for 1 h. Quench the crude material with MeOH and acetic acid. The crude mixture was purified by column chromatography on silicone using a gradient elution of 0%–100% EtOAc / EtOH (containing 1% TEA) in heptane, yielding 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyridino[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol, dissolved in 2 mL of acetonitrile. The mixture was cooled to 0°C, and then HCl (4 M in diethyl sulfoxide, 0.4 mL) was added. The reaction was stirred for 1 h. The mixture was concentrated under reduced pressure and then purified by reverse-phase HPLC to give 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol (8.0 mg, 0.01 mmol, 35% yield) as a 2,2,2-trifluoroacetate and an off-white solid (8.0 mg, 0.01 mmol, 35% yield). m / z (ESI): 638.2 (M+H)+.1H NMR (400 MHz, methanol-d 4) δ ppm 9.57 - 9.87 (m, 1 H), 7.60 - 8.01 (m, 1 H), 7.17 - 7.45 (m, 2 H), 6.86 - 7.14 (m, 1 H), 5.45 - 5.83 (m, 1 H), 4.42 - 4.81 (m, 4 H), 3.61 - 4.34 (m, 8 H), 3.47 - 3.58 (m, 1 H), 2.31 - 2.82 (m, 6 H), 2.11 - 2.27 (m, 2 H), 1.46 - 1.80 (m, 2 H), 1.00 - 1.19 (m, 2 H), 0.72 - 0.93 (m, 3 H). 6-Cyclopropyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-ol (Example 74) Example 74.

[0279] Synthesized in a manner similar to Example 73 using a solution of cyclopropylmagnesium bromide in THF. The product was isolated as a TFA salt. m / z (ESI): 650.2 (M+H)+. 1H NMR (400 MHz, methanol-d 4) δ ppm 9.56 - 9.79 (m, 1 H), 7.51 - 7.86 (m, 1 H), 7.18 - 7.44 (m, 2 H), 6.94 - 7.12 (m, 1 H), 5.22 - 6.00 (m, 1 H), 4.56 - 4.74 (m, 4 H), 4.18 - 4.34 (m, 1 H), 3.80 - 4.11 (m, 7 H), 3.64 - 3.80 (m, 1 H), 3.46 - 3.59 (m, 1 H), 2.05 - 2.91 (m, 8 H), 0.91 - 1.12 (m, 1 H), 0.84 (s, 3 H), 0.51 - 0.69 (m, 2 H), 0.33 - 0.50 (m, 2 H). 4-(4-(2-(difluoromethyl) α-lino)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol (Example 75)

[0280] 7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (20 mg, 0.04 mmol, intermediate B) was dissolved in N,N-dimethylacetamide (0.50 mL). HATU (60 mg, 0.16 mmol, Compibrco), DIPEA (25 mg, 34 µL, 0.20 mmol, Sigma-Aldrich), 2,4-dimethoxytoluene (12 mg, 12 µL, 0.08 mmol, Oram Pharmaceuticals), and 2-(difluoromethyl)phosphono-4-onium chloride (11 mg, 0.06 mmol, Enimi) were added, and the mixture was stirred overnight at room temperature. Water (0.5 mL) was then added, and the mixture was stirred overnight. Using 0.1% formic acid and MeCN in H₂O as the mobile phase, an XSelect column (19 x 100 mm, 5 μm) was used in MS mode: ESI + to purify the crude reaction mixture to yield 4-(4-(2-(difluoromethyl)phosphono)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol (5.3 mg, 7.8 μmol, 20% yield) as the formate ester. m / z(ESI): 630.2 (M+H) +. 1H NMR (500...

Claims

1. A compound having formula (I): (I) or a pharmaceutically acceptable salt of said compound, wherein: --- is a single or double bond; W is C, CH or N, wherein when W is CH or N, --- is a single bond; X is O, S, S(O), S(O)(NR z) or S(O) 2; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; p is 0, 1, 2 or 3; each R x is a hydroxyl, halogen, syloxy, cyano, -N(R z) 2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5-7 heteroaryl, -TR y, or two R x with adjacent carbon atoms can together form a C 3-7 cycloalkyl or a 5-7 heterocycloalkyl, wherein each C 3-7 cycloalkyl or 5-7 heterocycloalkyl are further substituted by Ry appearing 0-3 times, or two Rx can form a bridging ring together, wherein the bridge is selected from one of the following: -C1-4 alkyl, -C1-4 alkyl-OC1-4 alkyl-, -O-, -S-, or -C1-4 alkyl-SC1-4 alkyl-, and wherein each C1-4 alkyl chain is further substituted by Ry appearing 0-2 times; L-series C1-6 alkyl, -OC1-6 alkyl, -SC1-6 alkyl, NRz, O, or S, wherein each C1-6 alkyl, -OC1-6 alkyl, and -SC1-6 alkyl chain is substituted by R2 appearing 0-2 times; R1 series hydroxyl, aryl, heteroaryl, C3-8 cycloalkyl, or heterocycloalkyl substituted by R5 appearing 0-3 times; R2 series halogen, hydroxyl, C2 1-4 alkyl groups, or two R2 groups on the same or adjacent carbon atoms that can together form a C3-7 cycloalkyl group; R3 groups are aryl or heteroaryl groups substituted by R6 groups appearing 0-3 times; R4 groups are hydrogen, hydroxyl, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-7 cycloalkyl, or cyano groups; each R5 group is halogen, oxy group, hydroxyl group, amino group, cyano group, or C1-4 alkyl group; each R6 group is halogen, hydroxyl, cyano group, -N(R2)2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C2-4 alkynyl, or C3-6 cycloalkyl group; T-groups are C1-4 alkyl groups, -S(O)2-, -C(O)-, -C 1-4 alkyl-C(O)-, C 1-4 alkyl-S(O) 2- or -S-; Ry-series halogens, C 1-4 alkyl groups, C 1-4 haloalkyl groups, C 1-4 alkoxy groups, hydroxyl groups, cyano groups or -N(Rz) 2; and Rz-series halogens or C 1-4 alkyl groups, wherein p is not zero when X is O, R3 is an aryl group substituted by R6 (occurring only once), and R6 is a hydroxyl group.

2. The compound as claimed in claim 1, wherein when R is a 3-based and R is a 4-based fluorine, then it is not , , , , , , , or.

3. The compound as claimed in claim 1, wherein when R is a 3-based and R is a 4-based fluorine, then it is not , , , , , , , , or.

4. The compound as claimed in claim 1, wherein when R is a 3-based and R is a 4-based fluorine, then it is not or 5. The compound as claimed in claim 1, wherein when R is a 3-based and R is a 4-based fluorine, then it is not , , or.

6. The compound as claimed in claim 1, wherein when R is a 3-based and R is a 4-based fluorine, then it is not or 7. The compound as claimed in claim 1, wherein when R is a 3-based and R is a 4-based fluorine, then it is not or 8. The compound as claimed in claim 1, wherein when R is a 3-based and R is a 4-based fluorine, then it is not or 9. The compound as claimed in claim 1, wherein it is not fluorine when R is a 3-based and R is a 4-based fluorine.

10. The compound as claimed in claim 1, wherein it is not fluorine when R is a 3-based and R is a 4-based fluorine.

11. The compound as claimed in claims 1-10, wherein L is a -OC 1-6 alkyl group substituted by R 2 (e.g., -O-methylene-, -O-ethyl-, or -O-propylene) appearing 0-2 times.

12. The compound as claimed in claim 11, wherein L is a -O-ephedroxy or -O-propylidene substituted with R 2 0 to 2 times.

13. The compound as claimed in claim 12, wherein R1 is a hydroxyl group or heterocyclic alkyl group substituted by R5 appearing 0 to 3 times.

14. The compound as claimed in any one of claims 1-10, wherein R is a halogen, cyano, C1-4 alkyl or lateral oxygen group.

15. The compound as claimed in claim 14, wherein -LR 1 is a series of , , , , , , , , , , or .

16. The compound as claimed in claim 15, wherein -LR 1 is a series of , , or .

17. The compound as claimed in any one of claims 1-10, wherein R3 is an aryl group substituted by R6 appearing 0-3 times.

18. The compound as claimed in claim 17, wherein R3 is a phenyl or naphthyl group substituted by R6 appearing 0 to 3 times.

19. The compound as claimed in claim 18, wherein R3 is a heteroaryl group substituted by R6 appearing 0-3 times.

20. The compound as claimed in claim 18, wherein R is a 6-hydroxyl group, a halogen, a C1-4 alkyl group, a C1-4 haloalkyl group, a C2-4 alkynyl group, a C3-6 cycloalkyl group, or -N(Rz)2.

21. The compound as claimed in claim 18, wherein R 6 is a hydroxyl, methyl, ethyl, trifluoromethyl, difluoromethyl, ethynyl, fluorine, chlorine, cyclopropyl or -NH 2.

22. The compound as claimed in claim 18, wherein R 3 is a series of , , , , , , , , , , , , or .

23. The compound as claimed in claim 22, wherein R is a series of , , , or .

24. The compound as claimed in any one of claims 1-10, wherein W is N and --- is a single bond.

25. The compound as claimed in any one of claims 1-10, wherein X is S, S(O)2, S(O) or S(O)(NR z).

26. The compound as claimed in claim 25, wherein p is 0, 1 or 2.

27. The compound of claim 25, wherein each Rx is a -T-Ry, or two Rx together form a bridging ring, wherein the bridging ring is further replaced by -C1-4 alkyl groups of Ry appearing 0-2 times.

28. The compound as claimed in claim 27, wherein each Rx is a -CH2OH group, or two Rx groups together form a bridging ring, wherein the bridging group is further substituted with methylene or ethyl groups by Ry appearing 0-2 times.

29. The compound as claimed in claim 25, wherein the compounds are , , , , , , , , , , , , , or.

30. The compound as claimed in any one of claims 1-10, wherein X is an O-type compound.

31. The compound as claimed in claim 30, wherein n is a series 1 and m is a series 1.

32. The compound of claim 31, wherein each Rx is a C1-4 alkyl, C1-4 haloalkyl, lateral oxy or -TRy, or two Rx together form a bridging ring, wherein the bridge is selected from a -C1-4 cycloalkyl further substituted with Ry 0-2 times, or two Rx together with an adjacent carbon atom form a C3-7 cycloalkyl further substituted with Ry 0-3 times.

33. The compound as claimed in claim 32, wherein each Rx is a methyl, difluoromethyl, -CH2CN, CH2OH, -C(O)NH2 or -CH2OMe, or two Rx together form a bridging ring, wherein the bridge is selected from a methylene or ethyl group further substituted by Ry 0-2 times, or two Rx together with an adjacent carbon atom form a cyclopropyl group further substituted by Ry 0-3 times.

34. The compound as claimed in claim 31, wherein the compounds are , , , , , , , , , , , , , or.

35. The compound as claimed in claim 30, wherein n is a 1 and m is a 2, or n is a 2 and m is a 2.

36. The compound of claim 35, wherein each Rx is a side-oxygen group, a C1-4 alkyl group, a C1-4 alkoxy group, a C2-4 alkynyl group, a C3-6 cycloalkyl group, a hydroxyl group, a halogen group, a cyano group, or a -TRy group, or two Rx groups together form a bridging ring, wherein the bridging group is -O- or -C1-4 alkyl, wherein the -C1-4 alkyl group is further substituted by Ry appearing 0 to 2 times.

37. The compound as claimed in claim 36, wherein each Rx is methyl, ethyl, ethynyl, fluorine, cyclopropyl, cyano, syloxy, hydroxyl, methoxy, -C(O)N(H)(Me), -C(O)NH 2, -CH 2OH or -SO 2NH 2, or two Rx together form a bridging ring, wherein the bridging ring is -O- or methylene, wherein the methylene is further substituted by Ry appearing 0 to 2 times.

38. The compound as claimed in claim 35, wherein the compounds are , ...

39. The compound as claimed in any one of claims 1-10, wherein R4 is a C1-4 alkyl, C1-4 alkoxy, hydroxyl, halogen, or C1-4 haloalkyl.

40. The compound as claimed in claim 39, wherein R4 is a C1-4 alkyl, hydroxyl, or halogen.

41. The compound as claimed in claim 1, wherein the compound is selected from one of the following compounds: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; R)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-6-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide;4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazetane-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(1,4-thiazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2 S,4)-yl)-1-oxazetane-6-one; R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3- [d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( S)-6-methoxy-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1- ... S)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-carboxylonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalene-2-ol;Or (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-ol.

42. The compound as claimed in claim 1, wherein the compound is selected from one of the following compounds: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyridino[4,3-d]pyrimidin-7-yl)naphth-2-ol; R)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 4-(4-(6,6-difluoro-1,4-oxazacycloheptane-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphth-2-ol H)-yl)methoxy)-4-(1,4-oxazacycloheptane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)-4-(( R)-6-(hydroxymethyl)-1,4-oxazetane-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2 R,7a S)-2-fluorotetrahydro-1 H-pyrrolo-7a(5 H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazoline 1,1-dioxide;Or 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolo-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-one.

43. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of any one of claims 1-42, and a pharmaceutically acceptable excipient.

44. The compound described in any one of claims 1-42, or its tautomer, or a pharmaceutically acceptable salt of the compound, or a pharmaceutical composition described in claim 43, may be used as a medicament.

45. A compound or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-42, or a pharmaceutical composition as described in claim 43, for use in the treatment of cancer.

46. ​​A compound or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-42, or a pharmaceutical composition as described in claim 43, for use in the treatment of cancer, wherein one or more cells express the KRAS G12D mutant protein.

47. The compound or pharmaceutical composition used as described in claim 45, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer type, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelometaplasia / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

48. Use of any compound described in any of claims 1-42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 43, in the preparation of a medicament for treating cancer.

49. Use of any compound of claims 1-42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 43, in the preparation of a medicament for treating cancer, wherein one or more cells express the KRAS G12D mutant protein.

50. The use as described in claim 48 or 49, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary origin, 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, myelometaplasia / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

51. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1-42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 43.

52. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1-42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 43, wherein one or more cells express the KRAS G12D mutant protein.

53. The method as described in claim 51 or 52, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer type, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelometaplasia / myeloproliferative neoplasm, head and neck cancer, esophageal and gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

54. The method as described in claim 51 or 52, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary origin, ampullary cancer, gastric cancer, small bowel cancer, sinus cancer, bile duct cancer, or melanoma.

55. The method as described in claim 54, wherein the cancer is non-small cell lung cancer.

56. The method as described in claim 54, wherein the cancer is colorectal cancer.

57. The method as described in claim 54, wherein the cancer is pancreatic cancer.

58. The method as described in any one of claims 51-57, wherein the subject has cancer, and the cancer is identified as having one or more cells expressing the KRAS G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.