Heterocyclic compounds and methods of use

Abstract

The present disclosure provides compounds useful for inhibiting KRAS G12D, the compounds having the general formula I: TIFF2024517695000311.tif32170, and the variables of formula I are defined herein. The disclosure also provides pharmaceutical compositions comprising the compounds, such as the use of the compounds and compositions for the treatment of cancer.

Description

[Technical field]

[0001] The present disclosure provides compounds having activity as inhibitors of G12D mutant KRAS protein. The present disclosure also provides pharmaceutical compositions comprising the compounds, uses and methods for treating certain diseases, such as cancer, including, but not limited to, non-small cell lung cancer (NSCLC), colon cancer and / or pancreatic cancer. [Background technology]

[0002] Since its identification in 1982 as one of the first human oncogenes (Der et al., 1982), KRAS (Kirsten rat sarcoma viral oncogene homolog) has been the focus of extensive academic and industrial research as a key node in the MAPK signal transduction pathway, as a transforming factor in a network of parallel effector pathways (e.g., PI3K / AKT) (Vojtek et al., 1998) and as a potential target for anticancer drugs (Malumbres et al., 2003). Despite advances in the development of inhibitors of upstream and downstream nodes of the MAPK pathway (e.g., EGFR (Sridhar et al., 2003), BRAF (Holderfield et al., 2014) and MOK (Caunt et al., 2015), the KRAS protein has historically proven resistant to direct inhibition.

[0003] KRAS is a G protein that couples extracellular mitogenic signaling to intracellular growth-promoting responses. KRAS serves as an intracellular "on / off" switch. Mitogen stimulation induces the binding of GTP to KRAS, resulting in a conformational change that allows KRAS to interact with downstream effector proteins, resulting in cell proliferation. Normally, growth-promoting signaling is regulated by the action of GTPase-activating proteins (GAPs), which pull KRAS back to its GDP-bound, non-proliferative state. Mutations in KRAS impair the regulated cycling of KRAS between these GDP-bound and GDP-bound states, leading to the accumulation of the GDP-bound active state and loss of cell proliferation (Simanshu et al., 2017).

[0004] Attempts to develop inhibitors of mutant KRAS proteins have historically been frustrated by the absence of a druggable pocket on the surface of the protein (Cox et al., 2014). In 2013, Shokat et al. identified a covalent inhibitor of a common (O'Bryan, 2019) oncogenic mutation in KRAS, KRAS G12C, that bound to a yet unrecognized allosteric pocket on GDP-KRAS G12C and prevented subsequent activation (Ostrem et al., 2013). This discovery led to a significant new effort in KRAS inhibitor research that has recently culminated in the entry of KRAS inhibitors into human clinical trials. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Der et al., 1982 [Non-Patent Document 2] Vojtek et al., 1998 [Non-Patent Document 3] Malumbres et al., 2003 [Non-Patent Document 4] Sridhar et al., 2003 [Non-Patent Document 5] Holderfield et al., 2014 [Non-Patent Document 6] Caunt et al., 2015 [Non-Patent Document 7] Simanshu et al., 2017 [Non-Patent Document 8] Cox et al., 2014 [Non-Patent Document 9] Ostrem et al., 2013 [Non-Patent Document 10] O'Bryan, 2019 Summary of the Invention [Problem to be solved by the invention]

[0006] Although some progress has been made with respect to KRAS G12C inhibitors, there is continuing interest and effort to develop inhibitors of KRAS, particularly other KRAS, such as KRAS G12D. Thus, there is a need to develop new inhibitors against KRAS G12D for the treatment of diseases such as cancer. [Means for solving the problem]

[0007] In one aspect, the present application provides a compound of formula (I): [ka] (In the formula, [ka] is a single bond or a double bond; W is C, CH or N; n is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; Each R x is hydroxyl, halogen, oxo, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C1~4 Haloalkyl, -TR y or two R x can be joined together to form a bridged ring, the bridge being -C 1~4 Alkylene, -OC 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene- or -C 1~4 Alkylene-SC 1~4 alkylene-; Z is CH, CR' or N; R' is halogen, cyano or C 1~4 is alkyl; L is a bond, C 1~6 Alkylene, C 1~6 Alkenylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S; R 1 is hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or R 5 is optionally substituted heterocycloalkyl with 0-3 occurrences of R 2 is hydrogen, hydroxyl, halogen, amino, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~8 cycloalkyl or cyano; R 3 is R 6 is an optionally substituted aryl or heteroaryl with 0-4 occurrences of R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~8 cycloalkyl or cyano; Each R 5 is halogen, hydroxyl, oxo, amino, C 1~4 Alkyl or -TR y and; Each R 6 is halogen, hydroxyl, amino, cyano, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Haloalkyl or C 3~7 is cycloalkyl; R 7 is hydrogen, halogen or C 1~4 is alkyl; T is for C 1~4 Alkylene, -O-, -S- or -C 1~4 alkylene-C(O)-; R y is halogen, hydroxyl, cyano or amino; and R z is hydrogen or C 1~4 is alkyl; If W is N, [ka] is a single bond, m is 2, 3 or 4, and two R x are taken together to form a bridged ring, the bridge being -C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene- or -C 1~4 Alkylene-SC 1~4 alkylene-) or a pharma- ceutically acceptable salt of said compound.

[0008] In a second aspect, provided herein is a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt of said compound, and a pharma- ceutically acceptable excipient.

[0009] In a third aspect, there is provided herein a compound of formula I, or a pharma- ceutically acceptable salt of said compound, or a pharmaceutical composition as described herein, for use in the treatment of cancer (e.g., NSCLC, colon cancer, or pancreatic cancer).

[0010] Reference will now be made in detail to the embodiments of the present disclosure. Although specific embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. On the contrary, reference to the embodiments of the present disclosure is intended to encompass such alternatives, modifications, and equivalents as may be encompassed within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] As an embodiment, the compound of formula (I): [ka] (In the formula, [ka] is a single bond or a double bond; W is C, CH or N; n is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; Each R x is hydroxyl, halogen, oxo, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, -TR y or two R x can be joined together to form a bridged ring, the bridge being -C 1~4 Alkylene, -OC 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene- or -C 1~4 Alkylene-SC 1~4 alkylene-; Z is CH, CR' or N; R' is halogen, cyano or C 1~4 is alkyl; L is a bond, C 1~6 Alkylene, C 1~6 Alkenylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O or S; R 1 is hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or R 5 is optionally substituted heterocycloalkyl with 0-3 occurrences of R 2 is hydrogen, hydroxyl, halogen, amino, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~8 cycloalkyl or cyano; R 3 is R 6 is an optionally substituted aryl or heteroaryl with 0-4 occurrences of R 4 is hydrogen, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~8 cycloalkyl or cyano; Each R 5 is halogen, hydroxyl, oxo, amino, C 1~4 Alkyl or -TR y and; Each R 6 is halogen, hydroxyl, amino, cyano, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Haloalkyl or C 3~7 is cycloalkyl; R 7 is hydrogen, halogen or C 1~4 is alkyl; T is for C 1~4 Alkylene, -O-, -S- or -C 1~4 alkylene-C(O)-; R y is halogen, hydroxyl, cyano or amino; and R z is hydrogen or C 1~4 is alkyl; If W is N, [ka] is a single bond, m is 2, 3 or 4, and two R x are taken together to form a bridged ring, the bridge being -C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene- or -C 1~4 Alkylene-SC 1~4 alkylene-) or a pharma- ceutically acceptable salt of said compound is provided herein.

[0012] As embodiment 2, provided herein is a compound according to embodiment 1, wherein Z is CH.

[0013] As embodiment 3, provided herein is a compound according to embodiment 1, wherein Z is CR'. As embodiment 4, provided herein is a compound according to embodiment 3, wherein R' is halogen, C 1~4 As embodiment 5, there is provided herein a compound according to embodiment 4, wherein R' is fluoro, chloro, methyl, ethyl, or cyano (e.g., fluoro or chloro).

[0014] As embodiment 7, there is provided herein a compound described in embodiment 1, wherein Z is N.

[0015] As embodiment 8, there is provided herein a compound according to any one of embodiments 1 to 7, wherein W is N.

[0016] As embodiment 9, provided herein is a compound according to any one of embodiments 8, wherein n is 1 and m is 2.

[0017] As embodiment 10, there is provided herein a compound as described in embodiment 9, wherein two R x are taken together to form a bridged ring, the bridge being -C 1~4 Alkylene-, -C 1~4 Alkylene-O-, -C 1~4 Alkylene-OC 1~4 Alkylene-, -C 1~4 Alkylene-SC 1~4 Alkylene- or -C 1~4 As embodiment 11, there is provided herein a compound according to embodiment 10, wherein two R x are taken together to form a bridged ring, the bridge being selected from one of methylene, ethylene, propylene, or -methylene-O-methylene-. As embodiment 12, there is provided herein a compound according to embodiment 11, wherein two R x are taken together to form a bridged ring, the bridge being -C 1~4 As embodiment 13, there is provided herein a compound according to embodiment 12, wherein two R x are taken together to form a bridged ring, and the bridge is methylene. As embodiment 14, there is provided herein a compound according to embodiment 12, wherein two R x are taken together to form a bridged ring, and the bridge is ethylene. As embodiment 15, there is provided herein a compound according to embodiment 12, wherein two R x taken together form a bridged ring, the bridge being propylene.

[0018] As embodiment 16, there is provided herein a compound according to embodiment 10, wherein two Rx are taken together to form a bridged ring, the bridge being -C 1~4 Alkylene-OC 1~4 Alkylene (eg, -methylene-O-methylene).

[0019] As embodiment 17, there is provided herein a compound according to embodiment 8, wherein n is 1 and m is 3.

[0020] As embodiment 18, there is provided herein a compound according to embodiment 17, wherein one R x is halogen (e.g., fluorine), C 1~4 Alkyl (e.g., methyl or ethyl), cyano, oxo or -TR y (For example, -CH 2 OH or -CH 2 CN) and the other two R x are taken together to form a bridged ring, the bridge being -C 1~4 Alkylene- (e.g., methylene or ethylene) or -C 1~4 Alkylene-OC 1~4 Alkylene (eg, -methylene-O-methylene-).

[0021] As embodiment 19, there is provided herein a compound according to embodiment 18, wherein one R x is oxo, and the other two R x are taken together to form a bridged ring, the bridge being -C 1~4 As embodiment 20, there is provided herein a compound according to embodiment 18, wherein one R x is a halogen (e.g., fluorine), and the other two R x are taken together to form a bridged ring, the bridge being -C 1~4 Alkylene- (eg, ethylene).

[0022] As embodiment 21, there is provided herein a compound according to embodiment 8, wherein n is 1 and m is 4.

[0023] As embodiment 22, there is provided herein a compound according to embodiment 21, wherein two R x are each independently 1~4 alkyl (e.g., methyl), and the other two R x are taken together to form a bridged ring, and the bridge is C 1~4 Alkylene (e.g., ethylene) or -C 1~4 Alkylene-OC 1~4 Alkylene- (eg, -methylene-O-methylene-).

[0024] As embodiment 23, provided herein is a compound according to embodiment 8, wherein n is 2 and m is 2.

[0025] As embodiment 24, there is provided herein a compound according to embodiment 23, wherein two R x are taken together to form a bridged ring, the bridge being -C 1~4 As embodiment 25, there is provided herein a compound according to embodiment 24, wherein two R x taken together form a bridged ring, the bridge being ethylene.

[0026] As embodiment 26, provided herein is a compound according to any one of embodiments 1 to 7, wherein W is C. As embodiment 27, provided herein is a compound according to embodiment 26, wherein [ka] is a double bond.

[0027] As embodiment 28, there is provided herein a compound according to embodiment 26 or 27, wherein n is 1 and m is 2.

[0028] As embodiment 29, there is provided herein a compound according to embodiment 28, wherein two R xare taken together to form a bridged ring, and the bridge is C 1~4 Alkylene (eg, ethylene).

[0029] As embodiment 30, provided herein is a compound according to any one of embodiments 1 to 29, wherein: [ka] teeth, [ka] It is.

[0030] As embodiment 31, provided herein is a compound as described in embodiment 30, wherein: [ka] teeth, [ka] It is.

[0031] As embodiment 32, provided herein is a compound as described in embodiment 31, wherein: [ka] teeth, [ka] It is.

[0032] As embodiment 33, provided herein is a compound according to embodiment 30, wherein: [ka] teeth, [ka] As embodiment 34, there is provided herein a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 35, provided herein is a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 36, provided herein is a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 37, provided herein is a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 38, there is provided herein a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 39, provided herein is a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 40, there is provided herein a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 41, there is provided herein a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 42, there is provided herein a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 43, there is provided herein a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 44, there is provided herein a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 45, provided herein is a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 46, there is provided herein a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 47, provided herein is a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 48, provided herein is a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 49, there is provided herein a compound according to embodiment 30, wherein [ka] teeth, [ka] As embodiment 50, there is provided herein a compound as described in embodiment 30, wherein [ka] teeth, [ka] It is.

[0033] As embodiment 51, there is provided herein a compound according to any one of embodiments 1 to 50, wherein L is -OC 1~6 and alkylene (e.g., -O-methylene-, -O-ethylene-, -O-isopentanylene, -On-propyl-, -O-(2-methylpropyl)-, -O-(2-methylbutyl)-, -O-(2-ethylbutyl)-, -O-1,2-dimethylpropyl-, or -O-(3-methylbutyl)-). Provided herein as embodiment 52 is a compound according to embodiment 51, wherein L is -O-methylene or -O-ethylene. Provided herein as embodiment 53 is a compound according to embodiment 52, wherein L is -O-methylene. Provided herein as embodiment 54 is a compound according to embodiment 52, wherein L is -O-ethylene.

[0034] As embodiment 55, there is provided herein a compound according to any one of embodiments 1 to 54, wherein R 1 is R 5 As embodiment 56, there is provided herein a compound according to embodiment 55, wherein R 1 is R 5 7-(hexahydro-1H-pyrrolidine), 2-pyrrolidine or 2-tetrahydrofuranyl substituted with 0 to 3 occurrences of

[0035] As embodiment 57, there is provided herein a compound according to embodiment 56, wherein R 1 is R 5 As embodiment 58, there is provided herein a compound according to embodiment 57, wherein R 1 is R 5 As embodiment 59, there is provided herein a compound according to embodiment 58, wherein R 5 is a halogen (e.g., fluorine).

[0036] As embodiment 60, provided herein is a compound as described in embodiment 57, wherein R 1 is R 5 As embodiment 61, there is provided herein a compound according to embodiment 60, wherein both R 5 is a halogen (e.g., fluorine).

[0037] As embodiment 62, provided herein is a compound according to embodiment 56, wherein R 1 is R 5 As embodiment 63, provided herein is a compound according to embodiment 62, wherein R 1 is R 5 As embodiment 64, there is provided herein a compound according to embodiment 63, wherein R 5 is a halogen, C 1~4 As embodiment 65, there is provided herein a compound according to embodiment 64, wherein R 5 is fluorine, chlorine, methyl or oxo.

[0038] As embodiment 66, provided herein is a compound as described in embodiment 62, wherein R 1 is R 5 As embodiment 67, there is provided herein a compound according to embodiment 66, wherein each R 5 is a halogen, C 1~4 As embodiment 68, there is provided herein a compound according to embodiment 67, wherein each R is alkyl or oxo. 5 is fluorine, methyl or oxo.

[0039] As embodiment 69, provided herein is a compound according to embodiment 56, wherein R 1 is R 5As embodiment 70, there is provided herein a compound according to embodiment 69, wherein R 1 is R 5 As embodiment 71, there is provided herein a compound according to embodiment 70, wherein one R 5 is oxo, and other R 5 is C 1~4 Alkyl (eg, methyl).

[0040] As embodiment 72, there is provided herein a compound according to any one of embodiments 1 to 54, wherein R 1 is R 5 As embodiment 73, there is provided herein a compound according to embodiment 72, wherein R 1 is R 5 As embodiment 74, there is provided herein a compound according to embodiment 73, wherein R 1 is R 5 As embodiment 75, there is provided herein a compound according to embodiment 74, wherein R 5 is C 1~4 Alkyl (eg, methyl).

[0041] As embodiment 76, there is provided herein a compound according to any one of embodiments 1 to 54, wherein R 1 is R 5 C replaced with 0-3 occurrences of 3~8 As embodiment 77, there is provided herein a compound according to embodiment 76, wherein R 1 is R 5 and cyclopropyl, cyclobutyl or cyclopentyl substituted with 0 to 3 occurrences of

[0042] As embodiment 78, there is provided herein a compound as described in embodiment 77, wherein R 1 is R 5 As embodiment 79, there is provided herein a compound according to embodiment 78, wherein R 1 is R 5 As embodiment 80, there is provided herein a compound according to embodiment 79, wherein R 5 is a halogen (e.g., fluorine or chlorine) or hydroxyl.

[0043] As embodiment 81, provided herein is a compound as described in embodiment 77, wherein R 1 is R 5 As embodiment 82, provided herein is a compound according to embodiment 81, wherein R 1 is R 5 is a cyclobutyl substituted with one occurrence of R 5 is hydroxyl.

[0044] As embodiment 83, there is provided herein a compound as described in embodiment 77, wherein R 1 is R 5 As embodiment 84, there is provided herein a compound according to embodiment 83, wherein R 1 is R 5 is cyclopentyl substituted with one occurrence of R 5 is hydroxyl.

[0045] As embodiment 85, provided herein is a compound according to embodiment 51, wherein L is -O-isopentanylene (i.e., -O-2,2-dimethylethylene). As embodiment 86, provided herein is a compound according to embodiment 85, wherein R 1 is hydroxyl.

[0046] As embodiment 87, provided herein is a compound according to embodiment 51, wherein L is -On-propyl. As embodiment 88, provided herein is a compound according to embodiment 87, wherein R 1 is hydroxyl.

[0047] As embodiment 89, provided herein is a compound according to embodiment 51, wherein L is -O-(2-methylpropyl). As embodiment 90, provided herein is a compound according to embodiment 89, wherein R 1 is hydroxyl.

[0048] As embodiment 91, provided herein is a compound according to embodiment 51, wherein L is -O-(2-methylbutyl). As embodiment 92, provided herein is a compound according to embodiment 91, wherein R 1 is hydroxyl.

[0049] As embodiment 93, provided herein is a compound according to embodiment 51, wherein L is -O-(2-ethylbutyl). As embodiment 94, provided herein is a compound according to embodiment 93, wherein R 1 is hydroxyl.

[0050] As embodiment 95, provided herein is a compound according to embodiment 51, wherein L is -O-1,2-dimethylpropyl. As embodiment 96, provided herein is a compound according to embodiment 95, wherein R 1 is hydroxyl.

[0051] As embodiment 97, provided herein is a compound according to embodiment 51, wherein L is -O-(3-methylbutyl). As embodiment 98, provided herein is a compound according to embodiment 97, wherein R 1 is hydroxyl.

[0052] As embodiment 99, there is provided herein a compound according to embodiment 51, wherein L is C 1~6 alkenylene (e.g., 3-methyl-buten-1-yl). As embodiment 100, provided herein is a compound according to embodiment 99, wherein R 1 is hydroxyl.

[0053] As embodiment 101, there is provided herein a compound according to any one of embodiments 1 to 100, wherein -LR 1 teeth, [ka] It is.

[0054] As embodiment 102, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] It is.

[0055] As embodiment 103, there is provided herein a compound according to embodiment 102, wherein -LR 1 teeth, [ka] It is.

[0056] As embodiment 104, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 105, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 106, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 107, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 108, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 109, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 110, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 111, provided herein is a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 112, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 113, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 114, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 115, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 116, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 117, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 118, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 119, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 120, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 121, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 122, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 123, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 124, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 125, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] As embodiment 126, there is provided herein a compound according to embodiment 101, wherein -LR 1 teeth, [ka] It is.

[0057] As embodiment 127, provided herein is a compound according to any one of embodiments 1 to 126, wherein R 3 is R 6 As embodiment 128, there are provided herein compounds according to embodiment 127, wherein R 3is R 6 is an aryl substituted with one occurrence of

[0058] As embodiment 129, provided herein is a compound according to embodiment 128, wherein R 3 is R 6 As embodiment 130, provided herein are compounds according to embodiment 129, wherein R 6 is halogen, amino, cyano, C 1~4 Alkyl (e.g., methyl or ethyl), C 1~4 haloalkyl (e.g., trifluoromethyl or difluoromethyl), hydroxyl, C 2~4 Alkenyl (e.g., 2-ethenyl) or C 2~4 As embodiment 131, there is provided herein a compound according to embodiment 130, wherein R 6 is fluorine, chlorine, amino, cyano, methyl, ethyl, trifluoromethyl, difluoromethyl, hydroxy, 2-ethenyl, or 2-ethynyl. 6 is fluorine or chlorine. As embodiment 133, there is provided herein a compound according to embodiment 131, wherein R 6 As embodiment 134, there is provided herein a compound according to embodiment 131, wherein R 6 As embodiment 135, there is provided herein a compound according to embodiment 131, wherein R 6 is trifluoromethyl or difluoromethyl.

[0059] As embodiment 136, provided herein is a compound according to embodiment 127, wherein R 3 is R 6 is an aryl substituted with two occurrences of

[0060] As embodiment 137, provided herein is a compound according to embodiment 136, wherein R 3 is R 6 As embodiment 138, provided herein are compounds according to embodiment 137, wherein each occurrence of R 6 is hydroxyl, C 2~4 Alkynyl, C 1~4 Alkyl, halogen, C 2~4 As embodiment 139, there is provided herein a compound according to embodiment 138, wherein each occurrence of R is alkenyl, cyano, or amino. 6 is hydroxyl, 2-ethynyl, methyl, ethyl, fluorine, chlorine, 2-ethenyl, cyano or amino (-NH 2 ).

[0061] As embodiment 140, provided herein is a compound according to embodiment 136, wherein R 3 is R 6 As embodiment 141, provided herein are compounds according to embodiment 140, wherein each occurrence of R 6 is C 1~4 Haloalkyl, C 1~4 Alkyl, halogen, C 3~7 As embodiment 142, provided herein are compounds according to embodiment 141, wherein each occurrence of R is cycloalkyl or amino. 6 is trifluoromethyl, methyl, chlorine, cyclopropyl or amino (-NH 2 ).

[0062] As embodiment 143, provided herein is a compound according to embodiment 127, wherein R 3 is R 6 is an aryl substituted with 3 occurrences of

[0063] As embodiment 144, provided herein is a compound according to embodiment 143, wherein R 3 is R 6As embodiment 145, provided herein are compounds according to embodiment 144, wherein each occurrence of R 6 is hydroxyl, C 2~4 Alkynyl, C 1~4 As embodiment 146, there is provided herein a compound according to embodiment 145, wherein each occurrence of R is alkyl or halogen. 6 is hydroxyl, 2-ethynyl, methyl, ethyl, fluorine or chlorine.

[0064] As embodiment 147, provided herein is a compound according to embodiment 143, wherein R 3 is R 6 As embodiment 148, provided herein are compounds according to embodiment 147, wherein each occurrence of R 6 is halogen, hydroxyl, C 1~4 Alkyl, C 3~7 As embodiment 149, provided herein are compounds according to embodiment 148, wherein each occurrence of 6 is hydroxyl, 2-ethynyl, cyclopropyl, methyl, ethyl, fluorine, chlorine, cyano or amino.

[0065] As embodiment 150, provided herein is a compound according to any one of embodiments 1 to 126, wherein R 3 is R 6 As embodiment 151, provided herein are compounds according to embodiment 150, wherein R 3 is R 6 and 2-pyridinyl, 8-quinolinyl, 5-quinolinyl, 4-isoquinolinyl, 1-isoquinolinyl, 8-isoquinolinyl, 4-(1H-indazolyl) or 7-(1H-indazolyl) substituted with 0 to 3 occurrences of.

[0066] As embodiment 152, provided herein is a compound according to embodiment 151, wherein R 3 is R6 As embodiment 153, provided herein are compounds according to embodiment 152, wherein R 3 is R 6 As embodiment 154, there is provided herein a compound according to embodiment 153, wherein R 6 is amino, C 1~4 Haloalkyl or C 3~7 As embodiment 155, there is provided herein a compound according to embodiment 154, wherein R 6 is amino, trifluoromethyl or cyclopropyl.

[0067] As embodiment 156, provided herein is a compound according to embodiment 152, wherein R 3 is R 6 As embodiment 157, there is provided herein a compound according to embodiment 156, wherein R 6 is amino, halogen, C 1~4 Haloalkyl or C 3~7 As embodiment 158, provided herein are compounds according to embodiment 157, wherein R 6 is amino, trifluoromethyl, methyl or cyclopropyl.

[0068] As embodiment 159, provided herein is a compound according to embodiment 151, wherein R 3 is R 6 As embodiment 160, provided herein are compounds according to embodiment 159, wherein R 3 is R 6 and R is 8-quinolinyl substituted with one occurrence of 6 is hydroxyl.

[0069] As embodiment 161, provided herein is a compound according to embodiment 151, wherein R 3 is R6 As embodiment 162, provided herein are compounds according to embodiment 161, wherein R 3 is R 6 and R is 5-quinolinyl substituted with one occurrence of 6 As embodiment 162, provided herein is a compound according to embodiment 161, wherein R 3 is R 6 and R is 5-quinolinyl substituted with one occurrence of 6 is oxo.

[0070] As embodiment 163, provided herein is a compound according to embodiment 151, wherein R 3 is R 6 As embodiment 164, provided herein are compounds according to embodiment 163, wherein R 3 is R 6 is 4-isoquinolinyl substituted with one occurrence of 6 is a halogen (e.g., chlorine).

[0071] As embodiment 165, provided herein is a compound according to embodiment 151, wherein R 3 is R 6 As embodiment 166, provided herein are compounds according to embodiment 165, wherein R 3 is R 6 and R is 8-isoquinolinyl substituted with one occurrence of 6 is hydroxyl.

[0072] As embodiment 167, provided herein is a compound according to embodiment 151, wherein R 3 is R 6 As embodiment 168, provided herein are compounds according to embodiment 167, wherein R 3 is R 6and R is 1-isoquinolinyl substituted with one occurrence of 6 is amino (-NH 2 ).

[0073] As embodiment 169, provided herein is a compound according to embodiment 151, wherein R 3 is R 6 As embodiment 170, provided herein are compounds according to embodiment 169, wherein R 3 is R 6 As embodiment 171, provided herein are compounds according to embodiment 170, wherein R 6 is C 1~4 Alkyl, C 3~7 Cycloalkyl, halo, C 1~4 Haloalkyl, cyano or C 1~4 As embodiment 172, there is provided herein a compound according to embodiment 171, wherein R is alkenyl. 6 is methyl, cyclopropyl, chlorine, trifluoromethyl, cyano or 2-methylprop-1-enyl.

[0074] As embodiment 173, provided herein is a compound according to embodiment 169, wherein R 3 is R 6 As embodiment 174, there is provided herein a compound according to embodiment 173, wherein each R 6 is C 1~4 As embodiment 175, there is provided herein a compound according to embodiment 174, wherein each R 6 is methyl, chlorine or amino.

[0075] As embodiment 176, provided herein is a compound according to embodiment 151, wherein R 3 is R 6As embodiment 177, provided herein are compounds according to embodiment 176, wherein R 3 is R 6 As embodiment 178, provided herein are compounds according to embodiment 177, wherein R 6 is C 1~4 Alkyl (eg, methyl).

[0076] As embodiment 179, provided herein is a compound according to embodiment 176, wherein R 3 is R 6 As embodiment 180, provided herein are compounds according to embodiment 179, wherein both R 6 is C 1~4 As embodiment 181, there is provided herein a compound according to embodiment 180, wherein one R 6 is halo (e.g., chloro), and other R 6 is C 1~4 Alkyl (eg, methyl).

[0077] As embodiment 182, provided herein is a compound according to embodiment 176, wherein R 3 is R 6 As embodiment 183, there is provided herein a compound according to embodiment 182, wherein all three occurrences of R 6 is C 1~4 Alkyl (eg, methyl).

[0078] As embodiment 184, provided herein is a compound according to any one of embodiments 1 to 183, wherein R 3 teeth, [ka] [ka] It is.

[0079] As embodiment 185, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] [ka] [ka] It is.

[0080] As embodiment 186, provided herein is a compound according to embodiment 185, wherein R 3 teeth, [ka] It is.

[0081] As embodiment 187, provided herein is a compound according to embodiment 186, wherein R 3 teeth, [ka] It is.

[0082] As embodiment 188, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 189, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 190, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 191, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 192, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 193, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 194, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 195, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 196, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 197, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 198, provided herein is a compound according to embodiment 184, wherein R3 teeth, [ka] As embodiment 199, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 200, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 201, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 202, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 203, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 204, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 205, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 206, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 207, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 208, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 209, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 210, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 211, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 212, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 213, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 214, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 215, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 216, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 217, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 218, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 219, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 220, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 221, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 222, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 223, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 224, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 225, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 226, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 227, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 228, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 229, provided herein is a compound according to embodiment 184, wherein R3 teeth, [ka] As embodiment 230, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 231, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 232, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 233, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 234, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 235, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 236, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 237, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 238, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 239, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 240, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 241, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 242, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 243, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] As embodiment 244, provided herein is a compound according to embodiment 184, wherein R 3 teeth, [ka] It is.

[0083] As embodiment 245, provided herein is a compound according to any one of embodiments 1 to 244, wherein R 2 As embodiment 246, there is provided herein a compound according to any one of embodiments 1 to 244, wherein R 2 is halogen (e.g., fluorine or chlorine). As embodiment 247, provided herein are compounds according to any one of embodiments 1 to 244, wherein R 2 is C 1~4 As embodiment 248, there is provided herein a compound according to any one of embodiments 1 to 244, wherein R 2 is C 2~4 alkenyl (eg, 2-ethenyl).

[0084] As embodiment 249, provided herein is a compound according to any one of embodiments 1 to 248, wherein R 4 As embodiment 250, there is provided herein a compound according to any one of embodiments 1 to 248, wherein R 4 As embodiment 251, there is provided herein a compound according to any one of embodiments 1 to 248, wherein R 4 As embodiment 252, provided herein is a compound according to any one of embodiments 1 to 248, wherein R 2 is C 1~4 Alkyl (eg, methyl).

[0085] As embodiment 253, provided herein is a compound according to any one of embodiments 1 to 252, wherein R 7 As embodiment 254, provided herein is a compound according to any one of embodiments 1 to 252, wherein R 7As embodiment 255, provided herein is a compound according to any one of embodiments 1 to 252, wherein R 7 is fluorine.

[0086] As embodiment 256, provided herein is a compound according to any one of embodiments 1 to 255, wherein R 3 As embodiment 257, there is provided herein a compound of any one of embodiments 1 to 255, wherein R 3 is not 2-aminobenzo[d]thiazole.

[0087] As embodiment 258, there is provided herein a compound according to embodiment 1, wherein the compound has Formula (III): [ka] It is a compound of the formula:

[0088] As embodiment 259, there is provided herein a compound according to embodiment 1, wherein the compound has Formula (IV): [ka] It is a compound of the formula:

[0089] As embodiment 260, provided herein is a compound according to embodiment 1, wherein the compound has formula (V): [ka] It is a compound of the formula:

[0090] As embodiment 261, provided herein is a compound according to embodiment 1, wherein the compound has Formula (VI): [ka] It is a compound of the formula:

[0091] As embodiment 262, provided herein is a compound according to embodiment 1, wherein the compound has formula (VII): [ka] It is a compound of the formula:

[0092] As embodiment 263, there is provided herein a compound according to embodiment 1, wherein the compound has Formula (VIII): [ka] It is a compound of the formula:

[0093] As embodiment 264, there is provided herein a compound according to embodiment 1, wherein the compound has formula (IX): [ka] It is a compound of the formula:

[0094] As embodiment 265, there is provided herein a compound according to embodiment 1, wherein the compound has formula (X): [ka] It is a compound of the formula:

[0095] As embodiment 266, there is provided herein a compound according to embodiment 1, wherein the compound has Formula (XI): [ka] It is a compound of the formula:

[0096] As embodiment 267, there is provided herein a compound according to embodiment 1, wherein the compound is selected from the group consisting of the following compounds: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylquinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylphenol; 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylphenol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol; 3-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylphenol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-4-(1-fluoro-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; or 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-hydroxy-1-naphthonitrile is selected from one of the following:

[0097] As embodiment 268, there is provided herein a compound according to embodiment 1, wherein the compound is selected from the group consisting of the following compounds: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylquinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylphenol; or 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylphenol is selected from one of the following:

[0098] As embodiment 269, there is provided herein a compound according to embodiment 1, wherein the compound is selected from the group consisting of the following compounds: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; or 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol is selected from one of the following:

[0099] The above merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way.

[0100] Formulation and Route of Administration In the described use, it may be possible to administer the compound disclosed herein alone, but the compound administered will usually be present as an active ingredient in a pharmaceutical composition.Therefore, in one embodiment, the pharmaceutical composition is provided herein that includes the compound disclosed herein in combination with one or more pharma- ceutically acceptable excipients, such as diluents, carriers, adjuvants, etc., and optionally other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0101] The compounds disclosed herein can be administered by any suitable route, in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment.The compounds and compositions presented herein can be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, parenterally, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by injection techniques, in dosage unit formulations containing conventional pharma- ceutically acceptable excipients.

[0102] The pharmaceutical composition may be in the form of, for example, tablets, chewable tablets, mini-tablets, caplets, pills, beads, hard capsules, soft capsules, gelatin capsules, granules, powders, lozenges, patches, creams, gels, sachets, microneedle arrays, syrups, flavored syrups, juices, drops, injections, emulsions, microemulsions, ointments, aerosols, aqueous suspensions or oily suspensions. Pharmaceutical compositions are typically made in the form of dosage units containing a particular amount of the active ingredient.

[0103] As embodiment 270, provided herein is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 269, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, and a pharma- ceutically acceptable excipient.

[0104] As embodiment 271, there is provided herein a compound according to any one of embodiments 1 to 269, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 270, for use as a medicament.

[0105] How to use As discussed herein (see the section entitled "Definitions"), the compounds described herein should be understood to include all stereoisomers, tautomers, or pharma- ceutically acceptable salts of any of the foregoing, or solvates of any of the foregoing. Accordingly, the scope of methods and uses provided in this disclosure should be understood to encompass methods and uses using all such forms.

[0106] In addition to being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs and cats may be treated with the compounds provided herein.

[0107] In one embodiment, the present disclosure provides a method of using a compound or pharmaceutical composition of the present disclosure to treat disease conditions including, but not limited to, conditions involving KRAS G12D mutations (e.g., cancer). The cancer types are non-small cell lung cancer, colon cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, cholangiocarcinoma, or melanoma.

[0108] KRAS G12D mutations occur at the mutation frequencies shown in the table below (TCGA dataset). 1-3 For example, this table shows that 32.4% of subjects with pancreatic cancer have cancer in which one or more cells express the KRAS G12D mutant protein. G12D (see the section entitled "Biological Evaluation" below), the compounds provided herein are useful for treating subjects with cancer, including but not limited to those cancers listed in the table below.

[0109] [Table 1]

[0110] As embodiment 272, there is provided herein a compound according to any one of embodiments 1 to 269, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 270, for use in treating cancer.

[0111] As embodiment 273, there is provided herein a compound according to any one of embodiments 1 to 269 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 270, for use in treating a cancer in which one or more cells express a KRAS G12D mutant protein.

[0112] As embodiment 274, there is provided herein a compound or pharmaceutical composition for use in embodiment 272 or 273, wherein the cancer is pancreatic cancer, colon cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary site, endometrial cancer, mixed cancer type, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0113] As embodiment 275, there is provided herein the use of a compound according to any one of embodiments 1 to 269 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 270, in the preparation of a medicament for treating cancer.

[0114] As embodiment 276, there is provided herein the use of a compound according to any one of embodiments 1 to 269 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 270, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12D mutant protein.

[0115] As embodiment 277, there is provided herein the use according to embodiment 275 or 276, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colon cancer, cancer of unknown primary site, 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, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0116] As embodiment 278, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1 to 269, or a pharma- ceutically acceptable salt thereof.

[0117] As embodiment 279, provided herein is a method of treating a cancer in which one or more cells express a KRAS G12D mutant protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1 to 269, or a pharma- ceutically acceptable salt thereof.

[0118] Provided herein as embodiment 280 is the method of embodiment 278 or 279, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colon cancer, cancer of unknown primary site, 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, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

[0119] As embodiment 281, provided herein is the method of embodiment 278 or 279, wherein the cancer is non-small cell lung cancer, colon cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer or melanoma.

[0120] As embodiment 282, provided herein is the method of embodiment 281, wherein the cancer is non-small cell lung cancer.

[0121] As embodiment 283, provided herein is the method of embodiment 281, wherein the cancer is colon cancer.

[0122] As embodiment 284, provided herein is the method of embodiment 281, wherein the cancer is pancreatic cancer.

[0123] Provided herein as embodiment 285 is a method according to any one of embodiments 278 to 284, wherein the subject has cancer determined to have one or more cells that express a KRAS G12D mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

[0124] Combination therapy The present disclosure provides a combination treatment method in which an overlapping set of agents or even target enzymes known to regulate other pathways or other components of the same pathway are used in combination with the compounds of the present disclosure or pharma- ceutically acceptable salts thereof. In one embodiment, such treatment includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to provide synergistic or additive therapeutic effects. See, for example, U.S. Patent No. 10,519,146B2, issued December 31, 2019, specifically paragraphs 201 (line 37) to 212 (line 46) and paragraphs 219 (line 64) to 220 (line 39), which are incorporated herein by reference.

[0125] Provided herein as embodiment 286 is the method of any one of embodiments 278 to 285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor, an AKT inhibitor, an arginase inhibitor, a CDK4 / 6 inhibitor, an ErbB family inhibitor, an ERK inhibitor, a FAK inhibitor, an FGFR inhibitor, a glutaminase inhibitor, an IGF-1R inhibitor, a KIF18A inhibitor, an MCL-1 inhibitor, a MEK inhibitor, an mTOR inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PI3K inhibitor, a Raf kinase inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Src kinase inhibitor, or one or more chemotherapeutic agents.

[0126] In one embodiment, the second compound is administered as a pharma- ceutically acceptable salt, hi another embodiment, the second compound is administered as a pharmaceutical composition comprising the second compound or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

[0127] Aurora kinase A inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.

[0128] Exemplary Aurora kinase A inhibitors for use in the methods provided herein include alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2-methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazine -1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3,6,8,10,12-hexaen-13-yl]morpholine), AMG 900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine), MLN 8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undec-2(7),3,5-trifluorophenyl)pyrimidin-2-yl)amino)

[0036] The above-listed compounds include, but are not limited to, 1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-1,3-thiazol-2-yl]urea), CYC116 (4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607.

[0129] AKT inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0130] Exemplary AKT inhibitors for use in the methods provided herein include afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one), SR13668 (indolo[2,3-b]carbazole-2,10-dicarboxylic acid, 5,7-dihydro-6-methoxy-2,10-diethyl ester), ONC201 (11-benzyl-7-[2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ 751 (N-(3-aminopropyl)-N-[(1R)-1-(3-anilino-7-chloro-4-oxoquinazolin-2-yl)but-3-ynyl]-3-chloro-2-fluorobenzamide), RX-0201, and LY2780301.

[0131] Arginase inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

[0132] Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidardistat and CB 280.

[0133] CDK4 / 6 inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

[0134] The term "CDK4 / 6" as used herein refers to cyclin-dependent kinases ("CDKs") 4 and 6, which are members of the mammalian serine / threonine protein kinases.

[0135] The term "CDK4 / 6 inhibitor" as used herein refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of CDK4 and / or 6.

[0136] Exemplary CDK4 / 6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfonyl-1)-4-piperidinyl]amino]).

[0137] In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0138] ErbB family inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

[0139] The term "ErbB family" as used herein refers to members of the mammalian transmembrane protein tyrosine kinase family that includes ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4).

[0140] The term "ErbB family inhibitor" as used herein refers to an agent, e.g., a compound or an antibody, capable of negatively modulating or inhibiting all or part of the activity of at least one member of the ErbB family. Modulation or inhibition of one or more ErbB tyrosine kinases can occur by modulating or inhibiting the kinase enzymatic activity of one or more ErbB family members, or by preventing homodimerization or heterodimerization of ErbB family members.

[0141] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, for example, an anti-EGFR antibody.Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab and cetuximab.In one embodiment, the anti-EGFR antibody is cetuximab.In one embodiment, the anti-EGFR antibody is panitumumab.

[0142] In another embodiment, the ErbB family inhibitor is a HER2 inhibitor, such as an anti-HER2 antibody. Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.

[0143] In yet another embodiment, the ErbB family inhibitor is a HER3 inhibitor, such as an anti-HER3 antibody, for example HMBD-001 (Hummingbird Bioscience).

[0144] In one embodiment, the ErbB family inhibitor is a combination of an anti-EGFR antibody and an anti-HER2 antibody.

[0145] In one embodiment, the ErbB family inhibitor is an irreversible inhibitor. Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide), PF 6274484 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide).

[0146] In one embodiment, the irreversible ErbB family inhibitor is afatinib.In one embodiment, the irreversible ErbB family inhibitor is dacomitinib.

[0147] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine), BMS Examples of compounds that may be used include, but are not limited to, 599626 ((3S)-3-morpholinylmethyl-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamate) and GW 583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

[0148] In one embodiment, the reversible ErbB family inhibitor is sapitinib.In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.

[0149] ERK inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0150] Exemplary ERK inhibitors for use in the methods provided herein include ulixertinib, lavoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6-dimethyl-2-[2-[(2-methyl

[0113] These include, but are not limited to, 1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187.

[0151] FAK inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0152] Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-N-methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), VS-4718 (2-[[2-(2-methoxy-4-morpholin-4-ylanilino)-5-(trifluoromethyl)pyridin-4-yl]amino]-N-methylbenzamide), and APG-2449.

[0153] FGFR inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0154] Exemplary FGFR inhibitors for use in the methods provided herein include futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5-dimethoxyphenyl)methoxy]pyrimidin-2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), Devio 1347 ([5-amino]pyrazole-1-yl)ethanol), and AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide). These include, but are not limited to, N-1-(2-methyl-3H-benzimidazol-5-yl)pyrazol-4-yl]-(1H-indol-2-yl)methanone), INCB062079, H3B-6527 (N-[2-[[6-[(2,6-dichloro-3,5-dimethoxyphenyl)carbamoyl-methylamino]pyrimidin-4-yl]amino]-5-(4-ethylpiperazin-1-yl)phenyl]prop-2-enamide), ICP-105, CPL304110, HMPL-453 and HGS1036.

[0155] Glutaminase Inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

[0156] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.

[0157] IGF-1R inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0158] Exemplary IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, lovatumumab, BMS-754807 ((2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.

[0159] KIF18A inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0160] Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, those disclosed in U.S. Patent Application Publication No. 2020 / 0239441, WO 2020 / 132649, WO 2020 / 132651, and WO 2020 / 132653, each of which is incorporated by reference in its entirety.

[0161] MCL-1 inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0162] Exemplary MEK inhibitors for use in the methods provided herein include murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29 hexahydro-2,3,24,33-tetramethyl-22H-9,4,8-(metheniminomethino)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 ((αR)-α-[[(5S)-5-[3-chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy]-2-[[2-(2-methoxyphenyl)-4-pyrimidinyl]methoxy]benzenepropanoic acid) and ABBV-467.

[0163] In one embodiment, the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax.

[0164] MEK inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0165] Exemplary MEK inhibitors for use in the methods provided herein include trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3- carboxamide), GDC-0623 (5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide), TAK-733 (3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5 -(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione), PD0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), CI-1040 (2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide), PD318088 (5-bromo-N-(2,3-dihydroxypropoxy)-3,4-difluorobenzamide),

[0033] Examples of suitable fluorochemicals include, but are not limited to, PD98059 (2-(2-amino-3-methoxyphenyl)-4H-chromen-4-one), PD334581 (N-[5-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl]-1,3,4-oxadiazol-2-yl]-4-morpholineethanamine), FCN-159, CS3006, HL-085, SHR 7390, and WX-554.

[0166] In one embodiment, the MEK inhibitor is trametinib.

[0167] mTOR inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0168] Exemplary mTOR inhibitors for use in the methods provided herein include everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, bistosertib, dactolisib, trilin-1(1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1, 6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea) and VS-5584 (SB2343, (5-(8-methyl-2-morpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine).

[0169] In one embodiment, the mTOR inhibitor is everolimus.

[0170] PD-1 inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0171] Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS001), dostallimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and anti-PD-1 antibodies as described in U.S. Pat. No. 10,640,504 B2 ("Anti-PD-1 Antibody A", column 66, lines 56 to 67, line 24 and column 67, lines 54-57), which are incorporated herein by reference.

[0172] In one embodiment, the PD-1 inhibitor is pembrolizumab. In another embodiment, the PD-1 inhibitor is anti-PD-1 antibody A.

[0173] PD-L1 inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.

[0174] Exemplary PD-L1 inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR-1316, MSB2311, MDX-1105, KN035, IMC-001, HLX20, FAZ053, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167.

[0175] In one embodiment, the PD-L1 inhibitor is atezolizumab.

[0176] PI3K inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0177] Exemplary PI3K inhibitors for use in the methods provided herein include idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, ambralisib, pictilisib, dactolisib, voxtalisib, sonolicisib, tenalisib, selavelisib, acalisib, CUDC-907 (N-hydroxy-2-[[2-(6-methoxypyridin-3-yl)-4-morpholin-4-ylthieno[ 3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-carboxamide), ME-401 (N-[2-methyl-1-[2-(1-methylpiperidin-4-yl)phenyl]propan-2-yl]-4-(2-methylsulfonylbenzimidazol-1-yl)-6-morpholin-4-yl-1,3,5-triazin-2-amine), IPI-549 (2-amino-N-[(1S)-1-[8-[2-(1-methyl pyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide), SF1126 (((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butadiene

[0113] The above-listed compounds include, but are not limited to, N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide, GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione) and AMG 319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine).

[0178] Raf kinase inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

[0179] The term "RAF kinase" as used herein refers to a member of the mammalian serine / threonine kinases that are composed of three isoforms (C-Raf, B-Raf and A-Raf) and includes homodimers of each isoform and heterodimers between the isoforms, e.g., C-Raf / B-Raf heterodimers.

[0180] The term "Raf kinase inhibitor" as used herein refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Raf family kinases, or disrupting Raf homo- or heterodimer formation to inhibit activity.

[0181] In one embodiment, the Raf kinase inhibitors include encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5-morpholino-6'-((tetrahydro- 2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-6 -yl)phenyl)urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), CCT19696 9 (1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea) and RO5126766 (N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide).

[0182] 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.

[0183] SHP2 inhibitors Provided herein are methods according to any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.

[0184] Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol), TNO155 ((3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and RMC-4630 (Revolution Medicine). In one embodiment, the SHP inhibitor for use in the methods provided herein is RMC-4630 (Revolution Medicine).

[0185] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1-azetidinyl)-4-pyridinyl]thio]-5-methyl-2-pyrazinemethanol (CAS 2172652-38-7) and 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyrazinemethanol (CAS 2172652-48-9).

[0186] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl-4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]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]pyrazine-2-methanol (CAS 2240982-69-6), 7-[(2-amino-3-chloro-4-pyridinyl)thio]-4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-73-2) and (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-77-6).

[0187] In one embodiment, the SHP inhibitor for use in the methods provided herein is (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4).

[0188] In another embodiment, exemplary SHP2 inhibitors for use in the methods provided herein include 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-60-1), (1R)-8-[6-(2,3-dichlorophenyl)-5-methyl-3-pyridinyl]-8-azaspiro[4.5]decane-1-amine (CAS 2238840-62-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyridinemethanol (CAS 2238840-63-4), (1R)-8-[6-[(2,3-dichlorophenyl)thio]-5-methyl-3-pyridinyl]-8-azaspiro[4.5]dec-1-amine (CAS 2238840-64-5), 5-(4-amino-4-methyl-1-piperidinyl)-2-[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-65-6), 5-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-2-[[(2,3-dichlorophenyl)thio]-3-pyridinol (CAS 2238840-66-7), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-hydroxy-2-pyridinemethanol (CAS 2238840-67-8), 3-(4-amino-4-methyl-1-piperidinyl)-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-68-9), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-69-0), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-methyl-2-pyridinemethanol (CAS 2238840-70-3), 3-(4-amino-4-methyl-1-piperidinyl)-6-[(2,3-dichlorophenyl)-5-methyl-2-pyridinemethanol (CAS 2238840-71-4), 6-[(2-amino-3-chloro-4-pyridinyl)thio]-3-(4-amino-4-methyl-1-piperidinyl)-2-pyridinemethanol (CAS 2238840-72-5), 5-[(2-amino-3-chloro-4-pyridinyl)thio]-2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-methyl-3-pyridinemethanol (CAS 2238840-73-6), 2-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-5-(2,3-dichlorophenyl)-6-methyl-3-pyridinemethanol (CAS 2238840-74-7), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-hydroxy-2-pyridinemethanol (CAS 2238840-75-8) and 2-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-5-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(hydroxymethyl)pyridin-3-ol.

[0189] In one embodiment, the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5).

[0190] In one embodiment, an SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in U.S. Pat. No. 10,590,090 B2, U.S. Patent Application Publication No. 2020 / 017517 A1, U.S. Patent Application Publication No. 2020 / 017511 A1, or WO 2019 / 075265 A1, each of which is incorporated by reference in its entirety.

[0191] SOS1 inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

[0192] Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine) and BI 1701963.

[0193] Src kinase inhibitors Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.

[0194] The term "Src kinase" as used herein refers to members 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 the Frk subfamily.

[0195] The term "Src kinase inhibitor" as used herein refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of one or more members of the Src kinases.

[0196] Exemplary Src kinase inhibitors for use in the methods provided herein include dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7-tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP These include, but are not limited to, 1 (1-(tert-butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), WH-4-023 (2,6-dimethylphenyl(2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate) and KX-01 (N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide).

[0197] In one embodiment, the Src kinase inhibitor is dasatinib. In one embodiment, the Src kinase inhibitor is saracatinib. In one embodiment, the Src kinase inhibitor is ponatinib. In one embodiment, the Src kinase inhibitor is vandetanib. In one embodiment, the Src kinase inhibitor is KX-01.

[0198] Chemotherapeutic agents Provided herein is the method of any one of embodiments 278-285, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agents.

[0199] Exemplary chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.

[0200] definition The following definitions are provided to facilitate understanding of the scope of the present disclosure.

[0201] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0202] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. In the case of conflict between the chemical structure and the chemical name, the chemical structure is determinative of the compound's identity.

[0203] stereoisomer The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with rotational hindrance, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropisomers. Thus, the scope of the present disclosure should be understood to encompass all possible stereoisomers of the exemplified compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and atropisomerically pure) as well as mixtures of stereoisomers (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and atropisomers, or mixtures of any of the foregoing) of any chemical structure (in whole or in part) disclosed herein, unless the stereochemistry is specifically specified.

[0204] If the stereochemistry of a structure or a portion of a structure is not shown, for example, with bold or dashed lines, then the structure or portion of the structure is to be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or portion of a structure is shown, for example, with bold or dashed lines, then the structure or portion of the structure is to be interpreted as encompassing only the specified stereoisomer, unless otherwise stated.

[0205] for example, [ka] teeth, [ka] Similarly, for example, the chemical name (4R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole represents (4R,5R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole and (4R,5S)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole.

[0206] As a further example, [ka] teeth, [ka] Similarly, for example, the chemical name 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione represents (M)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and (P)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

[0207] In certain cases, a bond drawn with a wavy line indicates that both stereoisomers are encompassed. This should not be confused with a wavy line drawn perpendicular to a bond indicating the point of attachment of the group to the remainder of the molecule.

[0208] The term "stereoisomer" or "stereoisomerically pure" compound as used herein refers to one stereoisomer (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of that compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and not more than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and not more than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and not more than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and not more than about 3% by weight of other stereoisomers of the compound.

[0209] The present disclosure also encompasses pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any of the compounds disclosed herein. Additionally, the present disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any of the compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof can be synthesized according to methods known in the art and disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents. Additionally, the present disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein with one or more other active 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, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0210] Tautomers As known to those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms.Since one chemical structure can only be used to represent one tautomeric form, for convenience, it will be understood that reference to a compound of a given structural formula includes other tautomeric forms of said structural formula.Therefore, the scope of the present disclosure should be understood to include all tautomeric forms of the compounds disclosed herein.

[0211] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharma- ceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of Formula I, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 36 Chlorine such as Cl, 18 Fluorine such as F 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P 35 Certain isotopically labeled compounds of formula I, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose given their ease of incorporation and ready means of detection. 2 Substitution with isotopes such as H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous in some circumstances. 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful, for example, in positron emission tomography (PET) studies to examine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the accompanying general synthetic schemes and examples, using appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[0212] solvate As discussed above, the compounds disclosed herein as well as the stereoisomers, tautomers, and isotopically labeled forms thereof, or pharma- ceutically acceptable salts of any of the foregoing, can exist in solvated or unsolvated forms.

[0213] The term "solvate" as used herein refers to a molecular complex comprising a compound as described herein or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutical acceptable solvent molecules in a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is referred to as a "hydrate."

[0214] Accordingly, the scope of the present disclosure should be understood to encompass all solvates of the compounds disclosed herein and their stereoisomers, tautomers, and isotopically labeled forms or pharma- ceutically acceptable salts of any of the foregoing.

[0215] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0216] The term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, the term "aryl" as used herein 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 optionally substituted with 1-4 substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S-, nitro, cyano, carboxy, alkyl-OC(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl and heterocyclyl.

[0217] As used herein, the term "C 1~4 Alkyl" and "C 1~6 "Alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 4 and 1 to 6 carbon atoms, respectively. 1~4 Alkyl or C 1~6 Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[0218] The term “C 1~4 Alkylene" and "C 1~6 "Alkylene" refers to a straight or branched chain divalent alkyl group, as defined herein, containing 1 to 4 and 1 to 6 carbon atoms, respectively. Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, and the like.

[0219] As used herein, the term "C 2~4 "Alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight-chain and branched-chain moieties. 2~4 Representative examples of alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0220] As used herein, the term "C 2~4 "Alkynyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with at least one carbon-carbon triple bond. The term includes both straight and branched chain moieties. 3~6 Representative examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, and 3-butynyl.

[0221] As used herein, the term "C 1~4 Alkoxy" or "C 1~6 "Alkoxy" is -OR # R # are C, as defined herein, 1~4 Alkyl group or C 1~6 Represents an alkyl group. 1~4 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy. 1~6 Representative examples of alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.

[0222] As used herein, the term "C 3~8 "Cycloalkyl" refers to a saturated carbocyclic molecule whose cyclic backbone has 3 to 8 carbons. 3~8 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.

[0223] The term "deuterium" as used herein as a prefix for another term in reference to a chemical group means that one or more hydrogen atoms have been replaced with a heavy atom ("D" or " 2 For example, the term "C 1~4 "Deuteroalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms have been replaced with D. 1~4 Refers to alkyl. 1~4 A representative example of a deuterated alkyl is -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CD 3 , -CDHCD 3 , -CD 2 CD 3 , -CH(CD 3 ) 2 , -CD(CHD 2 ) 2 and -CH(CH 2 D)(CD3 ), but are not limited to these.

[0224] The term "halogen" as used herein refers to -F, -CI, -Br or -I.

[0225] The term "halo," as used herein as a prefix of another term relating to a chemical group, refers to a modification of a chemical group in which one or more hydrogen atoms have been replaced with a halogen, as defined herein. The halogens are independently selected at each occurrence. For example, the term "C 1~4 "Haloalkyl" refers to a C alkyl group, as defined herein, in which one or more hydrogen atoms are replaced with halogen. 1~4 Refers to alkyl. 1~4 A representative example of a haloalkyl is -CH 2 F, -CHF 2 , -CF 3 , -CHFCl, -CH 2 CF 3 , -CFHCF 3 , -CF 2 CF 3 , -CH(CF 3 ) 2 , -CF(CHF 2 ) 2 and -CH(CH 2 F)(CF 3 ), but are not limited to these.

[0226] As used herein, the term "heteroaryl" refers to a 5-20 membered monocyclic, bicyclic or tricyclic aromatic ring system having 1-8 heteroatoms selected from N, O and S. In certain preferred embodiments, the heteroaryl is a 5-10 membered ring system (e.g., a 5-7 membered monocyclic, an 8-10 membered bicyclic or an 11-14 membered tricyclic) or a 5-7 membered ring system. Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl, 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.

[0227] The term "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings.

[0228] As used herein, the term "heterocycle", "heterocycloalkyl" or "heterocyclo" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6- or 7-membered monocyclic, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and containing at least one heteroatom selected from O, S and N, which may be optionally oxidized to various oxidation states. The heterocyclic group can be attached at a heteroatom or a carbon atom. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran, dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, azetidine, thiazolidine, and the like.

[0229] The term "pharmacologically acceptable" as used herein refers to generally accepted for use in a subject, particularly a human.

[0230] The term "pharmaceutical acceptable salt" as used herein refers to 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 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-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, etc. Additional examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd See also the Revised Edition (2011).

[0231] The term "pharmaceutical acceptable excipient" as used herein refers to a wide 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, vehicles, anti-adherents, glidants, disintegrants, flavorings, coatings, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0232] The term "subject" as used herein refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats and mice. In one embodiment, the subject is a human.

[0233] The term "therapeutically effective amount" as used herein refers to an amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, system, or subject desired by a researcher, veterinarian, medical doctor, or other clinician.

[0234] General synthetic procedure The compounds provided herein can be synthesized according to the procedures described in this section and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein can also be synthesized by alternative routes utilizing alternative synthetic strategies, as will be appreciated by those skilled in the art. It should be understood that the general synthetic procedures and specific examples provided herein are merely exemplary and should not be construed as limiting the scope of the present disclosure in any way.

[0235] In general, the compound of formula I can be synthesized according to the following scheme. Any variables used in the following scheme are as defined for formula I unless otherwise stated. All starting materials are either commercially available, for example from Merck Sigma-Aldrich Inc, Fluorochem Ltd and Enamine Ltd., or known in the art, and can be synthesized by using known procedures using conventional techniques. Starting materials can also be synthesized by the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures and reagents, for the schemes discussed in this section can be found in the examples provided herein.

[0236] [ka] Compounds of formula (I) can be prepared according to Scheme I. In step A, compound (I-1) is reacted with an optionally substituted mono Boc protected amine by reaction in a solvent such as acetonitrile and in the presence of a base such as N,N-diisopropylethylamine. NIn step B, compound (I-2) is pretreated with a fluoride source such as potassium fluoride or is reacted with a fluoride source such as 1,4-diazabicyclo[2.2.2]octane in the presence of a base such as sodium hydride or cesium carbonate in a solvent such as dimethylsulfoxide or a mixture of solvents such as tetrahydrofuran and N,N-dimethylformamide to give compound (I-3). 1 -LH with nucleophiles and S N In step C, compound (I-3) is coupled with an organometallic reagent such as a boronic acid (ester) to provide compound (I-4). This coupling reaction can be carried out in a solvent such as 1,4-dioxane and Pd(dppf)Cl with or without a base such as potassium phosphate. 2 The reaction proceeds in a catalyst such as . In step D, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. Silyl groups can be removed using a fluoride source.

[0237] [ka] Compounds of formula (II) can be prepared according to Scheme II. In step A, compound (II-1) is treated with sodium thiomethoxide in a solvent such as tetrahydrofuran to give compound (II-5). In step B, compound (II-5) is pretreated with a fluoride source such as potassium fluoride or is reacted with a fluoride source such as potassium fluoride to give compound (II-6) of formula R in a solvent such as dimethylsulfoxide or a mixture of solvents such as tetrahydrofuran and N,N-dimethylformamide in the presence of a base such as sodium hydride or cesium carbonate with or without a nucleophilic catalyst such as 1,4-diazabicyclo[2.2.2]octane. 1 -LH with nucleophiles and S NIn step C, compound (II-6) is coupled with an organometallic reagent such as a boronic acid (ester) to provide compound (II-7). This coupling reaction can be carried out in a solvent such as 1,4-dioxane and Pd(dppf)Cl with or without a base such as potassium phosphate. 2 In step D, compound (II-7) is coupled with an organometallic reagent such as a boronic acid (ester) to give compound (II-8). This coupling reaction can be carried out in the presence of an additive such as CuTC, with or without a base such as potassium phosphate, in a solvent such as 1,4-dioxane, and Pd(PPh 3 ) 4 In step E, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. Silyl groups can be removed using a fluoride source.

[0238] [ka] Compounds of formula (III) can be prepared according to Scheme III. In step A, compound (4) is coupled with a nucleophile or an organometallic reagent such as a boronic acid (ester) to provide compound (9). The coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as SPhos Pd G3, with or without a base such as potassium phosphate. In step B, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. Silyl groups can be removed using a fluoride source.

[0239] [ka] Compounds of formula (IV) can be prepared according to Scheme IV. In step A, compound (IV-9) is reduced using a reducing agent such as hydrogen gas with a catalyst such as Pd / C in a solvent such as ethanol to provide compound (IV-10). In step B, the protecting group is removed using conditions known in the art. For example, Boc can be removed using TFA or HCl. Silyl groups can be removed using a fluoride source.

[0240] [ka] Compounds of formula (V) can be prepared according to Scheme V. In step A, compound (V-4) can be prepared by the reaction of S with 4-methoxybenzyl alcohol in the presence of a base such as sodium hydride in a solvent such as tetrahydrofuran. N In step B, compound (V-11) is coupled with an organometallic reagent such as a boronic acid (ester) to provide compound (V-12). This coupling reaction can be carried out in the presence or absence of a base such as potassium phosphate, in a solvent such as 1,4-dioxane, and in the presence of Pd(dppf)Cl 2 The reaction proceeds in a catalyst such as . In step C, the protecting groups are removed using conditions known in the art. For example, PMB and Boc can be removed using TFA or HCl. Silyl groups can be removed using a fluoride source.

[0241] [ka] Compounds of formula (VI) can be prepared according to Scheme VI. In step A, compound (VI-3) is reacted with B in a solvent such as 1,4-dioxane. 2 pin 2 Reagents such as Pd(dppf)Cl 2In step B, compound (VI-13) undergoes a Pd-catalyzed coupling reaction with an aryl halide to provide. The coupling reaction proceeds in the presence of a base such as potassium phosphate, in a solvent such as 1,4-dioxane, and a catalyst such as XPhos Pd G3. The resulting compound may undergo further transformations such as deprotection to give compound (VI).

[0242] [ka] Compounds of formula (VII) can be prepared according to Scheme VII. In step A, compound (VII-2) is pretreated with a fluoride source such as potassium fluoride or is reacted with a fluoride source of formula R in a solvent such as dimethylsulfoxide or a mixture of solvents such as tetrahydrofuran and N,N-dimethylformamide in the presence of a base such as sodium hydride or cesium carbonate with or without a nucleophilic catalyst such as 1,4-diazabicyclo[2.2.2]octane. 1 -LH with nucleophiles and S N In step B, compound (VII-14) is combined with an organometallic reagent such as a boronic acid (ester) to provide compound (VII-15). This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as cataCXium A Pd G3, with or without a base such as potassium phosphate. In step C, compound (VII-15) is treated with an oxidizing agent such as 3-chloroperbenzoic acid to provide compound (VII-16). In step D, compound (VII-16) is converted to a carboxylic acid of formula R in a solvent such as tetrahydrofuran in the presence of a base such as potassium tert-butoxide. 1 -LH with nucleophiles and S N Ar reaction. The resulting product may undergo further transformations such as deprotection to provide compound (VII).

[0243] [ka] Compounds of formula (VIII) can be prepared according to Scheme VIII. In step A, compound (VIII-17) is reacted with a compound of formula R in the presence of a base such as sodium hydride in a solvent such as tetrahydrofuran. 1 -LH with nucleophiles and S N In step B, compound (VIII-18) is combined with an organometallic reagent such as a boronic acid (ester) to provide compound (VIII-19). This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as cataCXium A Pd G3 with or without a base such as potassium phosphate. In step C, compound (VIII-19) undergoes a palladium-catalyzed CN coupling reaction with an optionally substituted mono-Boc protected amine. This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as RuPhos Pd G4 with a base such as cesium carbonate. The resulting product can undergo further transformation to provide compound (VIII).

[0244] [ka] Compounds of formula (IX) can be prepared according to Scheme IX. In step A, compound (IX-20) is reacted with an optionally substituted mono-Boc protected amine in a solvent or solvent mixture such as dichloromethane and isopropanol with or without a base. N In step B, compound (IX-21) is treated with an oxidizing agent such as 3-chloroperbenzoic acid to give compound (IX-22). In step C, compound (IX-22) is combined with an organometallic reagent such as a boronic acid (ester). This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as cataCXium A Pd G3 with or without a base such as potassium phosphate. The resulting product may undergo further transformations such as deprotection to provide compound (IX). EXAMPLES

[0245] This section provides specific examples of compounds of Formula I and methods for their preparation.

[0246] List of abbreviations

[0247] [Table 2]

[0248] [Table 3]

[0249] [Table 4]

[0250] [Table 5]

[0251] General analytical and purification methods In this section, a description of the general analytical and purification methods used to prepare the specific examples provided herein is provided.

[0252] Chromatography: Unless otherwise indicated, crude products containing residues were purified by passing the crude material or concentrates through either a Biotage or ISCO brand silica gel column pre-packed with flash silica (SiO2) and eluting the product from the column with a solvent gradient as indicated.

[0253] Preparative HPLC Method: Where so indicated, the compounds described herein were purified by reverse-phase HPLC using a Waters FractionLynx semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) a Phenomenex Gemini column (5 micron, C18, 150 x 30 mm) or (b) a Waters X-select CSH column (5 micron, C18, 100 x 30 mm). A typical run through the instrument involves eluting with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) at 45 mL / min over 10 minutes; conditions can be varied to achieve optimal separation.

[0254] Proton NMR Spectra: Unless otherwise indicated, all 1H NMR spectra were collected at 300, 400 or 500 MHz on a Bruker NMR instrument. When so characterized, all observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as the reference.

[0255] Mass Spectrum (MS): Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or exemplary compounds are reported as mass / charge (m / z), with the molecular ion being [M+H]+. The reported molecular ions were obtained by electrospray detection (commonly referred to as ESI MS) utilizing a Waters Acquity UPLC / MS system. As will be appreciated by those skilled in the art, compounds with isotopic atoms, such as bromine, etc., are generally reported according to the detected isotopic pattern.

[0256] Preparation of intermediates ((2R,7aR)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (Intermediate A) [ka] Step 1: 1-(tert-butyl) 2-methyl(4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-1,2-dicarboxylate. A mixture of 1-tert-butyl 2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (45.0 g, 182 mmol) and HMPA (42.4 g, 237 mmol, 41.6 mL) in THF (250 mL) was diluted with LiHMDS (1.0 M, 237 mL) and N 2 The mixture was stirred at -70 °C for 1 h. Then 1-bromo-3-chloro-propane (143.3 g, 910 mmol, 90 mL) was added in portions under N 2 The mixture was added in portions at −70° C. under reduced pressure. The resulting mixture was warmed to 15° C. and stirred for 5 h. TLC showed that the starting material was completely consumed. The mixture was diluted with aqueous NH 4 The mixture was poured into 1-L of Cl and stirred for 20 min. The aqueous phase was extracted with EtOAc (500 mL x 3). The combined organic phase was washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel eluted with petroleum ether / EtOAc (10 / 1 to 1 / 1) to give 1-(tert-butyl) 2-methyl(4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-1,2-dicarboxylate (68.0 g, 210 mmol, 57% yield) as a yellow oil.

[0257] Step 2: Methyl (4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-2-carboxylate. CH 3 To a mixture of 1-(tert-butyl) 2-methyl (4R)-2-(3-chloropropyl)-4-fluoropyrrolidine-1,2-dicarboxylate (34.0 g, 105 mmol) in CN (200 mL), add HCl / dioxane (4 M, 150 mL) and dilute with N 2The mixture was stirred at 15° C. for 2 h. TLC showed that the starting material was completely consumed. The mixture was concentrated under reduced pressure at 45° C. The crude methyl (4R)-2-(3-chloropropyl)-4-fluoro-pyrrolidine-2-carboxylate (55.0 g, unpurified) was obtained and used directly in the next step.

[0258] Step 3: Methyl (2R)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-carboxylate. CH 3 To a mixture of methyl (4R)-2-(3-chloropropyl)-4-fluoro-pyrrolidine-2-carboxylate (55.0 g, 211 mmol) in CN (550 mL) was added NaHCO 3 (88.8 g, 1.06 mol, 41 mL) and KI (3.51 g, 21.1 mmol) were dissolved in N 2 The mixture was stirred at 50° C. for 12 h. TLC showed the starting material was completely consumed and one new spot appeared. The mixture was filtered and the filter cake was washed with EtOAc (100 mL×3). The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (3 / 1 to 0 / 1) to give methyl (2R)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)carboxylate (27.0 g, 144 mmol, 49% yield) as a yellow oil.

[0259] Step 4: ((2R)-2-Fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol. Methyl (2R)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)carboxylate (10.0 g, 53.4 mmol) in THF (100 mL) was reacted with LiAlH 4 (4.05 g, 107 mmol) was added in portions at -40°C. The mixture was then stirred at -40°C for 1 h. TLC showed that the reaction was complete. The reaction mixture was added with Na 2 SO 4 10H 2O (20 g) was added slowly in portions at 0° C. The mixture was diluted with THF (50 mL) and filtered. The filter cake was washed with THF (300 mL). The organic layer was concentrated under reduced pressure. Crude ((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (10.0 g, unpurified) was obtained as a colorless oil and used directly in the next step.

[0260] Step 5: (2R)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine. To a mixture of ((2R)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (20.0 g, 126 mmol) and imidazole (34.2 g, 503 mmol) in DMF (25 mL) was added TBDPSCl (69.1 g, 251 mmol, 64.54 mL). The mixture was then stirred at 20° C. for 3 h. TLC (EtOAc:MeOH=6:1) showed the reaction was complete. The mixture was diluted with H 2 The mixture was diluted with 2×O (100 mL) and extracted with EtOAc (400 mL×2). The combined organic layers were washed with brine (150 mL) and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with petroleum ether / EtOAc (20 / 1 to 10 / 1) to give (2R)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (11.0 g, 17.7 mmol, 26% yield over two steps) as a colorless oil. m / z (ESI, + ion): 398.3 (M+H). + .

[0261] Step 6: (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine. (2R)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (6.50 g, 16.4 mmol) was separated by column chromatography on silica gel eluting with petroleum ether / EtOAc (7 / 1 to 0 / 1) to give (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (2.35 g, 5.66 mmol, 36% yield, 96% purity) as a yellow oil.

[0262] Step 7: ((2R,7aR)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol. To a mixture of (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine (500 mg, 1.26 mmol) in DMF (5 mL) was added CsF (1.91 g, 12.6 mmol) 2 The mixture was stirred at 70° C. for 72 h. Another batch of 9 g of (2R,7aR)-7a-(((tert-butyldiphenylsilyl)oxy)methyl)-2-fluorohexahydro-1H-pyrrolidine was set up following the same procedure. The two batches were combined for purification. The crude product was diluted with EtOAc / methanol (6 / 1 to 1 / 1, NH 3 · H 2 Purification by column chromatography on silica gel, eluting with 50 mL of 2H-tetrafluoroethylene (O) afforded ((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (2.60 g, 16.3 mmol, 68% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 5.22 (dt, J = 54 Hz, 4.6 Hz, 1H), 3.47-3.31 (m, 3H), 3.00-2.98 (m, 1H), 2.88-2.75 (m, 1H), 2.67-2.65 (m, 1H), 2.25-2.15 (m, 1H), 1.92-1.80 (m, 4H), 1.60-1.55 (m, 1H).

[0263] Triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (Intermediate B) [ka] Step 1: ((8-bromonaphthalen-1-yl)ethynyl)triisopropylsilane. A 40 mL vial was charged with triethylamine (7.43 g, 10.3 mL, 73.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol), copper(I) iodide (0.10 g, 0.53 mmol), 1,8-dibromonaphthalene (0.75 g, 2.62 mmol) and (triisopropylsilyl)acetylene (0.53 g, 0.65 mL, 2.88 mmol). The reaction was purged with nitrogen for 5 min and then stirred at 80 °C. After 6 h, water (20 mL) and EtOAc (20 mL) were added. The mixture was transferred to a separatory funnel. The organic layer was separated and washed with saturated ammonium chloride solution and diluted with Na 2 SO 4 The crude product was purified by column chromatography on silica gel eluting with a gradient of 0-20% EtOAc in heptane to give ((8-bromonaphthalen-1-yl)ethynyl)triisopropylsilane (0.99 g, 2.56 mmol, 98% yield). m / z (ESI, + ion): 387.1 (M+H). + . 1H NMR(400MHz,DMSO-d6)δ ppm 7.99-8.14(m,2H),7.78-7.99(m,2H),7.51-7.61(m,1H),7.38-7.48(m,1H),1.10-1.17(m,18H),0.81-0.89(m,3H).

[0264] Step 2: Triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane. A 20 mL vial was charged with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.11 g, 0.16 mmol), bis(pinacolato)diboron (0.26 mg, 1.03 mmol), potassium acetate (0.15 g, 1.55 mmol) and ((8-bromonaphthalen-1-yl)ethynyl)triisopropylsilane (0.20 g, 0.52 mmol). The solid was suspended in toluene (4.7 mL). The reaction was purged with nitrogen for 5 min and then stirred at 80 °C. After 16 h, the reaction was cooled to room temperature and then concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-15% EtOAc in heptane to give triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (0.15 g, 0.34 mmol, 66% yield). m / z (ESI, + ion): 435.3 (M+H). + .

[0265] [Table 6]

[0266] Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (Intermediate I) [ka] Step 1: ((8-Bromo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane. A 20 mL vial was charged with ((8-bromonaphthalen-1-yl)ethynyl)triisopropylsilane (0.34 g, 0.88 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.28 g, 0.32 mL, 2.19 mmol, Sigma-Aldrich Corporation), 4,4'-di-tert-butyl-2,2'-dipyridyl (28.3 mg, 0.11 mmol, Sigma-Aldrich Corporation) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (58 mg, 0.088 mmol, Sigma-Aldrich Corporation). The reaction was purged with nitrogen for 5 min and then heated at 60° C. for 1 h. The solution was concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0-50% EtOAc in hexanes to give the product which was used in the next step without further manipulation.

[0267] Step 2: 4-Bromo-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol. A 50 mL round bottom flask was charged with ((8-bromo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.45 g, 0.88 mmol) in tetrahydrofuran (3.3 mL) and water (1.1 mL). Hydrogen peroxide (0.90 g, 0.81 mL, 7.91 mmol, Sigma-Aldrich) was added slowly at 0 °C followed by acetic acid (2.51 mL, 43.9 mmol). The reaction was stirred for 1 h. The reaction mixture was diluted with saturated Na 2 S 2 O 3The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc in hexanes to give a mixture of isomers. Another batch was prepared by the same method. A total of 600 mg of the mixture of isomers was purified by SFC using a mobile phase of 10% 2-propanol with a Chiralpak AD 21×250 mm, 5 micron, flow rate of 80 mL / min to give 280 mg of the desired product with >95% chemical purity. Peak assignments were determined by SFC with Chiralpak AD and 15% 2-propanol.

[0268] Step 3: ((8-Bromo-6-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane. A 250 mL round bottom flask was charged with 4-bromo-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (0.35 g, 0.87 mmol) and DIEA (0.34 g, 0.45 mL, 2.60 mmol, Sigma-Aldrich) in DCM (4.3 mL). Chloromethyl methyl ether (0.14 g, 0.13 mL, 1.74 mmol, Sigma-Aldrich Corporation) was added slowly at 0° C. The reaction was stirred for 90 min. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on a silica gel column eluting with a gradient of 0-30% EtOAc in heptane to give the product. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.77-7.61 (m, 3H), 7.38-7.22 (m, 2H), 5.27-5.32 (m, 2H), 3.52-3.55 (m, 3H), 1.13-1.28 (m, 21H).

[0269] Step 4: Triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane. A 20 mL vial was charged with ((8-bromo-6-(methoxymethoxy)naphthalen-1-yl)ethynyl)triisopropylsilane (0.13 g, 0.30 mmol), bis(pinacolato)diboron (0.15 g, 0.60 mmol, Combi-Blocks Inc.), potassium acetate (88 mg, 0.90 mmol, Sigma-Aldrich Corporation), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (65 mg, 0.090 mmol, Sigma-Aldrich Corporation) and toluene (4.0 mL). The reaction mixture was purged with nitrogen for 5 min and then stirred at 80 °C for 12 h. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on a silica gel column eluting with a gradient of 0-30% EtOAc in hexanes to give the product.

[0270] 5-Chloro-4-(trimethylstannyl)isoquinoline (Intermediate J) [ka] Add Pd(PPh) to an 8 mL vial. 3 ) 4 (90 mg, 0.078 mmol) and 4-bromo-5-chloroisoquinoline (0.19 g, 0.78 mmol). The vial was purged with nitrogen for 5 min and then the solid was suspended in degassed toluene (3.9 mL). Hexamethylditin (0.84 g, 0.53 mL, 2.55 mmol) was added. The reaction was then heated to 100 °C and stirred for 30 h. The reaction was then cooled to room temperature, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a gradient of 0-30% EtOAc in heptane to give 5-chloro-4-(trimethylstannyl)isoquinoline (0.20 g, 0.60 mmol, 76% yield). m / z (ESI, + ion): 328.1 (M+H). + .

[0271] 2-(8-Ethylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate K) [ka] Step 1: 1-Chloro-8-ethylnaphthalene. A 10 mL pressure vial was charged with 1-bromo-8-chloronaphthalene (3.5 g, 14.49 mmol, Ambeed), ethylboronic acid (3.21 g, 43.5 mmol, Combi-Blocks Inc.), potassium phosphate tribasic monohydrate (8.34 g, 36.2 mmol, Sigma-Aldrich Corporation) and dichloro-1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (0.592 g, 0.725 mmol, Strem Chemicals, Inc.) (0.3 M) in a 1,4-dioxane (46 mL) and water (2.3 mL) solvent mixture. The mixture was stirred at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by column chromatography on silica gel eluting with heptane to afford 1-chloro-8-ethylnaphthalene (2.4 g, 12.59 mmol, 87% yield) as a yellow liquid. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.75-7.78 (m, 1H), 7.69-7.75 (m, 1H), 7.56-7.59 (m, 1H), 7.37-7.44 (m, 2H), 7.29-7.35 (m, 1H), 3.49-3.57 (m, 2H), 1.35-1.42 (m, 3H).

[0272] Step 2: 2-(8-ethylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A pressure-release vial contained 1-chloro-8-ethylnaphthalene (1.77 g, 9.28 mmol), bis(pinacolato)diboron (2.83 g, 11.14 mmol, Sigma-Aldrich Corporation), potassium phosphate tribasic (5.91 g, 27.8 mmol, Sigma-Aldrich Corporation), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.146 g, 0.186 mmol, Sigma-Aldrich Corporation), and 2-dicyclohexylphosphino-2,4,6,-tri-i-propyl-1,1-biphenyl (0.044 g, 0.093 mmol, Sigma-Aldrich Corporation) in ethanol. A mixture of 8-(8-ethylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.23 g, 4.36 mmol, 47% yield) was purged with nitrogen, capped and stirred at 23 °C for 18 h. Upon completion, the resulting solution was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluting with 5% ethyl acetate in heptane to give 2-(8-ethylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.23 g, 4.36 mmol, 47% yield) as a white solid. m / z (ESI, + ion): 283.2. 1 H NMR(400MHz,chloroform-d)δ ppm 7.87(dd,J=8.2,1.5Hz,1H),7.60-7.74(m,2H),7.35-7.49(m,3H),3.24(q,J=7.5Hz,2H),1.43-1.48(m,12H),1.36-1.41(m,3H).

[0273] 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate L) [ka] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol. A pressure release vial was charged with potassium acetate (1.21 g, 12.3 mmol, Sigma Aldrich), 7-fluoro-1-naphthol (1.00 g, 6.17 mmol, Enamine), dichloro(p-cymene)ruthenium(II) dimer (0.378 g, 0.617 mmol, Alfa Aesar) and then purged with nitrogen gas for 5 minutes. The solid was then suspended in 1,4-dioxane (12 mL) and (bromoethynyl)triisopropylsilane (1.77 g, 1.63 mL, 6.78 mmol, Enamine) was added. The reaction was then stirred at 110 °C for 18 h, then at room temperature for 2 days. The volatiles were removed in vacuo and the crude material was absorbed onto silica gel. The crude product was purified by column chromatography on silica gel, eluting with a gradient of 0-20% EtOAc in heptane to afford 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.9 g, 5.55 mmol, 90% yield) as a yellow oil. m / z (ESI, + ion): 343.0 (M+H). + .

[0274] Step 2: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate. 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.00 g, 2.92 mmol) was dissolved in dichloromethane (11 mL) and cooled to 0° C. DMAP (0.07 g, 0.58 mmol, Sigma-Aldrich Corporation) and TEA (0.89 g, 1.23 mL, 8.76 mmol, Sigma-Aldrich Corporation) were added, followed by the dropwise addition of pivaloyl chloride (1.06 g, 1.08 mL, 8.76 mmol, Sigma-Aldrich Corporation). The mixture was allowed to warm to room temperature and stirred for 45 min. Water (10 mL) was added and the aqueous layer was extracted with DCM (2×10 mL). The combined organic phase was diluted with Na 2 SO 4The volatiles were removed in vacuo and the crude material was purified by column chromatography on silica gel eluting with a gradient of 0-10% EtOAc in heptane to afford 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate (1.40 g, 3.28 mmol, 112% yield) as a yellow crystalline solid. m / z (ESI, + ion): 427.4 (M+H). + .

[0275] Step 3: 8-Ethyl-7-fluoronaphthalen-1-ol. A centrifugal vial was charged with 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl pivalate (1.13 g, 2.65 mmol) and dissolved in DMF (12 mL). Cesium fluoride (4.02 g, 26.5 mmol, Sigma-Aldrich Corporation) was added and the mixture was stirred at room temperature for 30 min. Water (100 mL) was added and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at rt and then the volatiles were removed in vacuo to afford 8-ethynyl-7-fluoronaphthalen-1-yl pivalate (0.716 g, 2.65 mmol, quantitative) as a crude yellow oil which was used without further purification.

[0276] 8-Ethynyl-7-fluoronaphthalen-1-yl pivalate (716 mg, 2.65 mmol) was dissolved in MeOH (9 mL) and palladium on activated carbon (85 mg, 0.795 mmol, Sigma-Aldrich Corporation) was added. The reaction vessel was placed in H 2 Purge with H 2The mixture was stirred at room temperature under atmosphere (15 psi) for 2 h. The mixture was filtered over Celite, washed with EtOAc until the filtrate was clear, and the volatiles were removed in vacuo. The crude material was then dissolved in MeOH (10 mL) and potassium hydroxide (446 mg, 7.95 mmol, VWR International, LLC) was added. After stirring at room temperature for 2 h, the pH of the solution was adjusted to pH=3 using 1M aqueous HCl. Water (20 mL) was added and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C. and the volatiles were removed in vacuo. The crude material was purified by column chromatography on silica gel, eluting with a gradient of 0-20% EtOAc in heptane over three steps to afford 8-ethyl-7-fluoronaphthalen-1-ol (350 mg, 1.84 mmol, 70% yield) as a yellow oil. m / z (ESI, + ion): 191.2 (M+H). + .

[0277] Step 4: 8-Ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate. 8-Ethyl-7-fluoronaphthalen-1-ol (350 mg, 1.84 mmol) was dissolved in DCM and cooled to 0° C. TEA (279 mg, 0.388 mL, 2.76 mmol, Sigma-Aldrich Corporation) was added followed by 1M Tf 2 A solution of 2.02 mL of 2.02 mmol, Sigma-Aldrich Corporation was added dropwise. The mixture was stirred at room temperature for 20 min and poured into ice water (20 mL). The aqueous phase was extracted with DCM (2×10 mL) and the combined organic layers were washed with NaCl. 2 SO 4 The mixture was dried at 40° C. and the volatiles were removed in vacuo. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-5% EtOAc in heptane to afford 8-ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (474 ​​mg, 1.47 mmol, 80% yield) as a colorless oil. 1H NMR(400MHz,chloroform-d)δ ppm 7.86(dd,J=8.3,0.9Hz,1H),7.79(dd,J=9.4,6.5Hz,1H),7.59(dt,J=7.7,0.8Hz,1H),7.44 (t,J=8.2Hz,1H),7.36(t,J=9.4Hz,1H),3.32(qd,J=7.5,2.9Hz,2H),1.29(t,J=7.4Hz,3H).

[0278] Step E: 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Potassium acetate (429 mg, 4.38 mmol, Sigma-Aldrich Corporation) was placed in a pressure release vial and dried under vacuum. 8-Ethyl-7-fluoronaphthalen-1-yl trifluoromethanesulfonate (470 mg, 1.46 mmol), bis(pinacolato)diboron (741 mg, 2.92 mmol, Combi-Blocks Inc.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (107 mg, 0.15 mmol, Sigma-Aldrich Corporation) were then added and the mixture was stirred at 90°C for 3 h and then at room temperature for 12 h. The volatiles were removed in vacuo and the crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-15% EtOAc in heptane to afford 2-(8-ethyl-7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg, 0.50 mmol, 34% yield) as a yellow wax. m / z (ESI, + ions): 301.0 (M+H). + .

[0279] ((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (Intermediate M) [ka] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate. To a 25 mL round bottom flask was added 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (1.1 g, 3.21 mmol), TEA (0.487 g, 0.677 mL, 4.82 mmol) and DCM (32 mL). The solution was cooled to 0 °C and Tf 2 0 (1M in DCM, 3.53 mL, 3.53 mmol) was added. The cooling bath was removed and the reaction was stirred at room temperature for 45 min. Upon completion, the reaction was diluted with saturated NaHCO 3 The organics were dried over sodium sulfate and concentrated under reduced pressure to give 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (2.01 g, 4.24 mmol, 132% yield) as a dark red oil that was used as is in the next step. 1 H NMR (400 MHz, chloroform-d): δ ppm 7.82-7.89 (m, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.45-7.52 (m, 1H), 7.40 (t, J=8.7 Hz, 1H), 1.17-1.25 (m, 21H).

[0280] Step 2: ((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane. A 250 mL round bottom flask was charged with 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (2.01 g, 4.24 mmol), bis(pinacolato)diboron (2.15 g, 8.47 mmol), KOAc (1.46 g, 14.82 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.620 g, 0.847 mmol) in toluene (42 mL). The reaction was cooled to 100° C. for 2 hours. 2The mixture was purged with 500 mL of ethyl acetate for 5 min and then heated at 80 °C for 15 h. Upon completion, the reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a gradient of 0-40% EtOAc in heptane to give ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (783 mg, 1.730 mmol, 41% yield) as an orange solid. m / z (ESI, + ion): 453.2 (M+H). + .

[0281] 5-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (Intermediate N) [ka] Step 1: 2,4-Dibromo-5-chloronaphthalen-1-amine. To a stirred solution of 5-chloronaphthalen-1-amine (2.0 g, 11.26 mmol, Combi-Blocks Inc.) in chloroform (56.3 mL) was added bromine (3.60 g, 1.154 mL, 22.52 mmol) in chloroform (56.3 mL) dropwise. After the addition was complete, the reaction mixture was then heated to 50° C. After 3 h, additional bromine (1.80 g, 0.577 mL, 11.26 mmol) in chloroform (28 mL) was added dropwise. After stirring overnight, the reaction was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) and EtOAc (100 mL) were added and the reaction was transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude reaction mixture was purified by column chromatography on silica gel eluting with a gradient of 0-25% EtOAc in heptane to give 2,4-dibromo-5-chloronaphthalen-1-amine (2.46 g, 7.34 mmol, 65% yield) as a deep purple solid. m / z (ESI, + ion): 383.8 (M+H). + .

[0282] Step 2: 5-Bromo-6-chloronaphtho[1,2-d][1,2,3]oxadiazole. To a cooled stirred solution of 2,4-dibromo-5-chloronaphthalen-1-amine (500 mg, 1.491 mmol) in acetic acid (12.218 mL) and propionic acid (1104 mg, 1.115 mL, 14.91 mmol) was added sodium nitrite (154 mg, 2.236 mmol) at 0 °C. The reaction was stirred at this temperature for 30 min and then warmed to room temperature. After 1 h, the reaction was diluted with water (25 mL) and EtOAc (25 mL). The reaction was transferred to a separatory funnel and the layers were separated. The aqueous layer was then extracted with EtOAc (3 x 25 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude solid was carried forward without further purification. m / z (ESI, + ion): 283.0 (M + H) + .

[0283] Step 3: 4-Bromo-5-chloronaphthalen-2-ol. A 150 mL round bottom flask was charged with 5-bromo-6-chloronaphtho[1,2-d][1,2,3]oxadiazole (423 mg, 1.492 mmol) and the solid was dissolved in ethanol (22.606 mL) and tetrahydrofuran (22.61 mL). The mixture was then cooled to 0° C. and sodium borohydride (130 mg, 3.43 mmol) was added. The reaction was allowed to slowly warm to room temperature over 1.5 h and then stirred at room temperature. After an additional 2 h, the reaction was concentrated under reduced pressure and then water (25 mL), 1N HCl (25 mL) and EtOAc (50 mL) were added. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (3×50 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude oil was then purified by column chromatography eluting with a gradient of 0-25% EtOAc in heptane to give 4-bromo-5-chloronaphthalen-2-ol (128 mg, 0.497 mmol, 33.3% yield over two steps). m / z (ESI, + ion): 256.7 (M+H). + .

[0284] Step 4: 5-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol. A 20 mL vial was charged with 4-bromo-5-chloronaphthalen-2-ol (128 mg, 0.497 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (109 mg, 0.149 mmol), potassium acetate (146 mg, 1.491 mmol) and bis(pinacolato)diboron (189 mg, 0.746 mmol) in 1,4-dioxane (4971 μL). The reaction was purged with nitrogen for 5 min and then stirred at 80 °C. After 2 h, the reaction was cooled to room temperature to give a crude black oil. The crude material was absorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-30% EtOAc in heptane to give 5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (73.2 mg, 0.240 mmol, 48% yield) as a pink solid. m / z (ESI, + ion): 305.2 (M+H). + . 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.96(s,1H)7.71(dd,J=8.15,1.25Hz,1H)7.34-7.44(m,2H)7.20-7.23(m,1H)7.15-7.19(m,1H)1.36(s,12H).

[0285] ((5,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)triisopropylsilane (Intermediate O) [ka] Step 1: Methyl 2-(2-bromo-3,4-difluorophenyl)acetate. To a 100 mL round bottom flask was added 2-(2-bromo-3,4-difluorophenyl)acetic acid (2.0 g, 7.97 mmol, AstaTech) and DBU (1.213 g, 1.201 mL, 7.97 mmol) and toluene (40 mL). To the mixture was added MeI (2.26 g, 0.996 mL, 15.93 mmol) and the mixture was stirred at rt for 4 h. Upon completion, the reaction was diluted with water and extracted with EtOAc. The organic layers were combined, dried, concentrated and chromatographed with 0-50% EtOAc in heptane to give methyl 2-(2-bromo-3,4-difluorophenyl)acetate (1.62 g, 6.11 mmol, 77% yield) as a colorless oil. m / z (ESI): 264.96 (M+H) + .

[0286] Step 2: Methyl 2-(2-acetyl-3,4-difluorophenyl)acetate. A microwave vial was charged with methyl 2-(2-bromo-3,4-difluorophenyl)acetate (1.62 g, 6.11 mmol), trifluorotoluene (15 mL), tributyl(1-ethoxyvinyl)stannane (4.41 g, 12.22 mmol, Synthonix Inc.) and trans-dichlorobis(triphenylphosphine)palladium(II) (0.858 g, 1.222 mmol, Strem Chemicals, Inc.). The vial was purged with nitrogen for 2 min, sealed and placed in a microwave reactor at 150 °C for 12 h. Upon completion, the mixture was filtered through a celite / silica plug and concentrated. The resulting yellow oil was dissolved in THF (10 mL) and 5 mL of 5N HCl was added. The reaction was stirred at rt for 30 min. Upon completion, the reaction was washed with saturated NaHCO 3 The mixture was extracted with EtOAc, dried, concentrated, and chromatographed with 0-30% EtOAc in heptane to give methyl 2-(2-acetyl-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol, 87% yield) as a colorless oil. m / z (ESI): 229.07 (M+H). + .

[0287] Step 3: 7,8-Difluoronaphthalene-1,3-diol. To a 250 mL round bottom flask was added methyl 2-(2-acetyl-3,4-difluorophenyl)acetate (1.21 g, 5.30 mmol), KOtBu (1.785 g, 15.91 mmol) and THF (40 mL). The flask was capped and placed in a preheated aluminum block and kept at 80 °C for 3 h. Upon completion, the reaction was diluted with 1M HCl, extracted with DCM and dried to give 7,8-difluoronaphthalene-1,3-diol (1.04 g, 5.30 mmol, 100% yield) as a red oil which was carried forward as is. m / z (ESI): 197.04 (M+H). + .

[0288] Step 4: 7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol. To a 100 mL round bottom flask was added 7,8-difluoronaphthalene-1,3-diol (750 mg, 3.82 mmol), DIPEA (2.00 mL, 11.47 mmol) and DCM (38 mL). The solution was cooled to 0° C. and TIPS-Cl (663 mg, 0.729 mL, 3.44 mmol) was added. The reaction was allowed to warm to room temperature. Upon completion, the reaction was concentrated and chromatographed with 0-30% EtOAc in heptane. The isomers were separated on a silica gel column with 0-30% EtOAc in heptane to give 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol (883 mg, 2.505 mmol, 65.5% yield) (first eluting isomer) as the major product and 5,6-difluoro-4-((triisopropylsilyl)oxy)naphthalen-2-ol (175 mg, 0.496 mmol, 12.98% yield) (second eluting isomer) as the minor product. m / z (ESI): 353.17 (M+H). + .

[0289] Step 5: 7,8-Difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate. To a 100 mL round bottom flask was added 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-ol (883 mg, 2.50 mmol), DIPEA (1.31 mL, 7.51 mmol) and DCM (25 mL). The solution was cooled to 0 °C and Tf 2 0 (1M in DCM, 2.76 mL, 2.76 mmol) was added. The reaction was allowed to warm to rt and stirred for 1 h. Upon completion, the reaction was washed with saturated NaHCO 3 and extracted with DCM. The organics were dried and concentrated to give 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1214 mg, 2.505 mmol, 100% yield) as an orange oil that was used as is in the next step. m / z (ESI): 485.12 (M+H). + .

[0290] Step 6: ((5,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)triisopropylsilane. A 100 mL round bottom flask was charged with 7,8-difluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl trifluoromethanesulfonate (1.21 g, 2.497 mmol), bis(pinacolato)diboron (1.268 g, 4.99 mmol), potassium acetate (0.858 g, 8.74 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (0.365 g, 0.499 mmol) and toluene (25 mL). The reaction was purged with nitrogen for 5 min and then stirred at 80 °C for 12 h. Upon completion, the reaction was concentrated and chromatographed with a gradient of 0-40% EtOAc in hexanes to give ((5,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)oxy)triisopropylsilane (966 mg, 2.089 mmol, 84% yield). m / z (ESI): 463.26 (M+H).+ .

[0291] 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate P) [ka] Step 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol. To a mixture of 7-fluoronaphthalene-1,3-diol (3.30 g, 18.52 mmol) and 2-bromoethynyl(triisopropyl)silane (5.81 g, 22.23 mmol) in dioxane (60 mL) was added KOAc (3.64 g, 37.05 mmol) and dichloro(p-cymene)ruthenium(II) dimer (1.13 g, 1.85 mmol) with N 2 The mixture was stirred at 110° C. for 2 h. The mixture was cooled to 15° C. and poured into ice water (w / w=1 / 1, 60 mL). The mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with petroleum ether / ethyl acetate=8 / 1, 1 / 1 to give the product (4.30 g, 11.27 mmol, 65% yield) as a yellow solid. m / z (ESI): 359.2 (M+H). + .

[0292] Step 2: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-ol. To a mixture of 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (4.30 g, 11.99 mmol) in DCM (60 mL) was added DIPEA (4.65 g, 35.98 mmol, 6.27 mL). Then MOMCl (1.16 g, 14.39 mmol, 1.09 mL) was added to N 2The mixture was added in portions at 0° C. under reduced pressure. The mixture was stirred at 15° C. for 12 h. The mixture was poured into ice-water (w / w=1 / 1) (60 mL) and stirred for 20 min. The mixture was extracted with ethyl acetate (60 mL×3). The combined organic phase was washed with brine (60 mL×2) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate 4 / 1 to 1 / 1 to give 7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol (2.00 g, 4.97 mmol, 41% yield) as a brown solid.

[0293] Step 3: 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate. To a mixture of 7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol (2.5 g, 6.21 mmol) in DCM (30 mL) was added DIPEA (2.41 g, 18.63 mmol, 3.25 mL) 2 The mixture was then added in one portion at 15° C. under reduced pressure. 2 O (2.63 g, 9.32 mmol, 1.54 mL) 2 The mixture was stirred at -40°C for 1 h. The mixture was poured into ice-water (w / w=1 / 1, 30 mL). The aqueous phase was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with anhydrous Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with petroleum ether / ethyl acetate 40 / 1 to 8 / 1 to give 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (2.50 g, 4.68 mmol, 75% yield) as a yellow oil.

[0294] Step 4: ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane. To a mixture of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (2.50 g, 4.68 mmol) in toluene (25 mL) was added KOAc (1.38 g, 14.03 mmol), bis(pinacolato)diboron (2.37 g, 9.35 mmol) and Pd(dppf)Cl. 2 (0.34g, 0.47mmol) 2 The mixture was stirred at 130° C. for 3 h. The mixture was cooled to 15° C. and concentrated under reduced pressure at 45° C. The residue was poured into ice-water (w / w=1 / 1, 40 mL). The mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was washed with anhydrous Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate 40 / 1 to 10 / 1 to give ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.20 g, 2.34 mmol, 50% yield) as a yellow solid. m / z (ESI): 513.2 (M+H) + .

[0295] Step 5: 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. To a mixture of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.1 g, 2.15 mmol) in DMF (20 mL) was added CsF (1.96 g, 12.88 mmol, 0.47 mL) with N 2The mixture was poured into water (20 mL). The resulting aqueous mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (30 mL x 2) and diluted with anhydrous Na 2 SO 4 It was dried at 40° C., filtered and concentrated in vacuo to give crude 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, crude) as a brown oil.

[0296] Step 6: 2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. To a solution of 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.20 g, 3.37 mmol) in THF (10 mL) was added Pd-C (10%, 20 mg) under Ar. The suspension was degassed under vacuum and purified with H. 2 The mixture was purged with H several times. 2 The mixture was stirred at 15° C. under (15 psi) for 1 h. The reaction mixture was filtered and the filter cake was washed with THF (10 mL×3). The combined filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate 25 / 1 to 10 / 1 to give 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.62 g, 1.69 mmol, 75% yield over two steps) as a yellow solid. m / z (ESI): 361.1 (M+H) + .

[0297] tert-Butyl (1S,5S)-1-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Intermediates Q1 and Q2) [ka] Step 1: A 40 mL vial was charged with tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 4.71 mmol, Pharmablock, Inc.) and (chlorodiphenylmethyl)benzene (1.4 g, 4.99 mmol, Enamine). The solid was then dissolved in dichloromethane (24 mL) and triethylamine (0.60 g, 0.8 mL, 5.65 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 2 days. The reaction was then concentrated and purified by column chromatography on silica gel, eluting with a gradient of 0-40% EtOAc in heptane to give tert-butyl (1R,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 4.48 mmol, 95% yield) as a white solid.

[0298] Step 2: To an oven-dried vial was added tert-butyl (1R,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.35 g, 0.77 mmol) and N,N,N',N'-tetramethylethylenediamine (0.20 g, 0.3 mL, 1.75 mmol, Sigma-Aldrich Corporation) and the solid was suspended in diethyl ether (7.7 mL). The reaction was cooled to -40°C and sec-butyllithium solution (1.4 M in cyclohexane, 1.3 mL, 1.75 mmol, Sigma-Aldrich Corporation) was added dropwise. The reaction was slowly warmed to 0°C and then stirred for 60 min. 2-Fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (0.41 g, 1.93 mmol, Sigma-Aldrich Corporation) in ether (1.5 mL) and 2-methyl THF (1.5 mL) was then added. The reaction was left to stir at this temperature for an additional 3 h. The reaction was quenched with saturated ammonium chloride (10 mL) and then transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was then purified by column chromatography on silica gel, eluting with a gradient of 0-25% EtOAc in heptane to give a white solid. The sample was purified by SFC using a mobile phase of 15% methanol with triethylamine using (S,S)Whelk-O1 21x250, 5 micron, 80 mL / min flow rate to produce peak 1 with >95% ee of 138 mg and peak 2 with >99% ee of 139 mg. Peak assignments were determined by SCF using (S,S)Whelk-O1 and 15% methanol with 0.2% triethylamine. The two peaks were assigned to tert-butyl (1S,5S)-1-fluoro-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,5R)-1-fluoro-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0299] Step 3: A centrifugal vial was charged with tert-butyl 1-fluoro-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (92 mg, 0.20 mmol) and the solid was dissolved in 1,4-dioxane (1.9 mL). HCl in 1,4-dioxane (4 M, 0.1 mL, 0.58 mmol, Sigma-Aldrich Corporation) (diluted to 1 M) was then added dropwise and the reaction was allowed to stir for 6 h. Sodium bicarbonate (49 mg, 0.58 mmol, Sigma-Aldrich Corporation) was then added and the reaction was allowed to stir for an additional 30 min. The reaction was then concentrated under reduced pressure. The solid was then suspended in dichloromethane (5.0 mL) and passed through a short plug of celite. The organics were then concentrated to give the crude product, which was used directly in the next step without further purification. m / z (ESI, + ion): 175.2 (M- t Bu+H) + .

[0300] 4,6-Dichloro-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine (Intermediate R) [ka] Step 1: 4,6-Dichloro-5-iodopyridin-2-amine. 2-Amino-4,6-dichloropyridine (2.0 g, 12.27 mmol, CombiBlocks) was dissolved in acetonitrile (24.5 mL) and NIS (3.6 g, 15.95 mmol, Oakwood Products, Inc.) was added. The mixture was stirred at 55 °C for 4 h. A saturated solution of sodium thiosulfate was added until the mixture changed color. MeCN was removed in vacuo and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with anhydrous Na 2 SO 4The volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc in heptane to give 4,6-dichloro-5-iodopyridin-2-amine (2.6 g, 9.00 mmol, 73% yield). m / z (ESI): 288.9 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ ppm 6.73-6.78(m,2H),6.60-6.62(m,1H).

[0301] Step 2: 4,6-Dichloro-5-iodo-N,N-bis(4-methoxybenzyl)pyridin-2-amine. 4,6-Dichloro-5-iodopyridin-2-amine (0.92 g, 3.18 mmol) was dissolved in N,N-dimethylformamide (6.4 mL), potassium carbonate (1.8 g, 12.74 mmol, Sigma-Aldrich Corporation), potassium iodide (0.26 g, 1.59 mmol, Sigma-Aldrich Corporation) and 4-methoxybenzyl chloride (1.6 g, 1.4 mL, 10.23 mmol, TCI America) were added and the mixture was stirred at 110 °C for 8 h. After cooling to room temperature, water (20 mL) was added and the aqueous phase was extracted with EtOAc (2 x 15 mL). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and the volatiles were removed in vacuo. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-10% EtOAc in heptane to give 4,6-dichloro-5-iodo-N,N-bis(4-methoxybenzyl)pyridin-2-amine (0.63 g, 1.19 mmol, 37% yield). m / z (ESI, + ion): 529.0 (M+H). + .

[0302] Step 3: 4,6-dichloro-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine. Under a nitrogen atmosphere, 4,6-dichloro-5-iodo-N,N-bis(4-methoxybenzyl)pyridin-2-amine (0.62 g, 1.17 mmol) was dissolved in N,N-dimethylformamide (5.8 mL), and copper(I) iodide (0.33 g, 1.76 mmol, Strem Chemicals, Inc.) and 1,1-difluoro-2-methoxy-2-oxoethane-1-sulfonyl fluoride (0.34 g, 0.2 mL, 1.76 mmol, Sigma-Aldrich Corporation) were added, and the mixture was stirred at 100 °C for 4 h. The mixture was filtered through a syringe filter and purified by reverse phase HPLC to afford 4,6-dichloro-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine (0.43 g, 0.91 mmol, 78% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δ ppm 7.13-7.18(m,4H),6.86-6.91(m,4H),6.44-6.47(m,1H),4.63-4.73(m,4H),3.83(s,6H).

[0303] 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Intermediate S) [ka] Synthesized in a manner similar to intermediate R using 2-amino-4-methyl-6-bromopyridine (Ark Pharm, Inc.). m / z (ESI, + ion): 495.0 (M+H) + . 1 H NMR (400 MHz, chloroform-d) δ ppm 7.15-7.22 (m, 4H), 6.84-6.93 (m, 4H), 6.40-6.44 (m, 1H), 4.72-4.80 (m, 3H), 3.79-3.87 (m, 6H), 2.37-2.43 (m, 3H), 2.21-2.30 (m, 2H).

[0304] Experimental procedure 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (Example 1) [ka] Step 1: tert-Butyl (1R,5S)-8-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. To a mixture of 7-bromo-2,4-dichloro-8-fluoroquinazoline (1.23 g, 4.15 mmol, Enamine) in acetonitrile (10.4 mL) was added N,N-diisopropylethylamine (0.56 g, 0.76 mL, 4.35 mmol, Sigma-Aldrich Corporation) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.90 g, 4.23 mmol, PharmaBlock). The reaction was stirred at room temperature for 1 h. The mixture was then filtered. The solid product was collected and dried under vacuum to give tert-butyl (1R,5S)-8-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.46 g, 3.09 mmol, 75% yield). m / z (ESI, + ion): 471.0 (M+H). + .

[0305] Step 2: tert-Butyl (1R,5S)-8-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. A 20 mL vial was charged with 1,4-diazabicyclo[2.2.2]octane (4.9 mg, 0.043 mmol, Sigma-Aldrich Corporation), cesium carbonate (0.85 g, 2.61 mmol, Sigma-Aldrich Corporation), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol hydrochloride (0.26 g, 1.30 mmol, AChemBlock), tert-butyl (1R,5S)-8-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.21 g, 0.44 mmol), N,N-dimethylformamide (0.72 mL), and tetrahydrofuran (1.45 mL). The reaction was stirred at 40° C. overnight. The crude product was purified by column chromatography on silica gel, eluting with 0-50% 3:1 EtOAc / EtOH in heptane with 2% triethylamine additive to give tert-butyl (1R,5S)-8-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.22 g, 0.37 mmol, 84% yield). m / z (ESI, + ion): 594.0 (M+H). + .

[0306] Step 3: tert-Butyl (1R,5S)-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. An 8 mL vial was charged with [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.017 mmol, Sigma-Aldrich Corporation), potassium phosphate tribasic (54 mg, 0.25 mmol, Acros Organics), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthol (34 mg, 0.13 mmol, Aurum Pharmatech The reaction was charged with LLC), tert-butyl (1R,5S)-8-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (50 mg, 0.084 mmol), water (64.7 μL) and 1,4-dioxane (0.26 mL). The reaction was stirred at 90° C. for 1 h. After cooling, the crude mixture was purified by column chromatography on silica gel eluting with 0-50% 3:1 EtOAc / EtOH in heptane with 2% triethylamine additive to yield tert-butyl (1R,5S)-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (37 mg, 0.057 mmol, 67% yield). m / z (ESI, + ion): 658.3 (M+H). + .

[0307] Step 4: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol. tert-Butyl (1R,5S)-8-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was stirred in dichloromethane (0.26 mL) and trifluoroacetic acid (0.26 mL) at room temperature until completion. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC to yield 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (25 mg, 0.045 mmol, 54% yield). m / z (ESI, + ion): 558.8 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.05(d,J=0.6Hz,1H),7.71-7.83(m,1H),7.40-7.54(m,3H),7.19-7.32(m,2H),7.11-7.16(m,1H),5.46-5.69(m,1H),5.30(br s,2H),4.74(br s,2H),3.92(br s,3H),3.65-3.78(m,2H),3.41-3.54(m,3H),2.56-2.80(m,2H),2.28-2.52(m,5H),2.09-2.26(m,3H).

[0308] [Table 7]

[0309] [Table 8]

[0310]

Table 9

[0311]

Table 10

[0312]

Table 11

[0313]

Table 12

[0314]

Table 13

[0315]

Table 14

[0316]

Table 15

[0317]

Table 16

[0318]

Table 17

[0319]

Table 18

[0320]

Table 19

[0321]

Table 20

[0322]

Table 21

[0323]

Table 22

[0324]

Table 23

[0325]

Table 24

[0326]

Table 25

[0327]

Table 26

[0328]

Table 27

[0329]

Table 28

[0330]

Table 29

[0331]

Table 30

[0332]

Table 31

[0333]

Table 32

[0334]

Table 33

[0335]

Table 34

[0336]

Table 35

[0337]

Table 36

[0338]

Table 37

[0339]

Table 38

[0340]

Table 39

[0341] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol (Example 99) [ka] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol. An 8 mL vial was charged with 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (17.0 mg, 0.023 mmol, synthesized according to Example 1), cerium fluoride (18 mg, 0.12 mmol, Sigma-Aldrich Corporation) and N,N-dimethylformamide (0.23 mL). The reaction was stirred at room temperature overnight. The crude product was purified by reverse phase HPLC to yield 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol as bis(2,2,2-trifluoroacetate) (9.8 mg, 0.017 mmol, 73% yield). m / z (ESI, + ion): 582.2 (M+H). + . 1H NMR (400MHz, methanol-d4) δ ppm 7.93-7.99 (m, 1H), 7.83 (s, 1H), 7.45-7.55 (m, 2H), 7.38-7.44 (m, 1H), 7.29-7.33 (m, 1H), 7.05-7.09 (m, 1H), 5.45-5.68 (m, 1H), 5.28 (br s,2H),4.63-4.80(m,2H),3.81-4.09(m,3H),3.62-3.77(m,2H),3.41-3.54(m,3 H),2.89-2.94(m,1H),2.55-2.76(m,2H),2.27-2.52(m,5H),2.06-2.25(m,3H).

[0342] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(8-ethynylnaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (Example 100) [ka] Step 1: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazoline. A solution of tert-butyl (1R,5S)-8-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (15.4 mg, 0.018 mmol, synthesized according to Example 1) in dichloromethane (0.61 mL) was cooled to 0° C. and then boron trichloride (65.4 μL, 0.065 mmol) was added dropwise. The reaction was stirred at this temperature for 30 minutes. The reaction was quenched by the addition of saturated sodium bicarbonate. The mixture was then allowed to warm to room temperature and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with DCM (3 x 3 mL). The organic layers were then combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazoline. m / z (ESI, + ion): 740.397 (M+H). + .

[0343] Step 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(8-ethynylnaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-quinazoline. An 8 mL vial was charged with 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazoline and dissolved in THF (0.6 mL). The resulting solution was cooled to 0° C. and TBAF (1.0 M in THF, 33.0 μL, 0.033 mmol) was added slowly and the reaction was allowed to stir at this temperature. After 30 min, the reaction was concentrated under reduced pressure and purified by HPLC to give 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(8-ethynylnaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline as the bis(2,2,2-trifluoroacetate) (4.3 mg, 7.37 μmol, 40% yield over two steps) as a white solid. m / z (ESI, + ion): 584.3 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 8.06-8.17(m,2H),7.75-7.80(m,1H),7.64-7.73(m,2H),7.49-7.59(m,2H),5.45-5.68(m,1H),5.12-5.26(m,2H),4.65-4.76(m,2H),3 .81-4.07(m,3H),3.63-3.80(m,2H),3.43-3.54(m,3H),3.11-3.20(m,1H),3.02-3.08(m,1H),2.68(s,2H),2.42-2.50(m,1H),2.36(br d,J=5.0Hz,3H),2.08-2.24(m,3H).

[0344] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(5-chloroisoquinolin-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (Example 101) [ka] Step 1: tert-Butyl (1R,5S)-8-(7-(5-chloroisoquinolin-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. In an 8 mL vial was placed tert-butyl (1R,5S)-8-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (45 mg, 0.073 mmol, synthesized according to Example 1), copper(I) iodide (4.2 mmol), and 100% NaCl. g, 0.022 mmol), 5-chloro-4-(trimethylstannyl)isoquinoline (48 mg, 0.15 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.4 mg, 7.35 μmol), rac-2,2-bis(diphenylphosphino)-1,1-binaphthyl (9.2 mg, 0.015 mmol), and toluene (0.74 mL) were charged into the reaction mixture. The reaction was stirred at 100 °C for 26 h. After cooling, the crude mixture was concentrated under reduced pressure and then purified by column chromatography on silica gel eluting with 0-50% 3:1 EtOAc / EtOH in heptane with 2% triethylamine additive to give tert-butyl (1R,5S)-8-(7-(5-chloroisoquinolin-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. m / z (ESI, + ion): 695.2 (M+H).+ .

[0345] Step 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(5-chloroisoquinolin-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was stirred in dichloromethane (2.5 mL) and trifluoroacetic acid (0.33 mL) at 35° C. until completion. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC to yield 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(5-chloroisoquinolin-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline as the bis(2,2,2-trifluoroacetate) (18 mg, 0.031 mmol, 42% yield over two steps). m / z (ESI, + ion): 595.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 9.51(s,1H),8.48(s,1H),8.28-8.37(m,1H),7.92-8.02(m,1H),7.78(s,2H),5.47-5.71(m,1H),5.15-5.27(m,2H),4.70(br d,J=1.5Hz,2H),3.84-4.08(m,3H),3.63-3.80(m,2H),3.48(s,3H),2.55-2.79(m,2H),2.27-2.52(m,5H),2.17(s,3H).

[0346] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-8-ol (Example 102) [ka] Step 1: tert-Butyl (1R,5S)-8-(7-bromo-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-((4-methoxybenzyl)oxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. 4-Methoxybenzyl alcohol (34 mg, 31 μL, 0.25 mmol) in tetrahydrofuran (0.82 mL) was cooled to 0 °C and then sodium hydride (9.8 mg, 0.25 mmol) was added. The reaction was allowed to stir at 0 °C. After 5 min, the flask was allowed to warm to room temperature for 25 min, after which the flask was re-cooled to 0 °C. In a separate flask, tert-butyl (1R,5S)-8-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (75 mg, 0.12 mmol) was added and dissolved in tetrahydrofuran (1.6 mL). The solution was cooled to 0° C. and added dropwise to the flask containing 4-methoxybenzyl alcohol. The reaction was allowed to warm slowly to room temperature over 2 h and then stirred at this temperature for an additional 2 h. The reaction was then quenched by the addition of water (1.5 mL) and saturated ammonium chloride (1.5 mL) and the aqueous phase was extracted with EtOAc (3×5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude reaction mixture was then purified by column chromatography on silica gel eluting with 0-50% 3:1 EtOAc:EtOH mixture in heptane with 2% triethylamine to give tert-butyl (1R,5S)-8-(7-bromo-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-((4-methoxybenzyl)oxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (90 mg, 0.12 mmol, 100% yield). m / z (ESI, + ion): 730.0 (M+H). + .

[0347] Step 2 & 3: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-8-ol. Prepared as the bis(2,2,2-trifluoroacetate) in a manner similar to that of Example 1. m / z (ESI, + ion): 574.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 7.74-7.80(m,1H),7.40-7.47(m,2H),7.33-7.37(m,1H),7.26-7.31( m,1H),7.16-7.23(m,1H),7.09-7.13(m,1H),5.46-5.65(m,1H),5.13- 5.25(m,2H),4.73(s,2H),3.75-4.02(m,3H),3.65-3.74(m,2H),3.41- 3.52(m,3H),2.55-2.75(m,2H),2.30-2.49(m,5H),2.08-2.21(m,3H).

[0348] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-8-ol (Example 103) [ka] Prepared in a manner similar to Example 102 as the bis(2,2,2-trifluoroacetate salt). m / z (ESI, + ion): 548.2 (M+H) + . 1H NMR (400MHz, methanol-d4) δ ppm 7.77(s,1H), 7.44(d,J=9.8Hz,2H), 7.33-7.37(m,1H), 7.29(d,J=2.5Hz,1H), 7.17-7.25(m,1H), 7.11(s,1H), 5.35-5.57(m,1H), 5.13-5.24(m,2H), 5.00-5.10(m,1H), 4.70-4.79(m,1 H),4.18-4.29(m,1H),3.91-4.14(m,1H),3.65-3.74(m,2H),3.49-3.65(m,1H),3.41-3.49 (m,2H),3.16(d,J=2.9Hz,3H),2.60-2.76(m,1H),2.27-2.47(m,3H),2.15(d,J=8.2Hz,2H).

[0349] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(7-fluoro-8-vinylnaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (Example 104) [ka] Pd(OH) in a 25 mL vial 2 The reaction was charged with 1000 mg / C (9.49 mg, 0.068 mmol), tert-butyl (1R,5S)-8-(7-(8-ethynyl-7-fluoronaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (45 mg, 0.068 mmol) and EtOH (1 mL). The reaction was heated at 45 psi H 2Place under atmosphere and allow to stir at room temperature for 18 h. Upon completion, the mixture was filtered through a plug of Celite and concentrated to dryness. The resulting orange oil was suspended in DCM (1 mL) and TFA (521 μL, 6.76 mmol) was added. The reaction was allowed to stir for 1 h. Upon completion, the mixture was concentrated, resuspended in DMSO, filtered and purified by reverse phase chromatography to give 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(7-fluoro-8-vinylnaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (7.8 mg, 0.014 mmol, 20% yield) as the bis(2,2,2-trifluoroacetate salt) and a yellow solid. m / z (ESI, + ion): 568.2 (M + H) + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 8.14(d,J=8.8Hz,1H),7.73-7.82(m,2H),7.33-7.49(m,4H),7.17(d,J=6.9Hz,1H),5.36-5.76(m,4H),5.21(br dd,J=8.7,3.7Hz,1H),4.10(br dd,J=17.5,8.5Hz,1H),3.83-4.01(m,4H),3.63-3.79(m,3H),3.42-3.60(m,5H),2.16-2.40(m,9H).

[0350] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)naphthalen-2-ol (Example 105) [ka] Step 1: tert-Butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. Place tert-butyl (1R,5S)-3-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.231 mmol, Example 1) in a microwave vial. (synthesized in a manner similar to that described in ), vinylboronic acid pinacol ester (182 mg, 0.200 mL, 1.179 mmol), (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (72.1 mg, 0.092 mmol) and potassium phosphate (255 mg, 1.202 mmol) were added. The vial was purged with nitrogen and suspended in 1,4-dioxane (3 mL) / water (0.75 mL). The reaction was then heated to 150 °C in a microwave for 1 h. The reaction mixture was concentrated and purified using an ISCO Combiflash RF (4 g Redisep Gold column, 0-50% [3:1 EtOAc:EtOH, 2% Et 3 N+ / heptane gradient) to give tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (81 mg, 0.118 mmol, 51.2% yield) as a white solid. m / z (ESI, + ion): 684.2 (M+H). + .

[0351] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)naphthalen-2-ol. tert-Butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (16.0 mg, 0.023 mmol) was dissolved in dichloromethane (0.5 mL). Trifluoroacetic acid (765 mg, 0.5 mL, 6.71 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated and purified by HPLC to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)naphthalen-2-ol (13.0 mg, 0.022 mmol, 95% yield) as the bis(2,2,2-trifluoroacetate salt) and a pale yellow solid. 1 H NMR(400MHz, methanol-d4)δ ppm 8.11(s,1H),7.78(d,J=8.6Hz,1H),7.43(ddd,J=8.3,5.1,2.9Hz,1H),7.29(d,J=2.3Hz,1H),7.19(s,1H),7.18(d,J=4.4Hz,2H),7.01(s,1H) ,6.31(dd,J=17.3,11.1Hz,1H),5.75-5.83(m,1H),5.45-5.71(m,1H),5.17(d,J=11.3Hz,1H),4.84-4.89(m,1H),4.67-4.80(m,2H),4.29(br s,2H),3.82-4.07(m,5H),3.48(dt,J=10.1,5.3Hz,1H),2.55-2.86(m,2H),2.29-2.50(m,3H),2.12-2.24(m,5H).m / z(ESI,+ ion):584.2(M+H) + .

[0352] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (Example 106) [ka] Step 1: tert-Butyl (1R,5S)-3-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A test tube was charged with tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-vinylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65 mg, 0.095 mmol) and the solid was dissolved in ethanol (2.5 mL). To this was added 5% Pd(s) / carbon (20.23 mg, 9.51 μmol) and the reaction was placed under 40 Psi hydrogen gas and stirred at rt for 1 day. The reaction mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated and purified by HPLC to give tert-butyl (1R,5S)-3-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a pale yellow solid. m / z (ESI, + ion): 686.2 (M+H). + .

[0353] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol. tert-Butyl (1R,5S)-3-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (765 mg, 0.5 mL, 6.71 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated and purified by HPLC to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (39.8 mg, 0.068 mmol, 71.5% yield) as the bis(2,2,2-trifluoroacetate salt) and a pale yellow solid. 1 H NMR(400MHz, methanol-d4)δ ppm 7.81(s,1H),7.78(d,J=8.4Hz,1H),7.43(dt,J=8.3,4.0Hz,1H),7.29(d,J=2.3Hz,1H), 7.18(d,J=4.4Hz,2H),7.01-7.05(m,1H),5.44-5.68(m,1H),4.68-4.81(m,4H),4.29(br s,2H),3.81-4.07(m,5H),3.47(td,J=10.4,6.0Hz,1H),2.58-2.80(m,2H),2.3 2-2.57(m,5H),2.19(s,5H),1.05(t,J=7.5Hz,3H).m / z(ESI,+ion):586.2(M+H) + .

[0354] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-methylquinazolin-7-yl)naphthalen-2-ol (Example 107) [ka] Step 1: tert-Butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A microwave vial was charged with butyl (1R,5S)-3-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (46 mg, 0.066 mmol) and 1,4-diazabicyclo[2 A mixture of 2.2]octanebis(trimethylalmane) (34.1 mg, 0.133 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11.25 mg, 0.013 mmol) was suspended in degassed tetrahydrofuran and stirred at 70°C for 1 h. The reaction mixture was concentrated and purified by ISCO Combiflash RF (4 g Redisep Gold column, using a gradient of 0-50% [3:1 EtOAc:EtOH with 2% Et3N] / heptane) to give tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid. m / z (ESI, + ion): 672.2 (M+H). + .

[0355] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-methylquinazolin-7-yl)naphthalen-2-ol. tert-Butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-6-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was dissolved in 0.5 mL DCM. Trifluoroacetic acid (765 mg, 0.5 mL, 6.71 mmol) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated and purified by HPLC to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-methylquinazolin-7-yl)naphthalen-2-ol (23.9 mg, 0.042 mmol, 62.9% yield) as the bis(2,2,2-trifluoroacetate salt) and as a white solid. 1 H NMR(400MHz, methanol-d4)δ ppm 7.77-7.83(m,2H),7.44(ddd,J=8.3,5.5,2.5Hz,1H),7.28(d,J=2.5Hz,1H),7.19(d,J=4.9 Hz,2H),7.19(s,1H),7.01(t,J=2.2Hz,1H),5.42-5.72(m,1H),4.69-4.79(m,3H),4.28(br s,2H),3.82-4.07(m,5H),3.43-3.51(m,1H),2.53-2.82(m,2H),2.31-2.48(m,3H),2.12-2.23(m,8H).m / z(ESI,+ ion):571.9(M+H) + .

[0356] 4-(4-((8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol (Example 108) [ka] Step 1: 7-Bromo-2-chloro-4-(methylthio)quinazoline. To a stirred solution of 7-bromo-2,4-dichloroquinazoline (1.0 g, 3.60 mmol, Pharmablock) in THF (40 mL) and water (1 mL) at 0 °C was added NaSMe (0.277 g, 3.96 mmol). The reaction was stirred at room temperature for 6 h. Upon completion, the mixture was washed with MgSO 4 and concentrated to give 7-bromo-2-chloro-4-(methylthio)quinazoline (1.04 g, 3.59 mmol, 100% yield) as a yellow solid which was used in the next step without further treatment. m / z (ESI, + ion): 288.9 (M+H). + .

[0357] Step 2: 7-Bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline. A mixture of 7-bromo-2-chloro-4-(methylthio)quinazoline (1.05 g, 3.63 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol hydrochloride (1.064 g, 5.44 mmol, PharmaBlock), 1,4-diazabicyclo[2.2.2]octane (0.203 g, 1.813 mmol), and cesium carbonate (3.54 g, 10.88 mmol) in DMF (5 mL) and THF (30 mL) was stirred at 45° C. for 12 h. Upon completion, the reaction mixture was diluted with water and extracted with DCM. The organic layer was concentrated and purified by column chromatography eluting with 0-100% (3:1, EtOAc:EtOH with 2% TEA) in heptane to give 7-bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline (968 mg, 2.348 mmol, 65% yield) as a yellow solid. m / z (ESI, + ion): 412.0 (M+H). + .

[0358] Step 3: 4-(2-(((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)naphthalen-2-ol. A 100 mL round bottom flask was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (634 mg, 2.348 mmol, Aurum), potassium phosphate tribasic (1096 mg, 5.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (344 mg, 0.470 mmol, Sigma-Aldrich Corporation) and 7-bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazoline (968 mg, 2.348 mmol). The round bottom flask was purged with nitrogen gas and the solid was then suspended in degassed water (3.80 mL) and 1,4-dioxane (19 mL). The reaction was then stirred at 90° C. After 3 h, the reaction was cooled to room temperature and diluted with water (3 mL) and EtOAc (3 mL). The aqueous layer was extracted with EtOAc (3×30 mL). The organic layers were then combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel eluting with a gradient of 0% to 50% (3:1 EtOAc:EtOH with 2% TEA) in heptane to give 4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)naphthalen-2-ol (354 mg, 0.744 mmol, 32% yield) as a brown solid. m / z (ESI, + ion): 476.1 (M+H). + .

[0359] Step 4: 4-(4-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol. Add copper(I) thiophene-2-carboxylate (88 mg, 0.463 mmol), Pd(PPh3 ) 4 (48.6 mg, 0.042 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (155 mg, 0.463 mmol, Pharmablock), 4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)naphthalen-2-ol (100 mg, 0.210 mmol) and 1,4-dioxane. The vial was purged with nitrogen for 5 min, placed in a preheated aluminum block and kept at 50° C. for 12 h. Upon completion, 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 eluting with a gradient of 0% to 50% (3:1 EtOAc:EtOH with 2% TEA) in heptane to give tert-butyl 3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate as a red oil.

[0360] The resulting red oil was dissolved in DCM (1 mL) and TFA (1.62 mL, 21.03 mmol, Aldrich) was added. The reaction was allowed to stir at 50° C. for 30 min. Upon completion, the mixture was concentrated, redissolved in DMSO, filtered, and purified by reverse phase HPLC to give 4-(4-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol as the bis(2,2,2-trifluoroacetate salt) and an orange solid. m / z (ESI, + ion): 537.2 (M+H). + . 1 H NMR (400MHz, DMSO-d 6)δ ppm 8.42(d,J=8.6Hz,1H),7.77-7.93(m,3H),7.71(dd,J=8.6,1.7Hz,1H),7.63(d,J= 8.8Hz,1H),7.45-7.51(m,1H),7.25-7.31(m,2H),7.13(d,J=2.3Hz,1H),6.59(br d,J=5.6Hz,1H),5.51-5.72(m,1H),4.61-4.74(m,2H),4.51-4.58(m,1H),4.38(br s,1H),3.56-3.96(m,7H),3.17-3.24(m,1H),2.76(br d,J=18.2Hz,1H),2.60-2.69(m,1H),2.15-2.40(m,7H).

[0361] 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol (Example 109) [ka] Step 1: tert-Butyl (1S,4S)-5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate. To a stirred solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (0.50 g, 1.59 mmol, Enamine) in acetonitrile (8.0 mL) was added (1S,4S)-2-Boc-2,5-diazabicyclo(2.2.2)octane (0.36 g, 1.67 mmol, AstaTech,Inc) and N,N-dimethyltriethylamine (0.62 mg, 0.8 mL, 4.78 mmol, Sigma-Aldrich Corporation). The reaction was then stirred for 1 h. The reaction was then diluted with water (10 mL) and brine (10 mL). The resulting aqueous layer was then 2 Cl 2(3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (1S,4S)-5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (0.78 g, 1.59 mmol, 100% yield) as a pale yellow solid which was used without further purification. m / z (ESI, + ion): 488.8 (M+H). + .

[0362] Step 2: tert-Butyl (1S,4S)-5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate. A centrifugal vial was charged with tert-butyl (1S,4S)-5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (0.78 g, 1.59 mmol), cesium carbonate (1.60 g, 4.77 mmol, Sigma-Aldrich Corporation), 1,4-diazabicyclo[2.2.2]octane (36 mg, 0.32 mmol, Sigma-Aldrich Corporation) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.36 g, 2.23 mmol, PharmaBlock). The solid was then suspended in N,N-dimethylformamide (5.3 mL) and tetrahydrofuran (10.6 mL) and the reaction mixture was stirred at 35° C. After stirring for 2 days, the reaction was diluted with water (25 mL) and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 25 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude reaction mixture was then purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH blend with 2% triethylamine in heptane to give tert-butyl (1S,4S)-5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (0.84 g, 1.37 mmol, 86% yield) as a yellow solid. m / z (ESI, + ion): 612.2 (M+H) + .

[0363] Step 3: tert-Butyl (1S,4S)-5-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate. The vial was charged with tert-butyl (1S,4S)-5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (65 mg, 0.11 mmol), 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (65 mg, 0.19 mmol, LabNetwork), potassium phosphate (68 mg, 0.32 mmol, Sigma Aldrich corporation) and cataCXium A Pd G3 (12 mg, 0.016 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and the reactant was suspended in degassed tetrahydrofuran (1.0 mL) and water (0.1 mL). The reaction was then sealed and heated to 60° C. After stirring overnight, the reaction was cooled to room temperature and concentrated under reduced pressure. The crude oil was then purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane to give tert-butyl (1S,4S)-5-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate as an off-white solid, which was used directly in the next step. m / z (ESI, + ion): 748.2 (M + H) + .

[0364] Step 4: 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol. The above tert-butyl (1S,4S)-5-(7-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate product was dissolved in MeCN (3.3 mL). The solution was cooled to 0° C., after which HCl (4 M in 1,4-dioxane, 0.7 mL, 2.65 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 15 min. After an additional 15 min at rt, the reaction was concentrated under reduced pressure to give a crude orange oil. The oil was then purified by reverse phase HPLC to give 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol as the bis(2,2,2-trifluoroacetate salt) and a pale yellow solid (61 mg, 0.073 mmol, 69% yield). m / z (ESI, + ion): 604.2 (M+H) + . 1 H NMR (400MHz, methanol-d 4)δ ppm 7.84(dd,J=10.14,1.57Hz,1H)7.61-7.69(m,1H)7.34-7.41(m,1H)7.32(d,J=2.72Hz,1H)7.18 (d,J=6.27Hz,1H)6.95(d,J=2.51Hz,1H)5.46-5.71(m,1H)5.12-5.24(m,1H)4.60-4.73(m,2H)4 .50-4.59(m,1H)4.35-4.45(m,1H)3.83-4.09(m,5H)3.56-3.63(m,1H)3.43-3.53(m,1H)2.58-2 .81(m,2H)2.42-2.57(m,4H)2.33-2.42(m,2H)2.08-2.29(m,4H)0.93(td,J=7.37,3.45Hz,3H).

[0365]

Table 40

[0366]

Table 41

[0367]

Table 42

[0368]

Table 43

[0369]

Table 44

[0370]

Table 45

[0371]

Table 46

[0372]

Table 47

[0373]

Table 48

[0374]

Table 49

[0375]

Table 50

[0376]

Table 51

[0377]

Table 52

[0378]

Table 53

[0379]

Table 54

[0380]

Table 55

[0381]

Table 56

[0382] [Table 57]

[0383] [Table 58]

[0384] [Table 59]

[0385] [Table 60]

[0386] [Table 61]

[0387] [Table 62]

[0388] 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol (Example 180) [ka] Step 1: tert-Butyl (1S,4S)-5-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate. The vial was charged with tert-butyl (1S,4S)-5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (30 mg, 0.049 mmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)silane (48 mg, 0.098 mmol, LabNetwork), potassium phosphate (31 mg, 0.15 mmol, Sigma Aldrich Corporation) and cataCXium A Pd G3 (5.4 mg, 7.35 μmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and then the reactant was suspended in degassed tetrahydrofuran (0.4 mL) and water (0.04 mL). The reaction was then sealed and heated to 60° C. After stirring overnight, the reaction was cooled to room temperature and concentrated under reduced pressure. The crude oil was then purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane to give tert-butyl (1S,4S)-5-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate as an off-white solid. m / z (ESI, + ion): 900.4 (M+H). + .

[0389] Step 2: 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol. tert-Butyl (1S,4S)-5-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate was dissolved in MeCN (1.5 mL). The solution was cooled to 0° C. and then HCl (4 M in 1,4-dioxane, 0.3 mL, 1.23 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 15 min. After an additional 30 min at rt, the reaction was concentrated under reduced pressure to give 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol as a yellow solid. m / z (ESI, + ion): 755.8 (M+H). + .

[0390] Step 3: 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol. 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol was dissolved in DMF (1.5 mL). Cesium fluoride (74 mg, 0.49 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred overnight. The reaction was filtered through a syringe filter and purified by reverse phase HPLC to give 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol as the bis(2,2,2-trifluoroacetate salt) and an off-white solid (14 mg, 0.017 mmol, 34% coupled yield over three steps). m / z (ESI, + ion): 600.2 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.85(d,J=8.15Hz,1H)7.74(dt,J=9.98,2.01Hz,1H)7.51-7.56(m,1H)7.43(d,J=7.94H z,1H)7.36(d,J=2.51Hz,1H)7.07-7.11(m,1H)5.44-5.66(m,1H)5.09-5.16(m,1H)4.60 -4.73(m,2H)4.47-4.57(m,1H)4.33-4.43(m,1H)3.81-4.07(m,5H)3.55-3.64(m,1H)3. 40-3.52(m,1H)2.96-3.07(m,1H)2.57-2.74(m,2H)2.21-2.56(m,5H)2.04-2.20(m,3H).

[0391] [Table 63]

[0392] [Table 64]

[0393] [Table 65]

[0394] [Table 66]

[0395] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (Example 192) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-(6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. The vial was charged with tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 0.12 mmol), 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (89 mg, 0.24 mmol, PharmaBlock), potassium phosphate (55 mg, 0.26 mmol) and cataCXium A Pd G3 (15 mg, 0.024 mmol). The vial was purged with nitrogen gas and then the reactants were suspended in degassed 1,4-dioxane (1.0 mL) and water (0.2 mL). The reaction was then sealed and heated to 90° C. After stirring for 3 h, the crude material was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH blend (with 1% triethylamine) in heptane to give tert-butyl (1R,5S)-3-(7-(6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a tan solid which was used directly in the subsequent step. m / z (ESI, + ion): 763.750 (M+H). + .

[0396] Step 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline. tert-Butyl (1R,5S)-3-(7-(6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was dissolved in DCM (2 mL) and TFA (1 mL). The reaction was stirred at rt for 2 h. The mixture was purified by reverse phase HPLC to give 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline as the THA salt and as an off-white solid (40 mg, 0.058 mmol, 49% coupled yield over two steps). m / z (ESI, + ion): 580.2 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.95-8.06(m,1H),7.79(s,1H),7.60(s,1H),7.36-7.49(m,1H),5.51-5.71(m,1H),4.67-4.80(m,4H) ),4.22-4.38(m,2H),3.77-4.12(m,5H),3.40-3.59(m,1H),2.55-2.87(m,2H),2.33(s,6H),2.20(br s,5H).

[0397] [Table 67]

[0398] [Table 68]

[0399] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1H-indazole-5-carbonitrile (Example 197) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-(5-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. In a 4 mL vial was placed tert-butyl (1R,5S)-3-(7-(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.040 mmol, synthesized in a manner similar to Example 192), Na in dioxane (0.3 mL) and water (0.08 mL). 2 CO 3(0.5 mg, 5.00 μmol), potassium ferrocyanide trihydrate (8.4 mg, 0.020 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (3.8 mg, 8.00 μmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (3.4 mg, 4.00 μmol) were added to the reaction mixture and the mixture was stirred at 90 °C for 4 h. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH (with 1% triethylamine) in heptane to give tert-butyl (1R,5S)-3-(7-(5-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the subsequent step.

[0400] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1H-indazole-5-carbonitrile. The above material was dissolved in DCM (2 mL) and TFA (1 mL). The reaction was stirred at rt for 2 h. The mixture was purified by reverse phase HPLC to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1H-indazole-5-carbonitrile as a TFA salt and a white solid (10 mg, 0.015 mmol, 37% coupled yield over two steps). m / z (ESI, + ion): 557.2 (M+H). + . 1H NMR (400MHz, methanol-d 4 )δ ppm 7.92-8.17(m,2H),7.84(s,1H),7.55-7.74(m,1H),7.30-7.48(m,1H),5.38-5.78(m,1H),4.62-4 .85(m,4H),4.22-4.46(m,2H),3.80-4.10(m,5H),3.44-3.67(m,1H),2.30-2.88(m,5H),2.20(br s,5H).

[0401] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-(prop-1-en-2-yl)-1H-indazol-4-yl)quinazoline (Example 198) [ka] Step 1: tert-Butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A 4 mL vial was charged with tert-butyl (1R,5S)-3-(7-(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.067 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium dichloride (4.9 mg, 6.66 μmol), potassium phosphate (50 mg, 0.23 mmol) and (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isopropene (34 mg, 0.20 mmol, Combi-Blocks). The vial was purged with nitrogen and the reactants were suspended in 2-methylTHF (0.6 mL) and water (0.1 mL). The reaction was heated to 90° C. for 6 h. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH (with 1% triethylamine) in heptane to give tert-butyl (1R,5S)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the subsequent step. m / z (ESI, + ion): 756.4 (M+H). + .

[0402] Step 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-(prop-1-en-2-yl)-1H-indazol-4-yl)quinazoline. The above material was dissolved in DCM (2 mL) and TFA (1 mL). The reaction was stirred at rt for 2 h. The reaction was concentrated under reduced pressure. The mixture was purified by reverse phase HPLC to give 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(5-(prop-1-en-2-yl)-1H-indazol-4-yl)quinazoline as a TFA salt as a white solid (9 mg, 0.013 mmol, 19% coupled yield over two steps). m / z (ESI, + ion): 572.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 8.90-9.20(m,1H),8.22-8.42(m,1H),7.86-8.13(m,1H),7.63-7.68(m,1 H),7.61-7.77(m,1H),7.48(d,J=8.6Hz,1H),5.48-5.83(m,1H),4.96-5. 21(m,1H),4.84-4.95(m,1H),4.61-4.76(m,5H),4.20-4.39(m,2H),3.79 -4.16(m,5H),3.41-3.67(m,1H),3.00(s,3H),2.25-2.51(m,4H),2.20(br s,4H),1.99(s,2H).

[0403] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol (Example 199) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxyquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. In an 8 mL vial, add potassium hydroxide (43 mg, 0.77 mmol), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (41 mg, 0.051 mmol), and tert-butyl(1R,5S)-3-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxyphenyl)-2,4-diphenylphosphino)-2-(2-amino-1,1'-biphenyl)-palladium(II) methanesulfonate (41 mg, 0.051 mmol). The reaction was charged with 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.20 g, 0.26 mmol, prepared in a manner similar to Example 109), 1,4-dioxane (0.6 mL) and water (0.6 mL). The reaction was stirred at 100° C. for 1 h. The crude product was purified by column chromatography on silica gel eluting with 0-50% 3:1 EtOAc / EtOH blend in heptane with 2% triethylamine additive to yield tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxyquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (66 mg, 0.086 mmol, 34% yield). m / z (ESI, + ion): 764.2 (M+H). + .

[0404] Step 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol. tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxyquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (66 mg, 0.086 mmol) was stirred in HCl solution (4.0 M in dioxane, 0.4 mL, 1.73 mmol) and methanol (0.4 mL) at rt for 1 h. The solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC to yield 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol as the bis(2,2,2-trifluoroacetate) (35 mg, 0.041 mmol, 47% yield). m / z (ESI, + ion): 620.2 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.61-7.73(m,1H),7.18-7.34(m,3H),6.87-6.96(m,1H),5.44-5.71(m,1H),4.51-4.73(m,4H), 4.21-4.36(m,2H),3.70-4.10(m,5H),3.40-3.57(m,1H),2.20-2.59(m,12H),0.71-0.91(m,3H).

[0405] [Table 69]

[0406] 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 202) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-((4-methoxybenzyl)amino)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. An 8 mL vial was charged with 4-methoxybenzylamine (70 mg, 0.07 mL, 0.51 mmol), sodium tert-butoxide (74 mg, 0.77 mmol), BrettPhos Pd G4 (47 mg, 0.051 mmol, Sigma Aldrich Corporation), tert-butyl (1R,5S)-3-(6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.20 g, 0.26 mmol, synthesized in a manner similar to Example 109) and 1,4-dioxane (2.6 mL). The reaction was stirred at 100 °C for 3 h. The crude mixture was purified by column chromatography on silica gel eluting with 0-50% 3:1 EtOAc / EtOH in heptane with 2% triethylamine additive to yield tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-((4-methoxybenzyl)amino)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (38 mg, 0.043 mmol, 17% yield). m / z (ESI, + ion): 883.4 (M+H). + .

[0407] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-((4-methoxybenzyl)amino)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol. tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-((4-methoxybenzyl)amino)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (38 mg, 0.043 mmol) was stirred in HCl solution (4.0 M in dioxane, 0.2 mL, 0.86 mmol) and methanol (0.2 mL) at rt for 1 h. The solvent was removed under reduced pressure. The crude product was used in the subsequent step without further treatment. m / z (ESI, + ion): 739.4 (M+H) + .

[0408] Step 3: 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol. The crude 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-((4-methoxybenzyl)amino)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol was stirred in trifluoroacetic acid (0.2 mL) and dichloromethane (0.2 mL) at rt for 2 h. The solvent was then removed under reduced pressure. The crude product was purified by reverse phase HPLC to yield 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol bis(2,2,2-trifluoroacetate) (11 mg, 0.013 mmol, 30% coupled yield over two steps). m / z (ESI, + ion): 619.2 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.67-7.74(m,1H),7.32-7.35(m,1H),7.23-7.31(m,1H),7.11-7.16(m,1H),6.94-6.98(m,1H),5.43-5.65(m,1H),4.53-4 .71(m,3H),4.23-4.37(m,2H),3.69-4.07(m,5H),3.39-3.55(m,1H),2.57-2.78(m,3H),2.02-2.56(m,10H),0.84(s,3H).

[0409] 4-(6-amino-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 203) [ka] Synthesized in a manner similar to Example 202. The product was isolated as the bis(2,2,2-trifluoroacetic acid) salt. m / z (ESI, + ion): 601.0 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.64-7.75(m,1H),7.48-7.54(m,1H),7.34-7.38(m,1H),7.21-7.32(m,2H),6.89-6.97(m,1H),5.49-5.72(m,1H),4.79-4.87(m,4H), 4.26-4.37(m,2H),3.84-4.06(m,5H),3.42-3.58(m,1H),2.59-2.82(m,3H),2.33-2.57(m,4H),2.13-2.30(m,5H),0.77-0.86(m,3H).

[0410] 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-hydroxy-1-naphthonitrile (Example 204) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-(8-cyano-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. tert-Butyl (1R,5S)-3-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.10 g, 0.14 mmol, synthesized in a manner similar to Example 109), Na 2 CO 3(1.9 mg, 0.018 mmol), 2-dicyclohexylphosphino-2',4',6',-triisopropylbiphenyl (13 mg, 0.028 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (12 mg, 0.014 mmol, Sigma Aldrich Corporation) and potassium ferrocyanide trihydrate (30 mg, 0.070 mmol, Toronto Research Chemicals) were suspended in degassed dioxane (0.7 mL) and water (0.7 mL) and stirred at 90° C. for 90 min. After cooling to rt, water (3 mL) was added and the mixture was extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane to afford tert-butyl (1R,5S)-3-(7-(8-cyano-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.10 g) as a shiny white solid, which was used in the next step without complete drying.

[0411] Step 2: 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-hydroxy-1-naphthonitrile. The above product tert-butyl (1R,5S)-3-(7-(8-cyano-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was suspended in DCM (1.8 mL) and TFA was added (0.3 mL). The mixture was stirred at rt for 2 h. Volatiles were removed under reduced pressure and the residue was purified by reverse-phase HPLC to yield 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-hydroxy-1-naphthonitrile as bis(2,2,2-trifluoroacetate) (44 mg, 0.053 mmol, 38% yield). m / z (ESI, + ion): 601.0 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 8.16(dd,J=8.5,0.9Hz,1H),7.77-7.86(m,1H),7.72(br d,J=9.8Hz,1H),7.59(dd,J=8.4,7.3Hz,1H),7.47(d,J=2.5Hz,1H),7.28(d,J=2.3Hz,1H),5.50-5.68(m,1 H),4.63-4.79(m,5H),4.25-4.31(m,2H),3.85-4.09(m,5H),3.44-3.54(m,1H),2.32-2.80(m,5H),2.18(br s,5H).

[0412] 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-hydroxy-1-naphthonitrile (Example 205) [ka] Synthesized in a manner similar to Example 204. The product was isolated as the corresponding bis(2,2,2-trifluoroacetate). m / z (ESI, + ion): 583.2 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 8.00(d,J=8.4Hz,1H),7.82(d,J=8.8Hz,1H),7.44(d,J=1.0Hz,1H),7.41(d,J=6.7Hz,1H),7.13-7.29(m,3H),5.35(dd,J= 53.9,1.0Hz,1H),4.46-4.64(m,1H),4.20-4.35(m,2H),3.49-3.71(m,4H),3.14-3.28(m,3H),2.95-3.06(m,1H),2.58(br d,J=6.7Hz,7H),1.81-2.05(m,7H).

[0413] 4-(4-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-chloronaphthalen-2-ol (Example 206) [ka] Step 1: tert-Butyl (1R,4R)-5-(7-(4-chloro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate. To a stirred solution of tert-butyl (1R,4R)-5-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (47 mg, 0.070 mmol, synthesized in a manner similar to Example 109) in DMF (0.8 mL) was added N-chlorosuccinimide (9.3 mg, 0.070 mmol) at rt. The resulting mixture was stirred at rt for 2.5 h. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 30-100% 3:1 EtOAc / EtOH in heptane to give tert-butyl (1R,4R)-5-(7-(4-chloro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate as a colorless film which was taken on directly to the next step. m / z (ESI, + ion): 710.2 (M+H). + .

[0414] Step 2: 4-(4-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-chloronaphthalen-2-ol. To a stirred solution of a mixture of tert-butyl (1R,4R)-5-(7-(4-chloro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (30 mg, 0.042 mmol) in DCM (1.0 mL) was added TFA (4.8 mg, 1.0 mL, 0.042 mmol) at rt. The resulting mixture was stirred at rt for 2 h. The volatiles were removed and the residue was dissolved in MeOH and purified by reverse phase HPLC to give the mixture as a white solid, which was dissolved in MeOH / DCM and neutralized with ammonium hydroxide (commercially available). The mixture was purified by column chromatography on silica gel eluting with a gradient of 1-20% (20% MeOH in DCM with 0.5% ammonium hydroxide) in DCM to give 4-(4-((1R,4R)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-chloronaphthalen-2-ol as an off-white solid (2.7 mg, 0.004 mmol, 10% yield). m / z (ESI, + ion): 610.2 (M+H). + . 1 H NMR (methanol-d 4,400MHz)δ 8.22(d,1H,J=8.6Hz),7.83(dd,1H,J=1.7,10.7Hz),7.57(ddd,1H,J=1.3,6.8,8.4Hz),7.38(br d,1H,J=8.2Hz),7.3-7.3(m,1H),7.24(s,1H),5.2-5.4(m,1H),4.88(br s,1H),4.2-4.4(m,2H),4.1-4.2(m,2H),3.47(td,1H,J=2.5,11.5Hz),3.1-3.3(m, 5H), 3.00(dt,1H,J=5.9,9.3Hz),2.2-2.4(m,3H),2.0-2.1(m,5H),1.8-2.0(m,2H).

[0415] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline (Example 207) [ka] Step 1: tert-Butyl (1R,5S)-3-(6-chloro-7-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A microwave vial was charged with tert-butyl (1R,5S)-3-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.079 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole (85 mg, 0.20 mmol, CombiBlocks), potassium phosphate (59 mg, 0.28 mmol) and cataCXium A Pd G3 (8.7 mg, 0.012 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen gas and the reactant was then suspended in 2-methyl THF (0.7 mL) and water (0.1 mL). The reaction was then sealed and heated in a microwave at 115° C. for 120 minutes. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane with 1% triethylamine additive to give tert-butyl (1R,5S)-3-(6-chloro-7-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the subsequent step. m / z (ESI, + ion): 848.2 (M+H) + .

[0416] Step 2: tert-Butyl (1R,5S)-3-(6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a solution of the above tert-butyl (1R,5S)-3-(6-chloro-7-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in MeOH (2 mL) was added 0.5 mL of 10 N NaOH solution. The reaction was stirred at rt for 3 h. The reaction mixture was diluted with saturated NaCl solution (5 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with MgSO 4 The solution was filtered and concentrated in vacuo to give the crude product, which was further purified by reverse phase HPLC to give tert-butyl (1R,5S)-3-(6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol, 18% coupled yield over two steps). m / z (ESI, + ion): 694.2 (M+H). + .

[0417] Step 3: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline. A solution of tert-butyl (1R,5S)-3-(6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol) in DCM (2 mL) was treated with 1 mL of TFA. The reaction was stirred at rt for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-7-(3,5-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazoline as a TFA salt and as a white solid (3.8 mg, 0.005 mmol, 36% yield). m / z (ESI, + ion): 594.2 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.94-8.15(m,1H),7.50-7.59(m,1H),7.30-7.46(m,1H),5.57-5.83(m,1H),5.41-5.81(m,1H),4.70(br d,J=2.9Hz,3H),4.18-4.36(m,2H),3.81-4.13(m,5H),3.44-3.67(m,1H), 2.54-2.89(m,2H),2.29-2.50(m,3H),2.19(s,8H),1.91(d,J=1.9Hz,3H).

[0418] [Table 70]

[0419] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 210) [ka] Step 1: 7-Bromo-4-chloroquinolin-2(1H)-one. To a mixture of 7-bromo-2,4-dichloroquinoline (1.00 g, 3.61 mmol) in sulfuric acid (5.88 g, 5.9 mL, 59.9 mmol) diluted to 20% with water, 1,4-dioxane (30 mL) was added and the reaction was stirred at 100 °C for 22 h. After cooling to rt, the reaction mixture was quenched with water. The resulting solid was collected by filtration, washed with water, and dried in vacuum to give 7-bromo-4-chloroquinolin-2(1H)-one (0.78 g, 3.02 mmol, 84% yield) as an off-white solid. m / z (ESI, + ions): 258.1 (M+H) + .

[0420] Step 2: 7-Bromo-4-chloroquinolin-2-yl trifluoromethanesulfonate. To a suspension of 7-bromo-4-chloroquinolin-2(1H)-one (0.29 g, 1.13 mmol) in dichloromethane (3.8 mL) was added N,N-dimethyltriethylamine (0.22 mg, 0.3 mL, 1.69 mmol), followed by dropwise addition of trifluoromethanesulfonic anhydride solution (1 M in DCM, 1.2 mL, 1.24 mmol). The reaction mixture was stirred at rt for 1 h. The solvent was evaporated and the residual solid was used directly in the subsequent step. m / z (ESI, + ions): 391.6 (M+H) + .

[0421] Step 3: 7-Bromo-4-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline. To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.36 g, 2.23 mmol, PharmaBlock) in THF (2.0 mL) was added sodium hydride (94 mg, 2.34 mmol, TCI America). The reaction mixture was stirred at rt for 15 min. The mixture was then added to a solution of 7-bromo-4-chloroquinolin-2-yl trifluoromethanesulfonate (0.44 g, 1.11 mmol) in THF (2.0 mL). The vial was rinsed with THF (2.0 mL) and this solution was combined into the reaction mixture, which was stirred at 60 °C for 48 h. After cooling to rt, water was added to the reaction mixture and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with anhydrous Na 2 SO 4 The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-20% 3:1 EtOAc / EtOH in heptane to give 7-bromo-4-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline (80 mg, 0.20 mmol, 18% yield) as an off-white solid. m / z (ESI, + ion): 417.1 (M+H). + .

[0422] Step 4: 4-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline. A mixture of 7-bromo-4-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline (75 mg, 0.19 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.10 g, 0.28 mmol, LabNetwork), cataCXium A Pd G3 (27 mg, 0.038 mmol, Sigma Aldrich Corporation), and potassium phosphate (0.12 g, 0.56 mmol) in a round-bottom flask was flushed with nitrogen. 1,4-Dioxane (1.6 mL) and water (0.3 mL) were added and the reaction mixture was stirred at 85-90 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient of 0-25% 3:1 EtOAc / EtOH in heptane to give 4-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline (32 mg, 0.058 mmol, 31% yield) as an off-white solid. m / z (ESI, + ion): 552.9 (M+H). + .

[0423] Step 5: tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A mixture of 4-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinoline (32 mg, 0.058 mmol), 8-Boc-3,8-diazabicyclo[3.2.1]octane (25 mg, 0.11 mmol, Chem-Impex International, Inc.), RuPhos Pd G4 (9.8 mg, 0.012 mmol, Sigma Aldrich Corporation), and cesium carbonate (57 mg, 0.17 mmol) in a round-bottom flask was flushed with nitrogen. 1,4-Dioxane (0.4 mL) was added and the reaction mixture was stirred at 70 °C for 1 h. After cooling to rt, the crude material was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient of 0-80% EtOAc in heptane to give tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (16 mg, 0.022 mmol, 38% yield) as a white solid. m / z (ESI, + ion): 729.0 (M+H). + .

[0424] Step 6: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol. To a solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10 mg, 0.014 mmol) in acetonitrile (0.2 mL) cooled to 0° C. was added dropwise HCl solution (4.0 M in dioxane, 0.4 mL, 0.35 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated and the remaining white solid was triturated with diethyl ether (1 mL). The solid was dried under reduced pressure and then dissolved in MeOH and concentrated again. Dichloromethane was added and the mixture was concentrated in vacuo to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol trihydrochloride as the HCl salt (9.6 mg, 0.014 mmol, 100% yield, 95% purity) as a pale yellow solid. m / z (ESI, + ion): 585.2 (M+H). + . 1 H NMR (methanol-d 4 ,400MHz)δ 8.15(d,1H,J=8.6Hz),7.85(d,1H,J=1.5Hz),7.5-7.7(m,2H),7.2-7.3(m,2H),6.95(s,1H),6.83(s,1H),5.5-5.7(m,1H),4.32(br s,2H),3.8-4.0(m,5H),3.6-3.8(m,3H),3.5-3.6(m,3H),2.1-2.7(m,12H),0.74(t,3H,J=7.3Hz).

[0425] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 211) [ka] Synthesized in a manner similar to Example 210. m / z (ESI, + ion): 603.3 (M+H) + . 1 H NMR (methanol-d 4 ,400MHz)δ 7.98(br d,1H,J=8.4Hz),7.68(dd,1H,J=5.9,9.0Hz),7.56(br t,1H,J=6.6Hz),7.2-7.3(m,2H),6.8-7.0(m,2H),5.5-5.7(m,1H),4.32(br s,2H),3.6-4.0(m,7H),3.50(br d,3H,J=6.5Hz),2.2-2.8(m,11H),0.77(br t,3H,J=6.6Hz).

[0426] 5-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-2-yl)oxy)methyl)-5-methyldihydrofuran-2(3H)-one (Example 212) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (2.37 g, 7.54 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.70 g, 7.92 mmol) and DIPEA (2.90 g, 3.4 mL, 22.6 mmol) in acetonitrile (35 mL) was stirred at rt for 1 h. The precipitate was collected by filtration and washed with heptane. The filtrate was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated in vacuo to give tert-butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.70 g, 7.62 mmol, 101% yield) as a pale yellow solid, which was used directly in the next step without further purification. m / z (ESI, + ion): 490.0 (M+H). + .

[0427] Step 2: tert-Butyl (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A mixture of tert-butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.80 g, 1.63 mmol) and anhydrous potassium fluoride (0.14 g, 2.45 mmol) in dimethyl sulfoxide (6.0 mL) was stirred at 120° C. overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was concentrated with Na 2 SO 4Drying at 40° C. and evaporation in vacuo afforded tert-butyl (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.91 g), which was used in the next step without further purification. m / z (ESI, + ion): 473.0 (M+H). + .

[0428] Step 3: tert-Butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of tert-butyl (1R,5S)-3-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.91 g, 1.91 mmol) in tetrahydrofuran (8.0 mL) at 0° C. was added sodium methanethiolate (0.13 g, 1.91 mmol) in water (2.0 mL). The reaction was then stirred at rt for 4 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a gradient of 0-20% EtOAc in heptane to give tert-butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.44 g, 0.88 mmol, 46% yield) as a yellow solid. m / z (ESI, + ion): 501.0 (M+H). + .

[0429] Step 4: tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. In a vial, a mixture of tert-butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.44 g, 0.88 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.48 g, 1.33 mmol, LabNetwork), cataCXium A Pd G3 (0.13 g, 0.18 mmol, Sigma Aldrich Corporation), and potassium phosphate tribasic (0.56 g, 2.65 mmol) was suspended in degassed water (0.8 mL) and 1,4-dioxane (4.0 mL). The reaction was stirred at 90 °C for 1.5 h. The reaction mixture was concentrated and purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH in heptane with 2% triethylamine additive to give tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.46 g, 0.70 mmol, 79% yield) as a white solid. m / z (ESI, + ion): 655.2 (M+H). + .

[0430] Step 5: tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(methylsulfinyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a solution of tert-butyl (1R,5S)3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.46 mg, 0.70 mmol) in dichloromethane (3 mL) at 0° C. was slowly added 3-chloroperbenzoic acid (0.13 mg, 0.77 mmol) in dichloromethane (1.0 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH blend in heptane with 2% triethylamine additive to give tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(methylsulfinyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.38 g, 0.57 mmol, 81% yield) as a yellow solid. m / z (ESI, + ion): 671.2 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.79-7.85(m,2H),7.65(d,J=2.7Hz,1H),7.34(t,J=9.3Hz,1H),7.19(t,J=2.6Hz,1H),5.35(s,2H),4.60-4.79(m,2H),4.43(br s,2H),3.69-3.82(m,2H),3.53(s,3H),3.02(d,J=2.5Hz,3H),2.55-2.65(m ,1H),2.40-2.51(m,1H),1.78-2.03(m,4H),1.55(s,9H),0.76-0.88(m,3H).

[0431] Step 6: tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((2-methyl-5-oxotetrahydrofuran-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A mixture of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(methylsulfinyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.03 mmol), 5-(hydroxymethyl)-5-methyldihydrofuran-2(3H)-one (3.9 mg, 0.03 mmol), cesium carbonate (29 mg, 0.09 mmol), and 1,4-diazabicyclo[2.2.2]octane (0.7 mg, 5.96 μmol) in tetrahydrofuran (1.0 mL) and N,N-dimethylformamide (0.3 mL) was stirred at rt for 1 h. Volatiles were removed in vacuo and the crude residue was purified by column chromatography on silica gel eluting with a gradient of 0-18% MeOH in DCM to give tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((2-methyl-5-oxotetrahydrofuran-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the subsequent step. m / z (ESI, + ion): 737.2 (M+1). + .

[0432] Step 7: 5-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-2-yl)oxy)methyl)-5-methyldihydrofuran-2(3H)-one. To a solution of the above tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((2-methyl-5-oxotetrahydrofuran-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in MeCN (2.0 mL) was added HCl solution (4.0 M in dioxane, 0.2 mL, 0.95 mmol) at rt. The resulting mixture was stirred at rt for 1 h. The volatiles were removed under reduced pressure. The crude residue was purified by reverse phase HPLC to give 5-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-2-yl)oxy)methyl)-5-methyldihydrofuran-2(3H)-one as a TFA salt and as a white solid (2.5 mg, 0.004 mmol, 16% coupled yield over two steps). m / z (ESI, + ion): 593.2 (M+H). + . 1 H NMR (methanol-d 4 ,400MHz)δ 7.6-7.7(m,2H),7.31(d,1H,J=2.7Hz),7.25(t,1H,J=9.4Hz),6.98(d,1H,J=2.7Hz),4.5-4.7(m,4H),4.25(br s,2H),3.7-3.9(m,2H),2.8-2.9(m,1H),2.4-2.7(m,4H),2.1-2.3(m,5H),1.54(s,3H),0.7-0.9(m,3H).

[0433] [Table 71]

[0434] [Table 72]

[0435] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-((E)-3-hydroxy-3-methylbut-1-en-1-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 218) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((E)-3-hydroxy-3-methylbut-1-en-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A 5 mL conical microwave reaction vessel was charged with tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(methylthio)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (48 mg, 0.07 mmol), (3E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol (31 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 7.33 μmol, Strem), copper(I) thiophene-2-carboxylate (28 mg, 0.15 mmol, CombiBlocks) and THF (4.0 mL). The resulting mixture was purged with nitrogen for 5 min, then sealed and irradiated in a microwave at 90° C. for 1.5 h. Volatiles were removed under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0-90% MeOH in DCM to give tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((E)-3-hydroxy-3-methylbut-1-en-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white solid, which was used in the next step without further purification. m / z (ESI, + ion): 693.2 (M+H). + .

[0436] Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-((E)-3-hydroxy-3-methylbut-1-en-1-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol. To a stirred solution of the above tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-((E)-3-hydroxy-3-methylbut-1-en-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate in DCM (2.0 mL) was added TFA (1.50 g, 1.0 mL, 13.1 mmol) at rt. The resulting mixture was stirred at rt for 0.5 h. Volatiles were removed under reduced pressure. The crude residue was dissolved in MeOH / DCM, cooled in an ice bath, and then neutralized by the addition of ammonium hydroxide (1.0 mL). The resulting mixture was purified by column chromatography on silica gel eluting with a gradient of 0-100% MeOH in DCM with 0.5% ammonium hydroxide to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-((E)-3-hydroxy-3-methylbut-1-en-1-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (5 mg, 9.11 μmol, 13% coupled yield over two steps) as a white solid. m / z (ESI, + ion): 549.2 (M+H). + . 1 H NMR (methanol-d 4 ,400MHz)δ 7.68(dd,1H,J=6.0,9.1Hz),7.61(dd,1H,J=1.8,9.9Hz),7.33(d,1H,J=15.7Hz),7.30(d,1H,J=2.7Hz),7.24(t,1H, J=9.4Hz),7.01(d,1H,J=2.5Hz),6.69(d,1H,J=15.5Hz),4.4-4.5(m,2H),3.5-3.7(m,4H),2.3-2.7(m,2H),1.87(br s,4H),1.43(s,6H),0.81(t,3H,J=7.3Hz).

[0437] 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazoline-6-carbonitrile (Example 219) [ka] Step 1: tert-Butyl (1R,5S)-3-(6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A vial was charged with tert-butyl (1R,5S)-3-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (86 mg, 0.12 mmol, synthesized in a manner similar to Example 109), potassium ferrocyanide trihydrate (26 mg, 0.06 mmol), Na in dioxane (0.6 mL) and water (0.6 mL). 2 CO 3 (1.6 mg, 0.02 mmol) and 2-dicyclohexylphosphino-2',4',6',-triisopropylbiphenyl (12 mg, 0.03 mmol, Sigma Aldrich Corporation) were added. (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11 mg, 0.01 mmol, Sigma Aldrich Corporation) was then added. The vial was purged with Ar and the reaction was stirred at 90 °C for 1 h. The reaction was diluted with aqueous NaHCO 3 (5 mL), extracted with EtOAc (3 × 5 mL), and MgSO 4The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH in heptane to give tert-butyl (1R,5S)-3-(6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (72 mg, 0.11 mmol, 84% yield) as a light brown solid. m / z (ESI, + ion): 683.4 (M+H). + .

[0438] Step 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazoline-6-carbonitrile. To a vial was added tert-butyl (1R,5S)-3-(6-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (72 mg, 0.11 mmol) and TFA (0.24 mg, 0.2 mL, 2.09 mmol) in dichloromethane (1.0 mL). The reaction was stirred at 35° C. for 1 h. The reaction was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC. An acetonitrile / water solution of the product was dissolved in saturated NaHCO 3 (10 mL), extracted with EtOAc (3 x 10 mL), and MgSO 4The mixture was dried at 40° C. for 24 hours, filtered and concentrated in vacuo to give 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)quinazoline-6-carbonitrile (41 mg, 0.07 mmol, 67% yield) as a tan solid. m / z (ESI, + ion): 583.2 (M+H). + . 1 H NMR (400MHz, DMSO-d 6 )δ ppm 9.84-10.35(m,1H),8.38(s,1H),7.84(d,J=8.4Hz,1H),7.47(ddd,J=8.1,6.5,1.5Hz,1H),7. 33(d,J=2.3Hz,1H),7.23-7.32(m,2H),7.17(dd,J=2.3,0.8Hz,1H),5.18-5.39(m,1H),4.34- 4.48(m,2H),4.13(dd,J=10.5,4.2Hz,1H),4.04(dd,J=10.2,3.3Hz,1H),3.51-3.70(m,4H),2 .97-3.15(m,4H),2.78-2.90(m,1H),1.98-2.19(m,3H),1.74-1.90(m,3H),1.59-1.70(m,4H).

[0439] 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)isoquinolin-3-amine (Example 220) [ka] Step 1: (4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)boronic acid. A 20 mL vial was charged with tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 0.84 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.12 g, 0.17 mmol), potassium acetate (0.25 mg, 2.52 mmol) and bis(pinacolato)diboron (0.27 g, 1.05 mmol) in 1,4-dioxane (4.2 mL). The reaction was purged with nitrogen for 5 min and then stirred at 80° C. overnight. The reaction was then filtered through Celite and the plug was washed with EtOAc. The filtrate was then concentrated under reduced pressure. The crude material (0.72 g) was used in the subsequent step without further purification. m / z (ESI, + ion): 560.2 (M+H + ).

[0440] Step 2: tert-Butyl (1R,5S)-3-(7-(3-((tert-butoxycarbonyl)amino)isoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A vial containing (4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)boronic acid (0.05 g, 0.089 mmol), tert-butyl (1-bromoisoquinolin-3-yl)carbamate (0.040 g, 0.125 mmol), potassium phosphate tribasic (0.057 g, 0.27 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.013 g, 0.018 mmol, Sigma Aldrich) in dioxane (2 mL) and water (1 mL). The mixture with 1,2-dimethylformamide (Analytical Instruments Corporation) was purged with Ar, capped and stirred at 90 °C for 3 h. The reaction was then diluted with water and extracted with EtOAc. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc / EtOH in heptane (3:1) to give tert-butyl (1R,5S)-3-(7-(3-((tert-butoxycarbonyl)amino)isoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (27 mg, 0.036 mmol, 40% yield). m / z (ESI, + ion): 758.6 (M+H). + .

[0441] Step 3: 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)isoquinolin-3-amine. A mixture of tert-butyl (1R,5S)-3-(7-(3-((tert-butoxycarbonyl)amino)isoquinolin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (22 mg, 0.029 mmol) and TFA (0.099 g, 0.07 mL, 0.871 mmol) in DCM (2 mL) was stirred at rt for 2 h. The mixture was concentrated under reduced pressure. The resulting crude residue was purified by reverse phase HPLC to give 1-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)isoquinolin-3-amine tris(2,2,2-trifluoroacetate) (13 mg, 0.014 mmol, 50% yield). m / z (ESI, + ion): 558.3 ​​(M+H + ). 1 H NMR (400MHz, DMSO-d 6 )δ ppm 10.92-11.14(m,1H),9.35-9.54(m,1H),9.09-9.29(m,1H),7.92-8.03(m,1H),7.62-7.70(m,1H),7.29-7.54(m,4H),7.08-7.20( m,2H),6.80(s,2H),5.49-5.71(m,2H),4.61(s,6H),4.16-4.28(m,3H),3.68-3.97(m,7H),3.21-3.43(m,1H),2.11-2.40(m,4H).

[0442] [Table 73]

[0443] [Table 74]

[0444] 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-cyclopropyl-5-hydroxybenzonitrile (Example 227) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-(3-cyano-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. A vial was charged with tert-butyl (1R,5S)-3-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (41 mg, 0.055 mmol, synthesized in a manner similar to Example 109) in dioxane (0.3 mL) and water (0.3 mL). The vial was charged with 0.7 mg, 6.89 μmol), potassium ferrocyanide trihydrate (12 mg, 0.03 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (5 mg, 0.011 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (5 mg, 5.51 μmol). The vial was degassed and purged with nitrogen. The reaction was then sealed and stirred at 85° C. Upon completion, the reaction was brought to room temperature and concentrated under reduced pressure. The crude mixture was then purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH in heptane with 2% triethylamine additive to give tert-butyl (1R,5S)-3-(7-(3-cyano-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid, which was used in the next step without further purification.

[0445] Step 2: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-cyclopropyl-5-hydroxybenzonitrile. The above product tert-butyl (1R,5S)-3-(7-(3-cyano-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was dissolved in MeCN (2.5 mL). HCl solution (4M in dioxane, 0.3 mL, 1.38 mmol) was added and the reaction was stirred at 23 °C. After 1 h, the reaction was cooled to room temperature and concentrated under reduced pressure to give a crude mixture. The crude mixture was then purified by reverse phase HPLC to give 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-cyclopropyl-5-hydroxybenzonitrile as a TFA salt and a yellow liquid (2.2 mg, 0.004 mmol, 7% combined yield over two steps). m / z (ESI, + ion): 591.2 (M+H + ). 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.55-7.65(m,1H),7.14-7.19(m,1H),6.96-7.03(m,1H),5.20-5.41(m,1H),4.36-4.52(m,2H),4.19-4.32(m,2H),3.52-3.7 0(m,4H),3.15-3.29(m,3H),2.96-3.08(m,1H),2.09-2.44(m,3H),1.75-2.07(m,8H),0.61-0.74(m,2H),0.31-0.43(m,2H).

[0446] 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-chloro-5-(trifluoromethyl)pyridin-2-amine (Example 228) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-chloro-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. (4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)boronic acid (0.12 g, 0.21 mmol), cataCXium A Pd G3 (8.0 mg, 10.6 μmol, Sigma Aldrich Corporation), 4,6-dichloro-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.11 mmol, intermediate R) and tripotassium phosphate monohydrate (73 mg, 0.32 mmol) were stirred in degassed water (92 μL) and tetrahydrofuran (0.9 mL) at 70° C. for 6 h. The volatiles were removed in vacuo and the crude material was purified by elution with 0.5% 2N NH in MeOH. 3The crude product was purified by column chromatography on silica gel eluting with a gradient of 0-20% MeOH in CM to afford tert-butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-chloro-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, which was used directly in the next step.

[0447] Step 2: 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-chloro-5-(trifluoromethyl)pyridin-2-amine. tert-Butyl (1R,5S)-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-chloro-3-(trifluoromethyl)pyridin-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was stirred in TFA (1.0 mL) at 50° C. for 4 h. Volatiles were removed in vacuo and the crude residue was purified by reverse phase HPLC to afford 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-chloro-5-(trifluoromethyl)pyridin-2-amine as tetrakis(2,2,2-trifluoroacetate) and a colorless glassy material (18 mg, 0.017 mmol, 16% coupled yield over two steps). m / z (ESI, + ion): 610.0 (M+H) + ). 1 H NMR (400MHz, methanol-d 4)δ ppm 7.90(d,J=8.4Hz,1H),7.39(dd,J=8.7,6.8Hz,1H),6.84(s,1H),5.50-5.68(m,1H),4.70-4.73(m,3H),4.26(br s,2H),3.82-4.09(m,5H),3.46-3.56(m,1H),2.11-2.81(m,12H).

[0448] 6-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (Example 229) [ka] Synthesized in a manner similar to Example 228 using intermediate S. The product was isolated as the corresponding tetrakis(2,2,2-trifluoroacetate). m / z (ESI, + ion): 590.2 (M+H + ). 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.95(d,J=8.7Hz,1H),7.42(dd,J=8.6,6.7Hz,1H),6.83(s,1H),5.50-5.69(m,1H),4.69-4.78(m,4H),4.26(br s,2H),4.00-4.10(m,1H),3.87-3.98(m,4H),3.46-3.55(m,1H),2.34-2.80(m,9H),2.14-2.27(m,5H).

[0449] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 230) [ka] Step 1: To a stirred solution of 3-bromo-2-fluoro-5-methylaniline (1.00 g, 4.90 mmol, eNovation Chemicals LLC) in dichloromethane (8.0 mL) cooled in an ice bath was added a solution of ethoxycarbonyl isothiocyanate (0.60 g, 4.90 mmol, Sigma-Aldrich Corporation) in dichloromethane (5.0 mL). The resulting mixture was stirred at 0° C. for 5 min and then at rt for 4 h. The volatiles were removed and the crude was taken directly into the next step. m / z (ESI, + ions): 335.0 (M+H). + . 1 H NMR (chloroform-d, 400 MHz) δ 11.53 (br s, 1H), 7.9-8.3 (m, 2H), 7.25 (br d, 1H, J = 1.5 Hz), 4.32 (q, 2H, J = 7.1 Hz), 2.35 (s, 3H), 1.37 (t, 3H, J = 7.1 Hz).

[0450] Step 2: To a stirred solution of the above product in acetone (30 mL) at rt was added potassium carbonate (1.00 g, 7.35 mmol, Sigma-Aldrich Corporation) followed by iodoethane (0.90 g, 0.5 mL, 5.88 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at rt overnight. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 0-40% EtOAc in heptane to give the desired product (1.60 g, 4.32 mmol, 88% coupled yield over two steps) as a colorless liquid. m / z (ESI, + ions): 363.0 (M+H). + .

[0451] Step 3: A solution of the above product (1.70 g, 4.87 mmol) in diphenyl ether (8.0 mL) was subjected to microwave irradiation at 210 °C for 3 h. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane to give 7-bromo-2-(ethylthio)-8-fluoro-5-methylquinazolin-4(3H)-one (0.33 g, 1.03 mmol, 21% yield) as a white solid. m / z (ESI, + ion): 317.0 (M+H). + . 1 H NMR (chloroform-d, 400 MHz) δ 9.28 (br s, 1H), 7.29 (dd, 1H, J = 0.7, 6.2 Hz), 3.33 (q, 2H, J = 7.4 Hz), 2.77 (d, 3H, J = 0.8 Hz), 1.47 (t, 3H, J = 7.4 Hz).

[0452] Step 4: To a stirred solution of 7-bromo-2-(ethylthio)-8-fluoro-5-methylquinazolin-4(3H)-one (0.10 g, 0.32 mmol), triethylamine (80 mg, 0.1 mL, 0.79 mmol, Sigma-Aldrich Corporation) and 4-(dimethylamino)pyridine (3.9 mg, 0.03 mmol, Sigma-Aldrich Corporation) in DCM (2.5 mL) was added p-toluenesulfonyl chloride (0.12 mg, 0.63 mmol, Sigma-Aldrich Corporation) at rt. The resulting mixture was stirred at rt for 2 h. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc in heptane to give 7-bromo-2-(ethylthio)-8-fluoro-5-methylquinazolin-4-yl 4-methylbenzenesulfonate (99 mg, 0.21 mmol, 67% yield) as a colorless film. m / z (ESI, + ion): 470.8 (M+H). + .

[0453] Step 5: To a mixture of 7-bromo-2-(ethylthio)-8-fluoro-5-methylquinazolin-4-yl 4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (54 mg, 0.26 mmol, PharmaBlocks) was added isopropanol (2.0 mL) and DCM (0.20 mL) at rt. The resulting mixture was stirred at rt for 2.5 h. Additional amine (43 mg) was added and stirring was continued overnight. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-14% MeOH in DCM to give tert-butyl (1R,5S)-3-(7-bromo-2-(ethylthio)-8-fluoro-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.11 g, 0.21 mmol, 97% yield) as a white solid. m / z (ESI, + ion): 511.0 (M+H). + .

[0454] Step 6: To a stirred solution of tert-butyl (1R,5S)-3-(7-bromo-2-(ethylthio)-8-fluoro-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.11 g, 0.21 mmol) in DCM (3.0 mL) was added 3-chloroperbenzoic acid (48 mg, 0.22 mmol, Sigma-Aldrich Corporation) in one portion at 0 °C. The resulting mixture was stirred at 0 °C for 1.5 h. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-100% EtOAc in heptane to give tert-butyl (1R,5S)-3-(7-bromo-2-(ethylsulfonyl)-8-fluoro-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62 mg, 0.11 mmol, 56% yield) as a colorless film. m / z (ESI, + ion): 543.0 (M+H). + .

[0455] Step 7: To a stirred solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (33 mg, 0.21 mmol, LabNetwork) in THF (1.5 mL) was added dropwise potassium tert-butoxide in THF (1.0 M, 0.2 mL, 0.23 mmol, Sigma-Aldrich Corporation) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 15 min and slowly added to a stirred solution of tert-butyl (1R,5S)-3-(7-bromo-2-(ethylsulfonyl)-8-fluoro-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62 mg, 0.11 mmol) in tetrahydrofuran (2.0 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 30 min. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-18% MeOH in DCM to give tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.07 mmol, 65% yield) as a colorless film. m / z (ESI, + ion): 719.2 (M+H). + .

[0456] Step 8: A 5 mL conical microwave reaction vessel was charged with tert-butyl (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.07 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (47 mg, 0.13 mmol, LabNetwork), cataCXium A Pd G3 (9.6 mg, 0.01 mmol, Sigma Aldrich Corporation) and potassium phosphate tribasic (35 mg, 0.16 mmol, Acros Organics) followed by 1,4-dioxane (4.0 mL) and water (0.8 mL). The resulting mixture was purged with nitrogen for 10 min, then sealed and irradiated in a microwave at 80° C. for 2 h. Volatiles were removed under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0-17% MeOH in DCM to give tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as an off-white solid, which was taken on directly to the next step. m / z (ESI, + ion): 762.4 (M + H) + .

[0457] Step 9: To a stirred solution of tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (55 mg, 0.07 mmol) in MeCN (2.0 mL) at rt was added HCl in dioxane (4.0 M, 0.6 mL, 2.53 mmol, Sigma-Aldrich Corporation). The resulting mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure. The crude residue was dissolved in MeOH / DCM and cooled in an ice bath, then neutralized by the addition of ammonium hydroxide (1.0 mL). The resulting mixture was purified by column chromatography on silica gel eluting with a gradient of 2-20% MeOH with 0.5% ammonium hydroxide in DCM to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (28 mg, 0.05 mmol, 63% yield) as a white solid. m / z (ESI, + ion): 618.40 (M+H). + . 1 H NMR (methanol-d 4 ,400MHz)δ 7.63(dd,1H,J=6.0,9.1Hz),7.1-7.3(m,2H),7.04(br d,1H,J=6.3Hz),6.97(d,1H,J=2.5Hz),5.2-5.4(m,1H),4.3-4.7(m,1H),4.2-4.3(m,1H),4.2-4.2(m,1H),3.9-4.2(m,1H),3.74(br d,1H,J=2.1Hz),3.4-3.6(m,3H),3.1-3.3(m,3H),3.00(dt,1H,J=6.0,9.2Hz), 2.3-2.7(m,5H),1.8-2.3(m,6H),1.2-1.8(m,4H),0.77(dt,3H,J=1.5,7.3Hz).

[0458] 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 231) [ka] Synthesized from 3-bromo-2,5-difluoroaniline (eNovation Chemicals LLC) in a manner similar to Example 230. m / z (ESI, + ion): 622.3 (M+H) + . 1 H NMR (methanol-d 4 ,400MHz)δ 7.64(dd,1H,J=5.9,9.0Hz),7.2-7.3(m,2H),6.9-7.0(m,2H),5.1-5.4(m,1H),4.1-4.3(m,4H),3.4-3.6(m,4H),3.1-3 .3(m,3H),3.00(dt,1H,J=5.7,9.4Hz),2.4-2.6(m,2H),2.1-2.4(m,3H),1.7-2.0(m,7H),0.82(dt,3H,J=1.7,7.3Hz).

[0459] (M)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 232) [ka] Step 1: tert-Butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (1.00 g, 3.19 mmol, Enamine) in acetonitrile (16 mL) was added 8-Boc-3,8-diazabicyclo[3.2.1]octane (0.70 g, 3.34 mmol, Chem-Impex International, Inc.) and DIPEA (1.2 g, 1.7 mL, 9.56 mmol, Sigma-Aldrich Corporation). The reaction was then stirred for 1.5 h. The reaction was then diluted with water (50 mL) and brine (50 mL) and the aqueous layer was then purified by HCl distillation. 2 Cl 2 (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.70 g) as a pale yellow solid. The product was used without further purification. m / z (ESI, + ion): 488.8 (M+H). + .

[0460] Step 2: tert-Butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To a centrifugal vial was added tert-butyl (1R,5S)-3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.90 g, 3.82 mmol), cesium carbonate (3.70 g, 11.5 mmol, Sigma-Aldrich Corporation) and 1,4-diazabicyclo[2.2.2]octane (8.6 mg, 0.76 mmol, Sigma-Aldrich Corporation). The solid was then suspended in N,N-dimethylformamide (10 mL) and tetrahydrofuran (20 mL) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.90 g, 5.35 mmol, PharmaBlock) was added. The reaction mixture was then stirred at 35°C. After stirring for 22 h, the reaction was diluted with water (50 mL) and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude reaction mixture was then purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH with 2% triethylamine in heptane to give tert-butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.90 g, 3.16 mmol, 83% yield) as a yellow solid. m / z (ESI, + ion): 611.8 (M+H) + .

[0461] Step 3: tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. The vial was charged with tert-butyl (1R,5S)-3-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.40 g, 2.20 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.60 g, 4.41 mmol, LabNetwork), potassium phosphate (1.40 g, 6.61 mmol) and cataCXium A Pd G3 (0.3 g, 0.44 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and the reactant was suspended in degassed tetrahydrofuran (20 mL) and water (2.0 mL). The reaction 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, eluting with a gradient of 0-50% 3:1 EtOAc / EtOH (with 2% triethylamine) in heptane to give tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.50 g, 1.90 mmol, 86% yield) as an off-white foam. m / z (ESI, + ion): 766.2 (M+H). + .

[0462] Step 4: (M)-tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g) was purified using 80% CO with 0.2% diethylamine using a ChromegaChiral CCC column, 21 x 150 mm, flow rate of 80 mL / min. 2 and 20% isopropanol to yield 362 mg of peak 1 with >99% ee and 386 mg of peak 2 with >96% ee. Peak assignments were determined by SFC using a ChiraChromega CCC column, 80% CO2 and 20% methanol with 0.2% diethylamine in the mobile phase. Peak 2 was assigned to (M)-tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0463] Step 5: (M)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol. A vial was charged with (M)-tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (42 mg, 0.05 mmol) and the solid was dissolved in acetonitrile (1.7 mL). The solution was cooled to 0° C. and HCl in dioxane (4 M, 0.3 mL, 1.36 mmol) was added. The reaction was stirred for 15 min and then allowed to warm to room temperature. After stirring for an additional 15 min, the reaction was concentrated under reduced pressure and purified by reverse phase HPLC to give (M)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol as the bis(2,2,2-trifluoroacetate) (31 mg, 0.04 mmol, 68% yield) as a yellow solid. m / z (ESI, + ion): 622.2 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.71(s,2H)7.34(d,J=2.51Hz,1H)7.28(s,1H)6.94-7.03(m,1H)5.44-5.71(m,1H)4.70(d,J=4.81Hz, 4H)4.24-4.34(m,2H)3.82-4.11(m,5H)3.43-3.57(m,1H)2.53-2.82(m,3H)2.30-2.51(m,4H)2.20(br s,5H)0.82(t,J=7.42Hz,3H).

[0464] (M)-4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol (Example 233) [ka] Step 1: (M)-tert-Butyl (1S,4S)-5-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate. tert-Butyl (1S,4S)-5-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (60 mg, synthesized in a manner similar to Example 232) was purified by SFC using a mobile phase of 35% methanol with 0.2% triethylamine using a (S,S)Whelk-O1 21×500, 5 micron, 80 mL / min flow rate to produce 22 mg of peak 1 with >99% ee and 18 mg of peak 2 with >99% ee. Peak assignments were determined by SFC using (S,S)Whelk-O1 and 40% methanol with 0.2% triethylamine. Peak 2 was assigned to (M)-tert-butyl (1S,4S)-5-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate.

[0465] Step 2: (M)-4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol. A vial was charged with (M)-tert-butyl (1S,4S)-5-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (18 mg, 0.02 mmol) and the solid was dissolved in acetonitrile (0.8 mL). The solution was cooled to 0° C. and HCl in dioxane (4 M, 0.2 mL, 0.60 mmol) was added. The reaction was stirred for 15 min and then allowed to warm to room temperature. After 40 min, the reaction was concentrated under reduced pressure. The crude yellow solid was then purified by reverse phase HPLC to give (M)-4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol as the tris(2,2,2-trifluoroacetic acid) salt (5.6 mg, 5.87 μmol, 24% yield) as a yellow solid. m / z (ESI, + ion): 611.8 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.81-7.87(m,1H)7.60-7.69(m,1H)7.38-7.47(m,1H)7.34-7.38(m,1H)7.13-7.22(m,1H)5.45-5.71(m,1H)5.06-5.24(m,1H)4.63-4.7 5(m,2H)4.33-4.59(m,2H)3.78-4.12(m,5H)3.57-3.68(m,1H)3.43-3.54(m,1H)2.56-2.79(m,2H)2.30-2.56(m,4H)2.03-2.30(m,4H).

[0466] (M)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol. (Example 234) [ka] Step 1: (M)-tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxyquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. tert-Butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxyquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.12 g, synthesized in a manner similar to Example 199) was purified by SFC using a mobile phase of 30% 2-propanol with 0.2% triethylamine on a Chiralpak AD, 21×250 mm 5 μm column with a flow rate of 80 mL / min to produce peak 1 with 48.2 mg of >99% ee and peak 2 with 45.5 mg of >99% ee. Peak assignments were determined by SFC on a Chiralpak AD column using 30% 2-propanol with 0.2% triethylamine. Peak 1 was assigned to (M)-tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxyquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

[0467] Step 2: (M)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol. A vial was charged with (M)-tert-butyl (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-hydroxyquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (48 mg, 0.06 mmol), HCl in dioxane (4M, 0.3 mL, 1.26 mmol) and MeOH (0.3 mL). The reaction was stirred at rt for 1 h. The reaction was concentrated under reduced pressure. The crude product was then purified by reverse phase HPLC to give (M)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol as the bis(2,2,2-trifluoroacetic acid) salt (36 mg, 0.04 mmol, 67% yield) as a pale yellow solid. m / z (ESI, + ion): 620.0 (M+H). + . 1 H NMR (400MHz, methanol-d 4 )δ ppm 7.60-7.72(m,1H),7.27-7.33(m,2H),7.20-7.27(m,1H),6.92(d,J=2.5Hz,1H),5.46-5.66(m,1H),4.52-4. 73(m,4H),4.23-4.35(m,2H),3.71-4.07(m,5H),3.42-3.54(m,1H),2.10-2.79(m,13H),0.77-0.87(m,3H).

[0468] Biological evaluation In this section, a biological evaluation of the embodiments provided herein is provided.

[0469] KRAS G12D TR-FRET assay Compounds of interest were prepared in dose-response titrations in DMSO and 80 nL was added to each well of a 384-well plate (Perkin Elmer 6008280) by Labcyte Echo. His-tagged KRAS G12D protein (Amgen) was diluted in Assay Buffer (20 mM HEPES, pH 7.4, 10 mM MgCl 2 , 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 μM GDP) and 2 uL was added to the appropriate wells of a 384-well plate. Plates were incubated at room temperature for 30 minutes. Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in Assay Buffer and 2 μL was added to all wells and incubated at room temperature for 1 h. Detection Reagent (0.4 nM LANCE Eu-W1024 Anti-6xHis (Perkin Elmer AD0401), 5 nM Streptavidin-d2 (Cisbio 610SADLA)) was prepared in Assay Buffer and then 4 μL was added to the plate and incubated at room temperature for 1 h. Plates were read using a PerkinElmer EnVision (ex: 320 nm, em1: 665 nm, em2: 615 nm) and the em1 / em2 data was used to generate curve fits and calculate IC50 values ​​using a 4-parameter logistic model.

[0470] KRAS G12D-binding nucleotide exchange assay Purified GDP-bound KRAS protein (aa 1-169) containing both G12D and C118A amino acid substitutions and an N-terminal His tag was incubated in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl 2and 0.01% Triton X-100) for 2 h with compound dose-response titration. After compound pre-incubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 min. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa 1-149), nickel-chelating AlphaLISA acceptor beads (PerkinElmer AL108R) and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 min. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader using AlphaScreen® technology and the data were analyzed using a 4-parameter logistic model to determine IC 50 The value was calculated.

[0471] Phospho-ERK1 / 2 MSD assay A-427 (ATCC® HTB-53™) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1× Penicillin-Streptomycin-Glutamine (ThermoFisher Scientific 10378016). A-427 cells were seeded into 96-well cell culture plates at a density of 25,000 cells / well 16 hours prior to compound treatment and incubated at 37° C., 5% CO 2 Compound dose-response titrations were diluted in growth medium and added to appropriate wells of cell culture plates and then incubated at 37° C., 5% CO 2 After compound treatment, cells were incubated in ice-cold Dulbecco's phosphate-buffered saline, Ca 2+ or Mg 2+Cells were washed with PBS (ThermoFisher Scientific 14190144) and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1 / 2 in compound-treated lysates was assayed using the Phospho-ERK1 / 2 Whole Cell Lysate kit (Meso Scale Discovery K151DWD) according to the manufacturer's protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000 and data was analyzed using a 4-parameter logistic model to determine IC 50 The value was calculated.

[0472] Phospho-ERK1 / 2 MSD assay AsPC-1 (ATCC® CRL-1682™) cells were cultured in RPMI 1640 medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1× penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). AsPC-1 cells were seeded into 96-well cell culture plates at a density of 25,000 cells / well 16 h prior to compound treatment and incubated at 37° C., 5% CO 2 Compound dose-response titrations were diluted in growth medium and added to appropriate wells of cell culture plates and then incubated at 37° C., 5% CO 2 After compound treatment, cells were incubated in ice-cold Dulbecco's phosphate-buffered saline, Ca 2+ or Mg 2+Cells were washed with PBS (ThermoFisher Scientific 14190144) and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1 / 2 in compound-treated lysates was assayed using the Phospho-ERK1 / 2 Whole Cell Lysate kit (Meso Scale Discovery K151DWD) according to the manufacturer's protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000 and data were analyzed using a 4-parameter logistic model to determine IC 50 The value was calculated.

[0473] [Table 75]

[0474] [Table 76]

[0475] [Table 77]

[0476] [Table 78]

[0477] [Table 79]

[0478] [Table 80]

[0479] [Table 81]

[0480] [Table 82]

[0481] [Table 83]

[0482] [Table 84]

[0483] References All references cited in this specification, e.g., scientific publications or published patent applications, are incorporated by reference in their entirety for all purposes to the same extent as if each reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, 【Chemistry 2】 is a single bond or a double bond; W is C, CH or N; n is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; Each R ｘ is hydroxyl, halogen, oxo, cyano, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, -T-R ｙ or two R ｘ can be taken together to form a bridged ring, said bridge being -C １～４ Alkylene, —O—C １～４ Alkylene, -C １～４ Alkylene -O-C １～４ Alkylene- or -C １～４ Alkylene -S-C １～４ alkylene-; Z is CH, CR′ or N; R' is halogen, cyano or C １～４ is alkyl; L is a bond, C １～６ Alkylene, C １～６ Alkenylene, —O—C １～６ Alkylene, -S-C １～６ Alkylene, NR ｚ , O or S; R １ is hydroxyl, aryl, heteroaryl, C ３～８ Cycloalkyl or R ５ is heterocycloalkyl optionally substituted with 0-3 occurrences of R ２ is hydrogen, hydroxyl, halogen, amino, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C ３～８ cycloalkyl or cyano; R ３ is R ６ is an aryl or heteroaryl optionally substituted with 0-4 occurrences of R ４ is hydrogen, hydroxyl, halogen, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C ３～８ cycloalkyl or cyano; Each R ５ is halogen, hydroxyl, oxo, amino, C １～４ Alkyl or -T-R ｙ and Each R ６ is halogen, hydroxyl, amino, cyano, C １～４ Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C １～４ Haloalkyl or C ３～７ is cycloalkyl; R ７ is hydrogen, halogen or C １～４ is alkyl; T is for C １～４ Alkylene, —O—, —S— or —C １～４ alkylene-C(O)-; R ｙ is halogen, hydroxyl, cyano or amino; and R ｚ is hydrogen or C １～４ is alkyl; If W is N, then 【Chemistry 3】 is a single bond, m is 2, 3 or 4, and two R ｘ are taken together to form a bridged ring, said bridge being -C １～４ Alkylene, -C １～４ Alkylene -O-C １～４ Alkylene- or -C １～４ Alkylene -S-C １～４ alkylene-. or a pharma- ceutically acceptable salt of said compound.

2. R ３ The compound of claim 1 , wherein

3. The compound of claim 1, wherein Z is CH or CR'.

4. The compound of claim 3, wherein R' is fluorine, chlorine, methyl, ethyl or cyano.

5. The compound of claim 1 , wherein Z is N.

6. The compound of claim 1 , wherein W is N.

7. The compound of claim 1 , wherein n is 1.

8. The compound of claim 1 , wherein m is 2.

9. Two R's ｘ are taken together to form a bridged ring, said bridge being -C １～４ Alkylene, -C １～４ Alkylene-O-, -C １～４ Alkylene -O-C １～４ Alkylene-, -C １～４ Alkylene -S-C １～４ Alkylene- or -C １～４ 9. The compound of claim 8, wherein the alkylene-S- is selected from one of:

10. Two R's ｘ The compound of claim 9, wherein: taken together form a bridged ring, said bridge being selected from methylene, ethylene, propylene, or -methylene-O-methylene-.

11. The compound of claim 1 , wherein m is 3.

12. One R ｘ is halogen, C １～４ Alkyl, cyano, oxo or -T-R ｙ and the other two R ｘ are taken together to form a bridged ring, said bridge being -C １～４ Alkylene, or -O-C １～４ Alkylene, or -C １～４ Alkylene -O-C １～４ The compound of claim 11 which is alkylene-.

13. One R ｘ is fluorine, methyl, ethyl, cyano, oxo, -CH ２ OH or -CH ２ CN, and the other two R ｘ The compound of claim 12, wherein: taken together form a bridged ring, said bridge being methylene, ethylene, propylene or -methylene-O-methylene-.

14. The compound of claim 1 , wherein m is 4.

15. Two R's ｘ are each independently １～４ alkyl or halogen, and the other two R ｘ are taken together to form a bridged ring, said bridge being １～４ Alkylene or -C １～４ Alkylene -O-C １～４ The compound of claim 14 which is alkylene-.

16. W is C, and 【Chemistry 4】 The compound of claim 1 , wherein is a double bond.

17. 17. The compound of claim 16, wherein n is 1 and m is 2.

18. Two R's ｘ are taken together to form a bridged ring, said bridge being -C １～４ Alkylene or -C １～４ Alkylene -O-C １～４ 18. The compound of claim 17, wherein the aryl group is selected from one of: alkylene-.

19. Two R's ｘ are taken together to form a bridged ring, said bridge being selected from a single methylene, ethylene or -methylene-O-methylene-.

20. 【Chemical 5】 teeth, 【Chemistry 6】 2. The compound of claim 1 ,

21. [Chemical 7] teeth, 【Chemistry 8】 21. The compound of claim 20,

22. L is C １～６ Alkylene, —O—C １～６ Alkylene or C １～６ The compound of claim 1 which is an alkenylene.

23. 23. The compound of claim 22, wherein L is -O-methylene-, -O-ethylene-, -O-isopentanylene-, -On-propylene, -O-(2-methylpropylene)-, -O-(2-methylbutylene)-, -O-(2-ethylbutylene)-, -O-(1,2-dimethylpropylene)-, or -O-(3-methylbutylene)-.

24. R １ is hydroxyl, heterocycloalkyl or C ３～８ cycloalkyl, each heterocycloalkyl or C ３～８ Cycloalkyl is R ５ 2. The compound of claim 1, optionally substituted with 0 to 3 occurrences of:

25. R １ is hydroxyl, 7-(hexahydro-1H-pyrrolidine), 2-pyrrolidine, 2-tetrahydrofuranyl, 2-imidazolyl, cyclopropyl, cyclobutyl, or cyclopentyl.

26. R ５ are independently halogen, oxo, C １～４ 25. The compound of claim 24, which is alkyl or hydroxyl.

27. -L-R １ teeth, 【Chemistry 9】 2. The compound of claim 1 ,

28. -L-R １ teeth, 【Chemistry 10】 28. The compound of claim 27,

29. R ３ is R ６ 2. The compound of claim 1, wherein the aryl or heteroaryl is substituted with 0-3 occurrences of:

30. R ３ is R ６ 30. The compound of claim 29, which is phenyl or naphthyl substituted with 0 to 3 occurrences of:

31. R ３ is R ６ 30. The compound of claim 29, which is 8-quinolinyl, 5-quinolinyl, 4-isoquinolinyl, 1-isoquinolinyl, 8-isoquinolinyl, 4-(1H-indazolyl) or 7-(1H-indazolyl) substituted with 0 to 3 occurrences of:

32. Each R ６ is independently chlorine, fluorine, amino, cyano, methyl, ethyl, hydroxyl, ethenyl or ethynyl.

33. R ３ teeth, 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 2. The compound of claim 1 ,

34. R ３ teeth, 【Chemistry 14】 34. The compound of claim 33, wherein

35. R ２ The compound according to claim 1 , wherein is hydrogen, fluorine, chlorine, cyano, amino, methyl, ethyl or ethenyl.

36. R ４ The compound according to claim 1 , wherein is hydrogen, fluorine, methyl or hydroxyl.

37. R ７ The compound according to claim 1 , wherein is hydrogen, methyl or fluorine.

38. The following compound: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-methylquinazolin-7-yl)-5-ethynylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylphenol; 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylphenol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol; 3-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloro-4-cyclopropylphenol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-4-(1-fluoro-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5,6-difluoronaphthalen-2-ol; 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-fluoronaphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)naphthalen-2-ol; 4-(4-((1S,4S)-2,5-diazabicyclo[2.2.2]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-fluoronaphthalen-2-ol; 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; or 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-hydroxy-1-naphthonitrile 2. The compound of claim 1, wherein the compound is selected from one of the following:

39. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt of said compound and a pharma- ceutically acceptable excipient.

40. 40. A compound according to claim 1 or a tautomer thereof or a pharma- ceutically acceptable salt of said compound or a pharmaceutical composition according to claim 39 for use as a medicament.

41. 40. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, for use in the treatment of cancer.

42. 40. A compound according to claim 1 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, for use in the treatment of a cancer in which one or more cells express a KRAS G12D mutant protein.

43. 42. The compound or pharmaceutical composition for use according to claim 41, wherein the cancer is pancreatic cancer, colon cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary site, endometrial cancer, mixed type cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

44. 40. Use of a compound of claim 1 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition of claim 39 in the preparation of a medicament for treating cancer.

45. 40. Use of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12D mutant protein.

46. 45. The use of claim 44, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colon cancer, cancer of unknown primary, endometrial cancer, mixed type cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

47. 1. A pharmaceutical composition for use in a method of treating cancer in a subject in need thereof, comprising: The pharmaceutical composition comprises a therapeutically effective amount of a compound according to claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39; and 40. A pharmaceutical composition comprising administering to said subject a therapeutically effective amount of a compound of claim 1 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 39.

48. 1. A pharmaceutical composition for use in a method of treating cancer in a subject in need thereof, comprising: The pharmaceutical composition comprises a therapeutically effective amount of a compound according to claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 39; and 40. A pharmaceutical composition comprising administering to said subject a therapeutically effective amount of a compound of claim 1 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 39, wherein one or more cells express a KRAS G12D mutant protein.

49. 48. The pharmaceutical composition of claim 47, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colon cancer, cancer of unknown primary site, endometrial cancer, mixed type cancer, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia or melanoma.

50. 48. The pharmaceutical composition of claim 47, wherein the cancer is non-small cell lung cancer, colon cancer, pancreatic cancer, appendix cancer, endometrial cancer, esophageal cancer, cancer of unknown primary site, ampullary cancer, gastric cancer, small intestine cancer, paranasal sinus cancer, bile duct cancer or melanoma.

51. 51. The pharmaceutical composition of claim 50, wherein the cancer is non-small cell lung cancer.

52. 51. The pharmaceutical composition of claim 50, wherein the cancer is colon cancer.

53. 51. The pharmaceutical composition of claim 50, wherein the cancer is pancreatic cancer.

54. 48. The pharmaceutical composition of claim 47, wherein the subject has a cancer determined to have one or more cells that express the KRAS G12D mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

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