Heterocyclic compounds and methods of use

Abstract

The present disclosure provides compounds useful for inhibiting KRAS. The compounds have the general formula (I): where the variables of formula I are defined herein. The present disclosure also provides pharmaceutical compositions comprising the compounds, such as the use of the compounds and compositions for the treatment of cancer. TIFF2024532735000313.tif26170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 231,543, filed August 10, 2021, and U.S. Provisional Patent Application No. 63 / 289,576, filed December 14, 2021, each of which is incorporated by reference in its entirety.

[0002] The present disclosure provides compounds that have activity as inhibitors of G12D mutant KRAS protein. The present disclosure also provides pharmaceutical compositions containing 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]

[0003] Since its identification in 1982 as one of the first human cancer genes (Der et al., 1982), KRAS (Kirsten rat sarcoma viral oncogene homolog) has been the subject of extensive academic and industrial research as a key node in the MAPK signaling 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.

[0004] 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 GTP-bound states, leading to the accumulation of the GTP-bound active state and impaired cell proliferation (Simanshu et al., 2017).

[0005] Attempts to develop inhibitors of mutant KRAS proteins have historically been hampered by the absence of a druggable pocket on the protein surface (Cox et al., 2014). In 2013, Shokat et al. identified a covalent inhibitor of a common (O'Bryan, 2019) oncogenic mutant of KRAS, KRAS G12C, that bound to a previously unrecognized allosteric pocket on GDP-KRAS G12C and prevented subsequent activation (Ostrem et al., 2013). This discovery led to significant new efforts in the search for KRAS inhibitors, and has recently led to the entry of KRAS inhibitors into human clinical trials. [Prior art documents] [Non-patent literature]

[0006] [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] O'Bryan, 2019 [Non-Patent Document 10] Ostream et al., 2013 Summary of the Invention [Problem to be solved by the invention]

[0007] Although some progress has been made with respect to KRAS G12C inhibitors, there continues to be interest and effort in developing inhibitors of KRAS, particularly inhibitors of other KRAS such as KRAS G12D, G12V, G12A, G12S or G12C. Thus, there is a need to develop new inhibitors of KRAS G12D, G12V, G12A or G12S for the treatment of diseases such as cancer. [Means for solving the problem]

[0008] 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, and when W is CH or N, [ka] is a single bond; X is O, S, S(O), S(O)(NR z ), or S(O)2; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; Each R x is hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 3~6 Cycloalkyl, 5-7 membered heteroaryl, -TR y or two R x together with the adjacent carbon atom, C 3~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl, where each C 3~7 Cycloalkyl or 5- to 7-membered heterocycloalkyl is 0 to 3 R y or two R x can be taken together to form a bridged ring, the bridge being:-C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene-, -O-, -S-, or -C 1~4 Alkylene-SC 1~4 alkylene-, wherein each C 1~4 Alkylene is a group consisting of 0 to 2 R y is further replaced by the appearance of; L is for C 1~6 Alkylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O, or S, where each C 1~6 Alkylene, -OC 1~6 Alkylene, and -SC 1~6 The alkylene chain consists of 0 to 2 R 2 has been replaced by occurrences of; R 1is hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or 0 to 3 R 5 is a heterocycloalkyl substituted with occurrences of; R 2 is halogen, hydroxyl, C 1~4 alkyl or two R on the same or adjacent carbon atoms 2 Let's get together and 3~7 Can form a cycloalkyl; R 3 is aryl or 0 to 3 R 6 is heteroaryl substituted with 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 3~7 cycloalkyl or cyano; Each R 5 is halogen, oxo, hydroxyl, amino, cyano, or C 1~4 is alkyl; Each R 6 is halogen, hydroxyl, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 2~4 Alkynyl, or C 3~6 is cycloalkyl; T is for C 1~4 Alkylene, -S(O)2-, -C(O)-, -C 1~4 Alkylene-C(O)-, C 1~4 alkylene -S(O)-, or -S-; R y is a halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, hydroxyl, cyano, or -N(R z )2; R z is hydrogen or C 1~4 is alkyl] or a pharma- ceutically acceptable salt of said compound.

[0009] 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.

[0010] 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).

[0011] 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

[0012] As an embodiment, the present specification provides a compound represented by formula (I): [ka] [In the formula, [ka] is a single bond or a double bond; W is C, CH, or N, and when W is CH or N, [ka] is a single bond; X is O, S, S(O), S(O)(NR z ), or S(O)2; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; Each R x is hydroxyl, halogen, oxo, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 3~6 Cycloalkyl, 5-7 membered heteroaryl, -TR y or two R x together with the adjacent carbon atom, C 3~7 can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl, where each C 3~7 Cycloalkyl or 5- to 7-membered heterocycloalkyl is 0 to 3 R y or two R x can be taken together to form a bridged ring, the bridge being:-C 1~4 Alkylene, -C 1~4 Alkylene-OC 1~4 Alkylene-, -O-, -S-, or -C 1~4 Alkylene-SC 1~4 alkylene-, wherein each C 1~4 Alkylene is a group consisting of 0 to 2 R y is further replaced by the appearance of; L is for C 1~6 Alkylene, -OC 1~6 Alkylene, -SC 1~6 Alkylene, NR z , O, or S, where each C 1~6 Alkylene, -OC 1~6 Alkylene, and -SC 1~6 The alkylene chain consists of 0 to 2 R 2 has been replaced by occurrences of; R 1 is hydroxyl, aryl, heteroaryl, C 3~8 Cycloalkyl or 0 to 3 R 5is a heterocycloalkyl substituted with occurrences of; R 2 is halogen, hydroxyl, C 1~4 alkyl or two R on the same or adjacent carbon atoms 2 Let's get together and 3~7 Can form a cycloalkyl; R 3 is aryl or 0 to 3 R 6 is heteroaryl substituted with 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 3~7 cycloalkyl or cyano; Each R 5 is halogen, oxo, hydroxyl, amino, cyano, or C 1~4 is alkyl; Each R 6 is halogen, hydroxyl, cyano, -N(R z )2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 2~4 Alkynyl, or C 3~6 is cycloalkyl; T is for C 1~4 Alkylene, -S(O)2-, -C(O)-, -C 1~4 Alkylene-C(O)-, C 1~4 alkylene -S(O)-, or -S-; R y is a halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, hydroxyl, cyano, or -N(R z )2; R z is hydrogen or C 1~4 is alkyl] or a pharma- ceutically acceptable salt of said compound is provided.

[0013] As a second embodiment, the present invention relates to a compound in which L is 0 to 2 R 2 C replaced with occurrences of 1~6 As an embodiment, provided herein is a compound of embodiment 1, wherein L is an alkylene (e.g., methylene or ethylene). As an embodiment, provided herein is a compound of embodiment 3, wherein L is 0 to 2 R 2 Replaced by occurrence of -OC 1~6 As an embodiment 4, the present disclosure provides a compound of embodiment 1, wherein L is an alkylene (e.g., -O-methylene-, -O-ethylene-, or -On-propylene-). 2 As an embodiment 5, the compound of embodiment 3 is provided herein, wherein L is -O-ethylene or -On-propylene- substituted with 0 occurrences of R 2 The compound of embodiment 4 is provided, wherein the compound is -O-ethylene substituted with occurrences of:

[0014] As embodiment 6, the present specification provides 1 However, 0 to 3 R 5 As an embodiment 7, the present disclosure provides a compound of any one of embodiments 1 to 5, wherein R is a heterocycloalkyl substituted with an occurrence of 1 However, 0 to 3 R 5 As an embodiment 8, the compound of embodiment 6 is provided herein which is 7-(hexahydro-1H-pyrrolidine) substituted with an occurrence of R 1 But 0 R 5 As an embodiment 9, the compound of embodiment 7 is provided herein which is 7-(hexahydro-1H-pyrrolidine) substituted with an occurrence of R 1 But one R 5 As embodiment 10, the compound of embodiment 7 is provided herein which is 7-(hexahydro-1H-pyrrolidine) substituted with an occurrence of R 5 Compounds of embodiment 9 are provided, wherein is halogen (eg, fluorine).

[0015] As an eleventh embodiment, the present invention relates to a compound represented by the formula: 1 However, 0 to 3 R 5 As embodiment 12, the compound of embodiment 6 is provided herein, which is a 2-pyrrolidine or 3-pyrrolidine substituted with an occurrence of R 1 But one R 5 As embodiment 13, the compound of embodiment 11 is provided herein which is a 3-pyrrolidine substituted with occurrences of R 5 The compound of embodiment 12 is provided, wherein is cyano.

[0016] As embodiment 14, the present specification provides 1 But two R 5 As embodiment 15, the present disclosure provides a compound of embodiment 11, which is a 3-pyrrolidine substituted with one R 5 is methyl and other R 5 is cyano.

[0017] As embodiment 16, the present invention relates to a compound represented by the formula: 1 But two R 5 As embodiment 17, the compound of embodiment 11 is provided herein which is a 2-pyrrolidine substituted with occurrences of R 5 C 1~4 Compounds of embodiment 16 are provided in which one R is alkyl (e.g., methyl), oxo, cyano, or halogen (e.g., fluorine). 5 is methyl and other R 5 Compounds of embodiment 17, wherein R is fluorine. 5 is methyl and other R 5

[0046] 18. Compounds according to embodiment 17, wherein is oxo.

[0018] As an embodiment 20, the present invention relates to a compound in which L is selected from two R 2 As embodiment 21, provided herein is a compound of embodiment 3, which is -On-propylene substituted with occurrences of 2But together with the same carbon atom, C 3~7 Compounds of embodiment 20 are provided herein in which R is formed into a cycloalkyl (e.g., cyclopropyl). 1 However, 0 to 3 R 5 As embodiment 23, compounds of embodiment 21 are provided herein that are heterocycloalkyl substituted with occurrences of R (e.g., N-morpholinyl). 1 22. The compound of embodiment 21, wherein is hydroxyl.

[0019] As embodiment 24, the present specification provides -LR 1 but [ka] The compound of any one of embodiments 1-23 is provided, wherein

[0020] As embodiment 25, the present specification provides -LR 1 but [ka] 25. The compound of embodiment 24, wherein

[0021] As embodiment 26, the present invention relates to a compound represented by the formula: 1 but [ka] 25. The compound of embodiment 24, wherein As embodiment 27, the present specification provides -LR 1 but [ka] As embodiment 28, there is provided herein a compound of embodiment 24, wherein -LR 1 but [ka] As embodiment 29, provided herein is a compound of embodiment 24, wherein -LR 1 but [ka] As embodiment 30, provided herein is a compound of embodiment 24, wherein -LR 1 but [ka] As embodiment 31, provided herein is a compound of embodiment 24, wherein -LR 1 but [ka] As embodiment 32, provided herein is a compound of embodiment 24, wherein -LR 1 but [ka] As embodiment 33, provided herein is a compound of embodiment 24, wherein -LR 1 but [ka] As embodiment 34, there is provided herein a compound of embodiment 24, wherein -LR 1 but [ka] As embodiment 35, provided herein is a compound of embodiment 24, wherein -LR 1 but [ka] As embodiment 36, provided herein is a compound of embodiment 24, wherein -LR 1 but [ka] As embodiment 37, provided herein is a compound of embodiment 24, wherein -LR 1 but [ka] 25. The compound of embodiment 24, wherein

[0022] As embodiment 38, the present specification provides a method for the preparation of a compound comprising the steps of: 3 However, 0 to 3 R 6

[0043] There is provided a compound of any one of embodiments 1-37, wherein each occurrence of is substituted aryl (eg, phenyl or naphthyl).

[0023] As embodiment 39, the present specification provides a method for the preparation of a compound comprising the steps of: 3 But one R 6 As embodiment 40, provided herein is a compound of embodiment 38, wherein R is naphthyl substituted with an occurrence of 6 But halogen, amino, C 1~4 Alkyl (e.g., methyl), C 1~4 haloalkyl (e.g., trifluoromethyl or difluoromethyl), hydroxyl, or C 2~4 Provided herein as embodiment 39 is a compound where R is alkynyl (e.g., ethynyl). 6

[0082] There is provided a compound of embodiment 40, wherein is hydroxyl.

[0024] As embodiment 42, the present invention relates to a compound comprising R 3 But two R 6 As embodiment 43, provided herein is a compound of embodiment 40, wherein R is naphthyl substituted with an occurrence of 6 But, C 1~4 Alkyl, C 2~4 Alkynyl, C 3~6 Cycloalkyl, halogen, or -N(R z )2. As embodiment 44, compounds according to embodiment 42 are provided herein, wherein R 6is ethyl, ethynyl, cyclopropyl, fluorine, chlorine, hydroxyl, or -NH. 6 is ethynyl and other R 6 Compounds according to embodiment 42, wherein R is hydroxyl. 6 is ethyl, and the other R 6 Compounds of embodiment 42, wherein R is hydroxyl. 6 is ethyl, and the other R 6 Compounds according to embodiment 42, wherein R is fluorine. 6 Compounds according to embodiment 42, wherein R is fluorine are provided herein as embodiment 49, 6 is cyclopropyl, and the other R 6 Provided herein as embodiment 42 is a compound in which one R is hydroxyl. 6 is fluorine and other R 6 Compounds of embodiment 42, in which R is hydroxyl are provided herein as embodiment 51. 6 is chlorine and the other R 6 As embodiment 52, the present disclosure provides a compound of embodiment 42, wherein R is -NH2. 6 is ethynyl and other R 6

[0082] There is provided a compound of embodiment 42, wherein is fluorine.

[0025] As embodiment 53, the present invention relates to a compound comprising R 3 But, three R 6 As embodiment 54, provided herein is a compound of embodiment 40, wherein R is naphthyl substituted with an occurrence of 6 But, C 1~4 Alkyl, C 2~4 Compounds of embodiment 53 are provided herein, where R is alkynyl, halogen, or hydroxyl. 6Compounds according to embodiment 54, wherein R is ethyl, ethynyl, fluorine, or hydroxyl are provided herein as embodiment 56. 6 is hydroxyl and another R 6 is ethyl, and the last R 6 Compounds of embodiment 53, wherein is fluorine. As embodiment 57, compounds of embodiment 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 6 is hydroxyl and another R 6 is ethynyl and the last R 6 Compounds according to embodiment 53, wherein R is fluorine. 6 is halogen (e.g., fluorine or chlorine) and other R 6

[0046] Provided herein is a compound of embodiment 53, wherein is hydroxy.

[0026] As embodiment 59, the present specification provides a method for the preparation of a compound comprising the steps of: 3 But, three R 6 As embodiment 60, provided herein is a compound of embodiment 38, wherein the phenyl is substituted with one occurrence of R 6 is hydroxyl and another R 6 is cyclopropyl, and the last R 6 59. Compounds according to embodiment 59 are provided, wherein is chlorine.

[0027] As embodiment 61, the present invention relates to a compound represented by the formula: 3 However, 0 to 3 R 6 As embodiment 62, the present disclosure provides compounds of any one of embodiments 1 to 37, wherein R is a heteroaryl substituted with R (e.g., 4-(1H-indazole) or 4-benzo[d]thiazolyl). 3 But two R 6 As embodiment 63, provided herein is a compound of embodiment 61, which is a 4-(1H-indazole) substituted with one occurrence of R 6 is methyl and other R 6 Compounds of embodiment 62 are provided herein, in which R is chlorine. 3 But two R 6As embodiment 65, provided herein is a compound of embodiment 61, which is 4-benzo[d]thiazolyl substituted with one occurrence of R 6 is fluorine and other R 6 is -NH2.

[0028] As embodiment 66, the present specification provides a method for the preparation of a compound comprising the steps of: 3 but [ka] The compound of any one of embodiments 1-65 is provided, wherein

[0029] As embodiment 67, the present specification provides a method for the preparation of a compound comprising the steps of: 3 but [ka] 67. The compound of embodiment 66, wherein As embodiment 68, the present specification provides a method for the preparation of a compound comprising the steps of: 3 but [ka] As embodiment 69, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 70, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 71, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 72, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 73, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 74, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 75, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 76, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 77, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 78, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 79, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 80, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 81, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 82, provided herein is a compound of embodiment 66, wherein R 3 but [ka] As embodiment 83, provided herein is a compound of embodiment 66, wherein R 3 but [ka] 67. The compound of embodiment 66, wherein

[0030] As embodiment 84, the present specification relates to a compound wherein W is N; [ka] Compounds of any one of embodiments 1-83 are provided, wherein is a single bond.

[0031] As embodiment 85, provided herein is a compound of embodiment 84, wherein X is S. As embodiment 86, provided herein is a compound of embodiment 85, wherein n is 1 and m is 1. As embodiment 87, provided herein is a compound of embodiment 86, wherein p is 0. As embodiment 88, provided herein is a compound of embodiment 86, wherein p is 1. As embodiment 89, provided herein is a compound of embodiment 89, wherein R x Ga-TR y (e.g., CHOH). Provided herein as embodiment 90 is a compound of embodiment 85, where n is 1 and m is 2, or m is 1 and n is 2. Provided herein as embodiment 91 is a compound of embodiment 90, where p is 0.

[0032] Provided herein as embodiment 92 is a compound of embodiment 84, wherein X is S(O)2. Provided herein as embodiment 93 is a compound of embodiment 92, wherein n is 1 and m is 1. Provided herein as embodiment 94 is a compound of embodiment 92, wherein n is 1 and m is 2. Provided herein as embodiment 95 is a compound of embodiment 92, wherein n is 2 and m is 0. Provided herein as embodiment 96 is a compound of embodiment 93, 94, or 95, wherein p is 0.

[0033] As embodiment 97, provided herein is a compound of embodiment 93, wherein p is 2. As embodiment 98, provided herein is a compound of embodiment 93, wherein two R x are joined together to form a bridged ring, and the bridge is 0 to 2 R y Further replaced by the appearance of -C 1~4 Provided herein as embodiment 99 are compounds of embodiment 97, wherein R is an alkylene (e.g., methylene or ethylene). x are joined together to form a bridged ring, and the bridge is 0 R y is further substituted methylene or ethylene.

[0034] Provided herein as embodiment 100 is a compound of embodiment 84, where x is S(O). Provided herein as embodiment 101 is a compound of embodiment 100, where n is 1 and m is 1. Provided herein as embodiment 102 is a compound of embodiment 100, where n is 1 and m is 2. Provided herein as embodiment 103 is a compound of embodiment 101 or 102, where p is 0.

[0035] As described herein as embodiment 104, X is S(O)(NR z As embodiment 105, the compound of embodiment 84 is provided herein, wherein R zProvided herein as embodiment 104 is a compound of embodiment 104, wherein n is hydrogen. Provided herein as embodiment 106 is a compound of embodiment 105, wherein n is 1 and m is 1. Provided herein as embodiment 107 is a compound of embodiment 105, wherein n is 1 and m is 2. Provided herein as embodiment 108 is a compound of embodiment 106 or 107, wherein p is 0.

[0036] As embodiment 109, the present specification provides [ka] but [ka] The compound of any one of embodiments 1-83 is provided, wherein

[0037] As an embodiment 110, the present specification provides [ka] but [ka] As embodiment 111, provided herein is a compound of embodiment 109, wherein [ka] but [ka] As embodiment 112, provided herein is a compound of embodiment 109, wherein [ka] but [ka] As embodiment 113, provided herein is a compound of embodiment 109, wherein [ka] but [ka] Provided herein as embodiment 114 is a compound of embodiment 109, wherein [ka] but [ka] As embodiment 115, provided herein is a compound of embodiment 109, wherein [ka] but [ka] As embodiment 116, provided herein is a compound of embodiment 109, wherein [ka] but [ka] Provided herein as embodiment 117 is a compound of embodiment 109, wherein [ka] but [ka] Provided herein as embodiment 118 is a compound of embodiment 109, wherein [ka] but [ka] As embodiment 119, provided herein is a compound of embodiment 109, wherein [ka] but [ka] As embodiment 120, provided herein is a compound of embodiment 109, wherein [ka] but [ka] The compound of embodiment 109 is provided, wherein

[0038] As embodiment 121, provided herein is a compound of embodiment 84, where x is O. As embodiment 122, provided herein is a compound of embodiment 121, where n is 1 and m is 1. As embodiment 123, provided herein is a compound of embodiment 122, where p is 0.

[0039] As embodiment 124, provided herein is a compound of embodiment 122, wherein p is 1. As embodiment 125, provided herein is a compound of embodiment 122, wherein R x But, C 1~4 Alkyl, C 1~4 Haloalkyl, oxo, or -TR y Provided herein as embodiment 126 is a compound of embodiment 124, wherein -TR y Compounds according to embodiment 125 are provided herein, in which R is -CHCN, CHOH, -C(O)NH, or -CHOMe. x is methyl, difluoromethyl, -CH2CN, CH2OH, -C(O)NH2, or -CH2OMe.

[0040] As embodiment 128, provided herein is a compound of embodiment 122, wherein p is 2. As embodiment 129, provided herein is a compound of embodiment 122, wherein p is 2. x are joined together to form a bridged ring, and the bridge is 0 to 2 R y Further replaced by the appearance of -C 1~4 As embodiment 128, compounds are provided herein in which two R are selected from alkylene (e.g., methylene or ethylene). x are joined together to form a bridged ring, and the bridge is 0 R y is further substituted methylene or ethylene.

[0041] As an embodiment 131, the present invention relates to a compound having two R x Together with the adjacent carbon atom, 0 to 3 R y Further replaced by the appearance of C 3~7 Compounds according to embodiment 128 are provided herein in which two R x together with the adjacent carbon atom, 0 R y

[0073] There is provided a compound of embodiment 131, wherein occurrences of form a further substituted cyclopropyl.

[0042] As embodiment 133, provided herein is a compound of embodiment 122, wherein p is 3. As embodiment 134, provided herein is a compound of embodiment 122, wherein two R x are joined together to form a bridged ring, and the bridge is 0 to 2 R y Further replaced by the appearance of -C 1~4 As embodiment 135, provided herein is a compound of embodiment 133, wherein two R are selected from alkylene (e.g., -n-propylene-). x are joined together to form a bridged ring, and the bridge is one R y As embodiment 136, provided herein is a compound of embodiment 134, which is n-propylene- further substituted with occurrences of R y

[0046] Provided herein is a compound of embodiment 135, wherein is cyano.

[0043] As embodiment 137, the present specification provides [ka] but [ka] The compound of any one of embodiments 1-83 is provided, wherein

[0044] As embodiment 138, the present specification provides [ka] but [ka] Provided herein as embodiment 139 is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 140 is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 141 is a compound of embodiment 137, wherein [ka] but [ka] As embodiment 142, provided herein is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 143 is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 144 is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 145 is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 146 is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 147 is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 148 is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 149 is a compound of embodiment 137, wherein [ka] but [ka] Provided herein as embodiment 137 is a compound, wherein: [ka] but [ka] Provided herein as embodiment 151 is a compound of embodiment 137, wherein [ka] but [ka] The compound of embodiment 137 is provided, wherein

[0045] As embodiment 152, provided herein is a compound of embodiment 121, wherein n is 1 and m is 2. As embodiment 153, provided herein is a compound of embodiment 152, wherein p is 0. As embodiment 154, provided herein is a compound of embodiment 152, wherein p is 1. As embodiment 155, provided herein is a compound of embodiment 121, wherein n is 1 and m is 2. x But, Oxo, C 1~4 Alkyl, C 1~4Alkoxy, hydroxy, halogen, cyano, or -TR y As embodiment 156, provided herein is a compound of embodiment 154, wherein R x is methyl, cyano, oxo, hydroxy, methoxy, -C(O)N(H)(Me), -C(O)NH2, -CH2OH, or -SO2NH2.

[0046] As embodiment 157, provided herein is a compound of embodiment 152, wherein p is 2. As embodiment 158, provided herein is a compound of embodiment 152, wherein R x But hydroxy, halogen, C 1~4 Alkyl, C 2~4 Alkynyl, C 3~6 Cycloalkyl or two R x together form a bridged ring, and the bridge is -C 1~4 Compounds of embodiment 157 are provided herein, where R is alkylene (e.g., methylene). x Compounds according to embodiment 158, wherein R is hydroxy, methyl, ethyl, fluorine, ethynyl, or cyclopropyl are provided herein as embodiment 160. x is hydroxy and other R x Compounds according to embodiment 158, wherein R is methyl or ethyl are provided herein as embodiment 161. x is hydroxy and other R x Provided herein as embodiment 162 is a compound of embodiment 158, wherein R is cyclopropyl. x is hydroxy and other R x Compounds according to embodiment 158, wherein R is ethynyl. x

[0046] 158 is a compound of embodiment 158, wherein is fluorine.

[0047] As embodiment 164, the present disclosure provides a method for the preparation of a compound having two R x are joined together to form a bridged ring, and the bridge is 0 to 2 R yAs embodiment 165, compounds are provided herein in which R is a methylene further substituted with occurrences of x are joined together to form a bridged ring, and the bridge is 0 R y Provided herein as embodiment 166 are compounds of embodiment 164, wherein R is a methylene further substituted with occurrences of x are joined together to form a bridged ring, and the bridge is one R y Compounds according to embodiment 164 are provided, wherein the occurrence of is methylene further substituted.

[0048] As embodiment 167, provided herein is a compound of embodiment 121, wherein n is 2 and m is 2. As embodiment 168, provided herein is a compound of embodiment 167, wherein p is 2. As embodiment 169, provided herein is a compound of embodiment 121, wherein n is 2 and m is 2. x are taken together to form a bridged ring, and the bridge is -O- or -C 1~4 alkylene, -C 1~4 Alkylene is 0 to 2 R y Further replaced by the appearance of -C 1~4 Provided herein as embodiment 168 is a compound in which R is an alkylene. x Compounds according to embodiment 169 are provided in which R are joined together to form a bridged ring, and the bridge is -O-. As embodiment 171, compounds according to embodiment 172, x are joined together to form a bridged ring, and the bridge is one R y Provided herein as embodiment 172 are compounds of embodiment 169, wherein R is methylene further substituted with occurrences of y Compounds of embodiment 171 are provided, wherein is hydroxy.

[0049] As embodiment 173, the present specification provides [ka] but [ka] The compound of any one of embodiments 1-83 is provided, wherein

[0050] As embodiment 174, the present specification provides [ka] but [ka] As embodiment 175, provided herein is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 176 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 177 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 178 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 179 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 180, [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 181, [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 182, [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 183, wherein [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 184, [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 185, [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 186, [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 187, [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 188, [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 189, [ka] but [ka] Provided herein as embodiment 190 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 191 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 192 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 193 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 194 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 195 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 196 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 197 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 198 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 199 is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 200, [ka] but [ka] As embodiment 201, provided herein is a compound of embodiment 173, wherein [ka] but [ka] Provided herein as embodiment 173 is a compound, wherein: [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 203, [ka] but [ka] Provided herein as embodiment 173 is a compound of embodiment 204, [ka] but [ka] As embodiment 205, provided herein is a compound of embodiment 173, wherein [ka] but [ka] The compound of embodiment 173 is provided, wherein

[0051] As embodiment 206, the present specification provides a method for producing a compound comprising the steps of: 4 But, C 1~4 Alkyl, C 1~4 Alkoxy, hydroxyl, halogen, or C 1~4 As embodiment 207, provided herein is a compound of any one of embodiments 1 to 205, wherein R is haloalkyl. 4 But, C 1~4Compounds of embodiment 206 are provided, wherein R is alkyl, hydroxyl, or halogen. 4 But, C 1~4 Compounds of embodiment 207 are provided herein, wherein R is alkyl or halogen. 4 Compounds of embodiment 208 are provided in which R is halogen (e.g., fluorine or chlorine). 4

[0082] Provided herein is a compound of embodiment 209, wherein is fluorine.

[0052] As embodiment 211, the present specification relates to a compound having formula (II): [ka] The compound of embodiment 1 is provided, which is a compound of

[0053] As embodiment 212, the present specification relates to a compound having formula (III): [ka] The compound of embodiment 1 is provided, which is a compound of

[0054] As embodiment 213, the present specification relates to a compound having formula (IV): [ka] The compound of embodiment 1 is provided, which is a compound of

[0055] As embodiment 214, the present specification relates to a compound having formula (V): [ka] The compound of embodiment 1 is provided, which is a compound of

[0056] As embodiment 215, the present specification provides 3 but [ka] If [ka] but [ka] Provided is a compound of any one of embodiments 1-214, wherein:

[0057] As embodiment 216, the present specification provides 3 but [ka] If [ka] but [ka] Provided is a compound of any one of embodiments 1-214, wherein:

[0058] As embodiment 217, the present specification provides 3 but [ka] If [ka] but [ka] Provided is a compound of any one of embodiments 1-214, wherein:

[0059] As embodiment 218, the present specification provides 3 but [ka] If [ka] but [ka] Provided is a compound of any one of embodiments 1-214, wherein:

[0060] As embodiment 219, the present specification provides a method for producing a compound comprising the steps of: 3 but [ka] If [ka] but [ka] Provided is a compound of any one of embodiments 1-214, wherein:

[0061] As an embodiment 220, the present specification provides 3 but [ka] If [ka] but [ka] Provided is a compound of any one of embodiments 1-214, wherein:

[0062] As an embodiment 221, the present invention relates to a compound comprising R 3 but [ka] If [ka] but [ka] Provided is a compound of any one of embodiments 1-214, wherein:

[0063] As an embodiment 222, the present invention relates to a compound comprising R 3 but [ka] If [ka] but [ka] Provided is a compound of any one of embodiments 1-214, wherein:

[0064] As an embodiment 223, the present invention relates to a compound comprising R 3 but [ka] If [ka] but [ka] Provided is a compound of any one of embodiments 1-214, wherein:

[0065] As embodiment 224, the present specification relates to a compound comprising: 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholine; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)methanol; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(8-fluoro-2-((l-methylpyrrolidin-2-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 1-(4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)methanesulfonamide; (4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-2-yl)methanol; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carboxamide; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-(methylsulfonyl)-1,4-oxazepane; (4-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)methanol; 4-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(l,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(l,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[1,3d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; (S)-4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (R)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-bromo-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-bromo-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-(hydroxymethyl)-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (2R,6R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)-6-methyl-1,4-oxazepan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(2,2-dimethyl-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; or 4-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol The compound of embodiment 1 is provided, wherein:

[0066] As embodiment 225, the present specification provides a compound comprising 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholine; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)methanol; 4-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(8-fluoro-2-((l-methylpyrrolidin-2-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; or (S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol The compound of embodiment 1 is provided, wherein:

[0067] As embodiment 226, the present specification provides the following compound: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; or (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0068] As embodiment 227, the present specification provides the following compound: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; or 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0069] As embodiment 228, the present specification provides the following compound: (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 2); 5-ethyl-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-6-carboxamide (isomer 2); or 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0070] As embodiment 229, the present specification provides the following compound: (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; or 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2) The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0071] As embodiment 230, the present specification provides the following compound: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-thiomorpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.2.1]octan-8-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane; 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; (R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 4-(4-((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4R)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-methylpyrrolidin-2-one; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-3-carbonitrile; 5-ethyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-3-carbonitrile; (S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6 -Thiomorpholine 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1 λ 6,4-thiazepane 1-oxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thiomorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-2-carboxamide (isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-2-carboxamide (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-6-carboxamide (isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-6-carboxamide (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carboxamide (isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carboxamide (isomer 2); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-2-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylmorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-(methoxymethyl)morpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(7-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)morpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-sulfonamide; 4-(4-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 2-(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)acetonitrile; 4-(4-((1R,6S)-2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazepan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 1); 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 2); 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 6-cyclopropyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 4-(4-(2-(difluoromethyl)morpholino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholine-2-carboxamide; or 5-Ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0072] As embodiment 231, the present specification provides the following compound: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-thiomorpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.2.1]octan-8-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane; 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; (R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 4-(4-((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4R)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-methylpyrrolidin-2-one; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-3-carbonitrile; 5-ethyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-3-carbonitrile; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6 -Thiomorpholine 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6 ,4-Thiazepane 1-oxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thiomorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-2-carboxamide (isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-2-carboxamide (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-6-carboxamide (isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-6-carboxamide (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carboxamide (isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carboxamide (isomer 2); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 1); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-2-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylmorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-(methoxymethyl)morpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(7-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)morpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-sulfonamide; 4-(4-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 2-(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)acetonitrile; 4-(4-((1R,6S)-2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazepan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 1); 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 2); 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 6-cyclopropyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 4-(4-(2-(difluoromethyl)morpholino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholine-2-carboxamide; or 5-Ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0073] As embodiment 232, the present specification provides the following compound: 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-thiomorpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.2.1]octan-8-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane; 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4R)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-methylpyrrolidin-2-one; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-3-carbonitrile; 5-ethyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-3-carbonitrile; (S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ6 -Thiomorpholine 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6 ,4-Thiazepane 1-oxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thiomorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-2-carboxamide (isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-2-carboxamide (isomer 2); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-2-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylmorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-(methoxymethyl)morpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(7-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)morpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(4-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 2-(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)acetonitrile; 4-(4-((1R,6S)-2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazepan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 1); 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 2); 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 6-cyclopropyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 4-(4-(2-(difluoromethyl)morpholino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholine-2-carboxamide; or 5-Ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0074] As embodiment 233, the present specification provides the following compound: 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-thiomorpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.2.1]octan-8-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(8-fluoro-4-(1,4-oxazepan-4-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane; 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 4-(4-((1R,5S)-3,9-dioxa-7-azabicyclo[3.3.1]nonan-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-((1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-((1S,4R)-2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-5-methylpyrrolidin-2-one; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-3-carbonitrile; 5-ethyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-3-carbonitrile; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6 -Thiomorpholine 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ6 ,4-Thiazepane 1-oxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thiomorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-2-carboxamide (isomer 1); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-2-carboxamide (isomer 2); 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-2-carboxamide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-methylmorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-2-(methoxymethyl)morpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(7-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-ol; 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)morpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(4-((1R,5S)-9-oxa-3-azabicyclo[3.3.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 2-(4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholin-2-yl)acetonitrile; 4-(4-((1R,6S)-2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazepan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 1); 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 2); 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 6-cyclopropyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 4-(4-(2-(difluoromethyl)morpholino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholine-2-carboxamide; or 5-Ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0075] As embodiment 234, the present specification provides the following compound: (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 2); 5-ethyl-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-6-carboxamide (isomer 2); or 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0076] As embodiment 235, the present specification provides the following compound: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 2); 5-ethyl-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-1,4-oxazepane-6-carboxamide (isomer 2); or 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0077] As embodiment 236, the present specification provides the following compound: (S)-4-(8-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-4-(7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol; (S)-6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 2); 5-ethyl-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; or 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0078] As embodiment 237, the present specification provides the following compound: 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 3-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile (isomer 2); 5-ethyl-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; or 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-morpholinopyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The compound of embodiment 1 is provided, wherein the compound is selected from one of:

[0079] As embodiment 238, provided herein is a compound of embodiment 1, wherein the compound is not Example 42, 43, 49, 50, 63, 64, 74, 83, 111, 149, 195, 200, 201, 249, 269, 270, 271, 289, 291, 315, 321, 334, 342, 343, 345, 361, 386, 391, 400, 401, 419, 420, 457, 496, 497, 499, 501, or 522 from WO 2022 / 132200 (International Application No. PCT / US2021 / 010065).

[0080] As embodiment 239, provided herein is a compound of embodiment 1, wherein the compound is not Example 42, 43, 49, 50, 63, 64, 74, 83, 111, 149, 195, 200, or 201 from International Publication No. WO 2022 / 132200 (International Application No. PCT / US2021 / 010065).

[0081] The foregoing description merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way.

[0082] Formulation and Route of Administration In the disclosed use, the compound disclosed herein may be administered alone, but the compound administered will usually be present as an active ingredient in a pharmaceutical composition.Therefore, in one embodiment, the pharmaceutical composition provided herein comprises the compound disclosed herein in combination with one or more pharma- ceutically acceptable excipients such as diluents, carriers, adjuvants, and other active ingredients as necessary. See, for example, Remington: The Science and Practice of Pharmacy, Volume I and Volume II, 22nd Edition, 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), 1st Edition, Royal Society of Chemistry, edited by GD Tovey, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0083] The compounds disclosed herein may be administered by any suitable route of administration in the form of a pharmaceutical composition adapted for such route and in a dose effective for the intended treatment. The compounds and compositions provided herein may be administered, for example, orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, intravaginally, or by injection techniques in dosage unit formulations containing conventional pharma- ceutically acceptable excipients.

[0084] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, mini-tablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. Pharmaceutical compositions are typically made in the form of a dosage unit containing a particular amount of the active ingredient.

[0085] As embodiment 240, provided herein is a pharmaceutical composition comprising a compound of any one of embodiments 1-239, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, and a pharma- ceutically acceptable excipient.

[0086] As embodiment 241, there is provided herein a compound of any one of embodiments 1 to 239, or a tautomer thereof, or a pharma- ceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition of embodiment 240, for use as a medicament.

[0087] How to use As described herein (see the section entitled "Definitions"), the compounds described herein are understood to include all stereoisomers, tautomers, or pharma- ceutically acceptable salts of any of the above, or solvates of any of the above. Thus, the scope of the methods and uses provided in this disclosure should be understood to encompass methods and uses using all such forms.

[0088] 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.

[0089] In one embodiment, the present disclosure provides a method of using a compound or pharmaceutical composition of the present disclosure to treat a disease state, including but not limited to a condition (e.g., cancer) caused by a KRAS G12D, G12V, G12A, G12S, or G12C mutation, the type of cancer being non-small cell lung cancer, colorectal 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.

[0090] KRAS G12D mutations occur with the alteration frequencies shown in the table below (TCGA dataset; 1-3 For example, the table shows that 32.4% of subjects with pancreatic cancer have cancer in which one or more cells express the KRAS G12D mutant protein. G12D Compounds provided herein that bind to (see the section entitled "Biological Evaluation" below) are useful for treating subjects with cancers, including but not limited to those listed in the table below.

[0091] [Table 1]

[0092] As embodiment 242, there is provided herein a compound of any one of embodiments 1 to 239, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 240, for use in treating cancer.

[0093] As embodiment 243, there is provided herein a compound of any one of embodiments 1 to 239, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 240, for use in treating a cancer in which one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein.

[0094] As embodiment 244, there is provided herein a compound or pharmaceutical composition for use in embodiment 242 or 243, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary site, endometrial cancer, mixed type cancer of unknown primary site, 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.

[0095] As embodiment 245, provided herein is the use of a compound of any one of embodiments 1 to 239, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 240, in the preparation of a medicament for treating cancer.

[0096] As embodiment 246, there is provided herein the use of a compound of any one of embodiments 1 to 239, or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 240, in the preparation of a medicament for treating a cancer in which one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein.

[0097] As embodiment 247, the present specification provides the use of embodiment 245 or 246, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed type cancer of unknown primary, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

[0098] As embodiment 248, 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 of any one of embodiments 1 to 239, or a pharma- ceutically acceptable salt thereof.

[0099] As embodiment 249, provided herein is a method of treating cancer in a subject in need thereof, wherein one or more cells express a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 239, or a pharma- ceutically acceptable salt thereof.

[0100] As embodiment 250, the present specification provides the method of embodiment 248 or 249, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed type cancer of unknown primary, 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.

[0101] As embodiment 251, the present specification provides the method of embodiment 248 or 249, wherein the cancer is non-small cell lung cancer, colorectal 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.

[0102] As embodiment 252, provided herein is the method of embodiment 251, wherein the cancer is non-small cell lung cancer.

[0103] As embodiment 253, provided herein is the method of embodiment 251, wherein the cancer is colorectal cancer.

[0104] As embodiment 254, provided herein is the method of embodiment 251, wherein the cancer is pancreatic cancer.

[0105] As embodiment 255, provided herein is the method of any one of embodiments 248-254, wherein the subject has a cancer determined to have one or more cells expressing a KRAS G12D, G12V, G12A, G12S, or G12C mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

[0106] Combination therapy The present disclosure further provides a method of combination therapy in which an overlapping set of agents known to regulate other pathways, or other components of the same pathway, or even target enzymes, is used in combination with the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof. In one embodiment, such therapy 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 produce synergistic or additive therapeutic effects. See, for example, U.S. Patent No. 10,519,146 B2, issued Dec. 31, 2019, specifically sections 201 (line 37) to 212 (line 46) and 219 (line 64) to 220 (line 39), which are incorporated herein by reference.

[0107] As embodiment 256, provided herein is the method of any one of embodiments 248 to 255, 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.

[0108] 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.

[0109] Aurora kinase A inhibitors Provided herein is the method of any one of embodiments 248-255, 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.

[0110] 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-20 76 (6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide), TT-00420 (4-[9-(2-chlorophenyl)-6-methyl-2,4,5,8,12-pentazatricyclo[8.4.0.03,7]tetradeca-1(14),3 ,6,8,10,12-Hexaen-13-yl]morpholine), AMG900 (N-[4-[3-(2-aminopyrimidin-4-yl)pyridin-2-yl]oxyphenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine), MLN8054 (4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid), PF-03814735 (N-[2-[(1R,8S)-4-[[4-(cyclobutylamino)-5-(trifluorophenyl)

[0036] SNS-314 (1-(3-chlorophenyl)-3-[5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-1,3-thiazol-2-yl]urea), CYC116 (4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine), TAS-119, BI 811283, and TTP607.

[0111] AKT inhibitors Provided herein is the method of any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.

[0112] Exemplary AKT inhibitors for use in the methods provided herein include afarestib, 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 ter), ONC201 (11 benzyl-7-[2-methylphenyl)methyl]-2,5,7,11 tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one), ARQ751 (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.

[0113] Arginase inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.

[0114] Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidardistat and CB280.

[0115] CDK4 / 6 inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4 / 6 inhibitor.

[0116] As used herein, the term "CDK4 / 6" refers to cyclin-dependent kinases ("CDKs") 4 and 6, which are members of the mammalian serine / threonine protein kinases.

[0117] As used herein, the term "CDK4 / 6 inhibitor" refers to a compound capable of negatively regulating or inhibiting all or part of the enzymatic activity of CDK4 and / or 6.

[0118] 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]).

[0119] In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0120] ErbB family inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.

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

[0122] The term "ErbB family inhibitor" as used herein refers to an agent, e.g., a compound or an antibody, capable of negatively regulating or inhibiting all or part of the activity of at least one member of the ErbB family. The regulation or inhibition of one or more ErbB tyrosine kinases can occur by regulating or inhibiting the kinase enzymatic activity of one or more ErbB family members, or by blocking homodimerization or heterodimerization of ErbB family members.

[0123] In one embodiment, the ErbB family inhibitor is an EGFR inhibitor, such as an anti-EGFR antibody.Exemplary anti-EGFR antibodies 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.

[0124] 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.

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

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

[0127] 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, AV412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide), PF6274484 (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI357 ((E)-N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide).

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

[0129] In one embodiment, the ErbB family inhibitor is a reversible inhibitor. Exemplary reversible ErbB family inhibitors for use in the methods provided herein include erlotinib, gefitinib, sapitinib, valitinib, taloxotinib, 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), BMS599626 ((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 GW583340 (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[2-[(2-methylsulfonylethylamino)methyl]-1,3-thiazol-4-yl]quinazolin-4-amine).

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

[0131] ERK inhibitors Provided herein is the method of any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.

[0132] Exemplary ERK inhibitors for use in the methods provided herein include ulixertinib, ravosertinibe, 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- ... 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.

[0133] FAK inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.

[0134] 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.

[0135] FGFR inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.

[0136] 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 -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.

[0137] Glutaminase Inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.

[0138] Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP330.

[0139] IGF-1R inhibitors Provided herein is a method according to any one of embodiments 234-241, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.

[0140] 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.

[0141] KIF18A inhibitors Provided herein is a method according to any one of embodiments 248 to 255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.

[0142] 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.

[0143] MCL-1 inhibitors Provided herein is the method of any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.

[0144] Exemplary MEK inhibitors for use in the methods provided herein include murizatoclax, tapotoclax, AZD5991 ((3aR)-5-chloro-2,11,12,24,27,29 hexahydro-2,3,24,33 tetramethyl-22H-9,4,8-(metheniminomethyl)-14,20:26,23 dimetheno-10H,20H-pyrazolo[4,3-l][2,15,22,18,19]benzoxadithiadiazacitate, cyclohexacosine-32-carboxylic acid), MIK665 ((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.

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

[0146] MEK inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a MEK inhibitor.

[0147] 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-carboxylate), cyclosporine, ... ruboxamide), 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-dihydro

[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.

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

[0149] mTOR inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.

[0150] Exemplary mTOR inhibitors for use in the methods provided herein include everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pitilisib, 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-norpholin-4-yl-9-propan-2-ylpurin-6-yl)pyrimidin-2-amine).

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

[0152] PD-1 inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.

[0153] 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 the anti-PD-1 antibodies described in U.S. Pat. No. 10,640,504 B2 ("Anti-PD-1 Antibody A," column 66, line 56 to column 67, line 24, and column 67, lines 54-57), which are incorporated by reference herein.

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

[0155] PD-L1 inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising the simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.

[0156] 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.

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

[0158] PI3K inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.

[0159] Exemplary PI3K inhibitors for use in the methods provided herein include idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, ambralisib, pitilisib, dactolisib, boctalisib, 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]phenyl) N-[(1S)-1-[8-[2-(1-methylpyrazol-4-yl)ethynyl]-1-oxo-2-phenylisoquinolinyl-3-yl]pyrazolo[1,5-a]pyrazolopyrimidine-3-carboxamide), SF1126 (((2S)-2-[[(2S)-3-carboxy-2-[[2-[[(2S)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl) morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate), XL147 (N-[3-(2,1,3 benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide), GSK1059615 ((5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione) and AMG319 (N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine).

[0160] Raf kinase inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.

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

[0162] 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 capable of disrupting Raf homodimer or heterodimer formation to inhibit activity.

[0163] 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-pyridinyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide), LY3009120 (1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl) urea), Tak-632 (N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide), CEP-32496 (1-(3-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)-3-(5-(1,1,1 trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea), CCT196969 (1-(3-(tert-bu and RO5126766 (N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide).

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

[0165] SHP2 inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.

[0166] 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).

[0167] 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 [(2-amino-3-chloro-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).

[0168] 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 (C AS2240981-78-4), (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 (CAS2240982-45-8), (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]decane-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]-7-(2,3-dichlorophenyl)-6-methyl-pyrazolo[1,5-a]pyrazine-2-methanol (CAS 2240982-69-6). -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).

[0169] 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 (CAS2240981-78-4).

[0170] 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 2238840-54-3), 238840-56-5), 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]decane-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 223 8840-69-0), 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.

[0171] In one embodiment, the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS2238840-56-5).

[0172] In one embodiment, the 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.

[0173] SOS1 inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.

[0174] Exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3-yl]oxyquinazolin-4-amine) and BI1701963.

[0175] Src kinase inhibitors Provided herein is a method according to any one of embodiments 248-255, further comprising simultaneous, separate or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.

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

[0177] As used herein, the term "Src kinase inhibitor" 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.

[0178] 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), PP1 (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).

[0179] 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.

[0180] Chemotherapeutic agents Provided herein is a method according to any one of embodiments 248-255, 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.

[0181] 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.

[0182] definition The following definitions are provided to aid in understanding the scope of the present disclosure.

[0183] 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 otherwise indicated, 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.

[0184] As used herein, when any variable occurs more than one time in a chemical formula, its definition at 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 determines the identity of the compound.

[0185] 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. Accordingly, 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 (all or part) disclosed herein, unless the stereochemistry is specifically specified.

[0186] If the stereochemistry of a structure or portion of a structure is not shown, e.g., with bold or dashed lines, then the structure or portion of a structure is to be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or portion of a structure is not shown, e.g., with bold or dashed lines, then the structure or portion of a structure is to be interpreted as encompassing only the specified stereoisomer. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This wavy line should not be confused with a wavy line drawn perpendicular to a bond, which indicates where a group is attached to the remainder of the molecule.

[0187] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer of a compound (e.g., geometric isomer, enantiomer, diastereomer, and atropisomer) 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. Typical stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and about 20% or less by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and about 10% or less by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and about 5% or less by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and about 3% or less by weight of other stereoisomers of the compound.

[0188] 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 the pharmaceutical compositions or mixtures of stereoisomers described above. These stereoisomers or mixtures thereof can be synthesized according to methods well 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, e.g., 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).

[0189] 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, reference to a compound of a given structural formula should be understood to include 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.

[0190] 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 usually 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) is particularly useful for this purpose given its 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. 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 analogous to those described in the accompanying general synthetic schemes and examples, using suitable isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0191] solvate As mentioned 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.

[0192] As used herein, the term "solvate" refers to a molecular complex comprising a compound described herein or a pharma- ceutically acceptable salt thereof and a stoichiometric or non-stoichiometric amount of one or more pharma- ceutical acceptable solvent molecules. When the solvent is water, the solvate is referred to as a "hydrate."

[0193] Accordingly, the scope of the present disclosure should be understood to encompass all solvates of 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.

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

[0195] The term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in 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 heterocycloalkyl.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] As used herein, "C 2~4 The term "alkynyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with at least one carbon-carbon triple bond. This 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.

[0200] As used herein, the term "C 1~4 Alkoxy" or "C 1~6 "Alkoxy" refers to -OR, where R is as defined herein. # are C 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, isopropoxy, and butoxy. 1~6 Representative examples of alkoxy include, but are not limited to, ethoxy, propoxy, isopropoxy, and butoxy.

[0201] 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.

[0202] When used herein as a prefix for another term of a chemical group, the term "deuterium" refers to an atom or atoms that are deuterium ("D" or " 2 This refers to the modification of a chemical group in which the group is replaced with a fluorine-containing fluorine atom (H). For example, "C 1~4 The term "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 Representative examples of deuterated alkyls include, but are not limited to, -CH2D, -CHD2, -CD3, -CH2CD3, -CDHCD3, -CD2CD3, -CH(CD3)2, -CD(CHD2)2, and -CH(CH2D)(CD3).

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

[0204] The term "halo," as used herein as a prefix of another term for a chemical group, refers to a modification of that chemical group in which one or more hydrogen atoms have been replaced with a halogen, as defined herein. Each occurrence of a halogen is independently selected. For example, "C 1~4 The term "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 Representative examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3).

[0205] As used herein, the term "heteroaryl" refers to a 5-20 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 or 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.

[0206] The term "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, aliphatic, or heterocycloalkyl rings.

[0207] 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 may be bonded at a heteroatom or a carbon atom. Heterocycloalkyl may 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, morpholine, and the like.

[0208] As used herein, the term "pharmaceutical acceptable" generally refers to something that is recognized for use in subjects, particularly humans.

[0209] As used herein, the term "pharmaceutical acceptable salt" refers to a salt of a compound that is pharmaceutical acceptable and has the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions, or aluminum ions; or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, etc. Further 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).

[0210] As used herein, the term "pharmaceutical acceptable excipient" refers to a wide range 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-adhesive agents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

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

[0212] As used herein, the term "therapeutically effective amount" refers to an amount of a compound disclosed herein that elicits the biological or medical response in a tissue, system, or subject desired by a researcher, veterinarian, medical doctor, or other clinician.

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

[0214] In general, the compound of formula I can be synthesized according to the following scheme. Any variables used in the following scheme are defined as for formula I unless otherwise noted. 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 may be synthesized by using known procedures using conventional techniques. Starting materials can also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures, and reagents for the schemes described in this section can be found in the examples provided herein.

[0215] [ka] Compounds of formula (I) can be prepared according to Scheme I. In step A, compound (I-1) is treated with an aliphatic alcohol, such as benzyl alcohol, and a base, such as Hunig's base, or a metal alkoxide, such as potassium tert-butoxide, in a solvent, such as 1,4-dioxane, to give compound (I-2). In step B, compound (I-2) is treated with an aliphatic alcohol, such as benzyl alcohol, and a base, such as Hunig's base, in a solvent, such as acetonitrile, to give compound (I-3). 1 -LH-bearing nucleophiles and S N In step C, compound (I-3) is coupled with an organometallic reagent, i.e., a boronic acid (ester), to give compound (I-4). The coupling reaction proceeds in a mixture of solvents, such as 1,4-dioxane and water, and a catalyst, such as cataCXium A Pd G3, with or without a base, such as potassium phosphate. In step D, compound (I-4) is treated with a suitable set of reagents, such as Pd / C with H2 to remove the alkyl group R to give compound (I-5). In step E, compound (I-5) is treated with an optionally substituted cyclic amine in the presence of a coupling reagent, such as HATU, and a base, such as Hunig's base, in a solvent, such as DMA, to give a compound of formula (I). Optionally, R 3 The species includes a protecting group, which can be removed during step D or after step E of the synthetic sequence.

[0216] [ka] Compounds of formula (I) can also be prepared according to Scheme II. In step A, compound (1) is reacted with an optionally substituted cyclic amine and S in the presence of a base such as Hunig's base in a solvent such as dichloromethane. N In step B, compound (I-10) is reacted with 1,2-dichlorophenyl ether to obtain a compound (I-10) of formula R 1 -LH-bearing nucleophiles and S NIn step C, compound (I-11) is coupled with an organometallic reagent, i.e., a boronic acid (ester), to give a compound of formula (I). This coupling reaction proceeds in a mixture of solvents, such as 1,4-dioxane and water, and a catalyst, such as cataCXium A Pd G3, with or without a base, such as potassium phosphate. In some cases, R 3 The species includes a protecting group, which can be removed after step C of the synthetic sequence. EXAMPLES

[0217] This section provides specific examples of compounds of Formula I and methods for their preparation.

[0218] [Table 2]

[0219] [Table 3]

[0220] [Table 4]

[0221] 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.

[0222] Chromatography: Unless otherwise indicated, residues containing crude product were purified by passing the crude material or concentrate through a Biotage or ISCO brand silica gel column pre-packed with flash silica (SiO2) and the product was eluted from the column with a solvent gradient as indicated.

[0223] Preparative HPLC Method: Where indicated, compounds described herein were purified by reversed-phase HPLC on a Waters FractionLynx or Gilson semi-preparative HPLC-MS system using one of two HPLC columns: (a) a Phenomenex Gemini column (5 microns, C18, 150×30 mm) or (b) a Waters X-select CSH column (5 microns, C18, 100×30 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.

[0224] Proton NMR spectra: All unless otherwise indicated. 1 H NMR spectra were collected at 300, 400 or 500 MHz on a Bruker NMR instrument. All observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as reference. Some protons may be due to exchange with D from MeOD or signal suppression. 1 The H signal may be lost.

[0225] Mass Spectrum (MS): Unless otherwise indicated, all mass spectrum data of starting materials, intermediates and / or exemplary compounds are reported as mass / charge (m / z) with [M+H]+ molecular ion. Reported molecular ions were obtained by electrospray detection (commonly referred to as ESI MS) using a Waters Acquity UPLC / MS system. As will be appreciated by those skilled in the art, compounds with isotopic atoms such as bromine are typically reported according to the detected isotopic pattern.

[0226] Preparation of intermediates 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (Intermediate A) [ka] Step 1: 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a 250 mL round bottom flask charged with activated 3A molecular sieves was added 1,4-dioxane (48 mL), DIPEA (9.22 g, 12.5 mL, 71.3 mmol), benzyl alcohol (3.86 g, 3.7 mL, 35.7 mmol), and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (6.00 g, 23.8 mmol). The mixture was stirred at 85° C. for 2 h. The volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel eluting with 0-100% 3:1 EtOAc / EtOH in heptane to give 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (3.30 g, 10.18 mmol, 43% yield). m / z (ESI): 325.9 (M+H). + .

[0227] Step 2: 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (3.30 g, 10.18 mmol) in acetonitrile (20 mL) was added ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.78 g, 11.20 mmol) and DIPEA (5.26 g, 7.1 mL, 40.7 mmol). The reaction was stirred at 80° C. for 1 h. The volatiles were removed under reduced pressure and the mixture was purified by column chromatography on silica gel eluting with 0-100% 3:1 EtOAc / EtOH blend in heptane with 2% triethylamine additive to give 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.60 g, 5.82 mmol, 57% yield). m / z (ESI): 447.0 (M+H). + .

[0228] Step 3: 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. To a solution of 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.60 g, 5.82 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.14 g, 8.73 mmol) in tetrahydrofuran (17 mL) and water (1.7 mL) was added potassium phosphate (3.70 g, 17.45 mmol) and cataCXium A Pd G3 (0.85 g, 1.16 mmol). The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was purified by column chromatography on silica gel eluting with 0-50% 3:1 EtOAc / EtOH blend in heptane with 2% triethylamine additive to give 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.42 g, 3.75 mmol, 65% yield). m / z (ESI): 645.0 (M+H). + .

[0229] Step 4: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. 4-(benzyloxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (2.42 g, 3.75 mmol) was dissolved in ethyl acetate (75 mL). Palladium on activated carbon (0.80 g, 0.75 mmol) was added and the mixture was stirred at room temperature under H2 atmosphere overnight. The mixture was filtered over Celite and the filter cake was washed with DCM:MeOH (2:1) until the filtrate was clear. The volatiles were removed in vacuo to give 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol as a slightly brown foam which was used without further purification. m / z(ESI): 555.0(M+H). + .

[0230] 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (Intermediate B) [ka] Step 1: 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine. To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.50 g, 9.90 mmol) in THF (3.5 mL) at -40°C, potassium tert-butoxide (1.0 M in THF, 14.9 mL, 14.85 mmol) was added slowly over 0.5 h. Additional 2-methyl-2-propanol potassium salt, 1.0 M in THF (2.5 mL) was added after 1 h. The resulting mixture was stirred at -40°C for 10 min, then poured onto ice and extracted with saturated aqueous ammonium hydroxide followed by EtOAc. The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 0-20% EtOAc in heptane to give 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (1.12 g, 3.86 mmol, 39% yield). m / z (ESI): 234.0 (M- t Bu+H) + .

[0231] Step 2: 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. A mixture of 4-(tert-butoxy)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (0.58 g, 2.00 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.45 g, 2.80 mmol), and 1,1'-dimethyltriethylamine (1.03 g, 1.4 mL, 8.00 mmol) in MeCN (6.0 mL) in a 10 mL microwave reaction vessel was subjected to microwave irradiation (75° C. for 16 h). Volatiles were removed under reduced pressure and the crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-50% (20% MeOH in DCM) in DCM to give 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.66 g, 1.60 mmol, 80% yield) as an off-white solid. m / z (ESI): 413.2 (M+H). + .

[0232] Step 3: 4-(tert-butoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine. A 5 mL microwave reaction vessel was charged with 4-(tert-butoxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.66 g, 1.60 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.92 g, 2.56 mmol), cataCXium A Pd G3 (0.23 g, 0.32 mmol), and potassium phosphate tribasic (0.85 g, 4.00 mmol), followed by 1,4-dioxane (10 mL) and water (1.8 mL). The resulting mixture was purged with nitrogen for 10 minutes, then sealed and microwaved at 85° C. for 3 hours. Volatiles were removed under reduced pressure and the crude residue was purified by column chromatography on silica gel eluting with a gradient of 0-50% (20% MeOH in DCM) in DCM to give 4-(tert-butoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.84 g, 1.38 mmol, 86% yield) as a colorless film. m / z (ESI): 611.2 (M+H). + .

[0233] Step 4: 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol. To a stirred solution of 4-(tert-butoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (0.84 g, 1.38 mmol) in MeCN (2.0 mL) was added a 4.0 M solution of HCl in dioxane (12 mL, 48.1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. Volatiles were removed under reduced pressure. The crude residue was dissolved in MeOH / DCM, cooled in an ice bath, neutralized with ammonium hydroxide, then loaded onto a silica gel precolumn and purified by column chromatography on silica gel eluting with a gradient of 0-50% in DCM (20% MeOH in DCM) to give 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (0.39 g, 0.76 mmol, 56% yield) as an off-white solid. m / z (ESI): 511.0 (M+H). + .

[0234] N-Methyl-1,4-oxazepane-2-carboxamide hydrochloride (Intermediate C1) [ka] Step 1: tert-Butyl 2-(methylcarbamoyl)-1,4-oxazepane-4-carboxylate. 4-[(tert-butoxy)carbonyl]-1,4-oxazepane-6-carboxylic acid (0.20 g, 0.82 mmol, AA Blocks), methylamine hydrochloride (0.10 g, 3.26 mmol, Spectrum Chemicals), DIPEA (0.43 mL, 2.45 mmol), and HATU (0.37 g, 0.98 mmol) were dissolved in DMF (4.0 mL). The reaction was stirred at room temperature for 16 h. Upon completion, the mixture was loaded onto a reverse phase column and purified by reverse phase HPLC to give tert-butyl 2-(methylcarbamoyl)-1,4-oxazepane-4-carboxylate (0.21 g, 0.82 mmol, 100% yield) as a colorless oil.

[0235] Step 2: N-Methyl-1,4-oxazepane-2-carboxamide hydrochloride. tert-Butyl 2-(methylcarbamoyl)-1,4-oxazepane-4-carboxylate (0.21 g, 0.82 mmol) was dissolved in 2.0 mL of MeCN and HCl (4.0 M in dioxane, 0.61 mL, 2.45 mmol). The reaction was stirred at room temperature for 30 minutes. Upon completion, the mixture was concentrated to give N-methyl-1,4-oxazepane-2-carboxamide (0.13 g, 0.82 mmol, 100% yield) as a white solid, which was used in the subsequent step without purification. m / z (ESI): 159.1 (M+H). + .

[0236] [Table 5] (1,4-Oxazepan-2-yl)methanol hydrochloride (Intermediate D1)

[0237] [ka]

[0238] Step 1: 4-(tert-Butyl) 2-methyl 1,4-oxazepane-2,4-dicarboxylate. To a 100 mL round bottom flask was added 4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (0.50 g, 2.04 mmol, enamine), toluene (10 mL), and DBU (0.31 g, 0.31 mL, 2.04 mmol). To the mixture was added MeI (0.38 mL, 6.12 mmol) and the reaction was stirred at room temperature for 16 h. Upon completion, the reaction was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a gradient of 0-100% EtOAc in heptane to give 4-(tert-butyl) 2-methyl 1,4-oxazepane-2,4-dicarboxylate (0.48 g, 1.86 mmol, 91% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d): δ ppm 4.07-4.38 (m, 3H), 3.79 (m, 4H), 3.55-3.72 (m, 1H), 3.07-3.36 (m, 2H), 1.86-2.06 (m, 2H), 1.49 (s, 9H).

[0239] Step 2: (1,4-Oxazepan-2-yl)methanol hydrochloride. To a 100 mL round bottom flask was added 4-(tert-butyl) 2-methyl 1,4-oxazepane-2,4-dicarboxylate (0.48 g, 1.86 mmol), THF (9.0 mL), and lithium aluminum hydride (2.0 M in THF, 1.88 mL, 3.77 mmol). The mixture was stirred at room temperature for 2 h. After completion, the mixture was quenched with saturated aqueous Rochelle's salt (0.5 mL) and stirred for an additional 1 h. The reaction mixture was then filtered through a Celite plug and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was redissolved in DCE (5 mL) and HCl (4.0 M in dioxane, 1.39 mL, 5.56 mmol). The reaction was stirred at room temperature for 2 h. Upon completion, the reaction was concentrated to give (1,4-oxazepan-2-yl)methanol hydrochloride (0.24 g, 1.85 mmol, 99% yield) as a white solid, which was used in the subsequent step without further purification. m / z (ESI): 132.2 (M+H). + .

[0240] (1,4-Oxazepan-6-yl)methanol hydrochloride (Intermediate D2) [ka] Synthesized in a similar manner to intermediate D1 using 4-(tert-butoxycarbonyl)-1,4-oxazepane-6-carboxylic acid (CAS#: 1269755-58-9, enamine).

[0241] Thiomorpholin-2-ylmethanol hydrochloride (Intermediate E) [ka] To a 100 mL round bottom flask was added 4-(tert-butyl) 2-ethylthiomorpholine-2,4-dicarboxylate (0.50 g, 1.82 mmol, Accela), THF (9.0 mL), and lithium aluminum hydride (2.0 M in THF, 1.82 mL, 3.63 mmol). The mixture was stirred at room temperature for 2 h. After completion, the mixture was quenched with saturated aqueous Rochelle's salt (0.5 mL) and stirred for an additional 1 h. The reaction mixture was then filtered through a Celite plug and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was redissolved in DCE (5 mL) and HCl (4.0 M in dioxane, 1.36 mL, 5.45 mmol). The reaction was stirred at room temperature for 2 h. Upon completion, the reaction was concentrated to afford thiomorpholin-2-ylmethanol (0.24 g, 1.80 mmol, 99% yield) as a white solid which was used in the subsequent step without further purification. 1 H NMR (400 MHz, methanol-d4): δ ppm 3.73-3.82 (m, 1H), 3.64-3.73 (m, 2H), 3.53-3.61 (m, 1H), 3.17-3.26 (m, 2H), 3.14-3.30 (m, 1H), 2.92-3.05 (m, 2H).

[0242] 3-Oxa-7-azabicyclo[3.3.1]nonan-9-ol (Intermediate F) [ka] To a 25 mL round bottom flask was added tert-butyl 9-hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate (0.20 g, 0.82 mmol, Ambeed), DCM (4.0 mL), and HCl solution (4.0 M in dioxane, 0.62 mL, 2.47 mmol). The mixture was stirred at room temperature for 4 h. Upon completion, the reaction was concentrated to give 3-oxa-7-azabicyclo[3.3.1]nonan-9-ol (0.12 g, 0.82 mmol, 100% yield), which was used in the subsequent step without further purification. m / z (ESI): 144.1 (M+H). + .

[0243] 2-(((tert-Butyldimethylsilyl)oxy)methyl)morpholine (Intermediate G) [ka]

[0244] Morpholin-2-ylmethanol (0.38 g, 3.21 mmol, Combi Blocks) was dissolved in dichloromethane (16 mL). Triethylamine (0.49 g, 0.67 mL, 4.82 mmol) was added and the solution was cooled to 0° C. tert-Butylchlorodimethylsilane (0.53 g, 3.53 mmol) was added in one portion and the mixture was allowed to warm to room temperature and stirred overnight. The crude mixture was loaded directly onto silica gel and purified by column chromatography on silica gel eluting with a gradient of 0-35% MeOH in DCM to give 2-(((tert-butyldimethylsilyl)oxy)methyl)morpholine (0.45 mg, 1.94 mmol, 60% yield). m / z (ESI): 232.2 (M+H) + .

[0245] 1,4-Oxazepane-6-carbonitrile (Intermediate H) [ka] Step 1: tert-Butyl 6-carbamoyl-1,4-oxazepane-4-carboxylate. 4-[(tert-butoxy)carbonyl]-1,4-oxazepane-6-carboxylic acid (0.20 g, 0.82 mmol), ammonium chloride (0.40 g, 7.48 mmol), DIPEA (0.32 g, 0.43 mL, 2.45 mmol), and HATU (0.37 g, 0.98 mmol) were dissolved in N,N-dimethylformamide (4.0 mL). The reaction was stirred overnight at room temperature. The mixture was loaded onto a reverse phase column and purified by reverse phase column chromatography (10-100% MeCN / H2O+0.01% TFA) to give tert-butyl 6-carbamoyl-1,4-oxazepane-4-carboxylate (0.16 g, 0.64 mmol, 78% yield) as a colorless oil. m / z(ESI):267.2(M+H) + .

[0246] Step 2: 1,4-Oxazepane-6-carbonitrile. tert-Butyl 6-carbamoyl-1,4-oxazepane-4-carboxylate (0.15 g, 0.61 mmol) was dissolved in pyridine (1.5 mL) and 1H-imidazole (84 mg, 1.23 mmol) was added. After the mixture was cooled to -30°C, phosphorus oxychloride (0.38 g, 0.23 mL, 2.46 mmol) was slowly added dropwise. The mixture was stirred at the same temperature for 1 h. Saturated NH4Cl (2 mL) was added to quench the reaction. The aqueous layer was extracted with EtOAc (3 x 2 mL) and the combined organic layers were dried over Na2SO4. The volatiles were removed in vacuo and the crude residue was purified by column chromatography on silica gel eluting with a gradient of 0-20% MeOH in DCM to give tert-butyl 6-cyano-1,4-oxazepane-4-carboxylate (94 mg, 0.42 mmol, 68% yield) as a colorless oil, which was then dissolved in DCM (2 mL) and TFA (200 μL). The mixture was stirred at room temperature for 1 h. The volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel eluting with a gradient of 0-30% MeOH in DCM (with 0.5% 2N NH3 in MeOH) to give 1,4-oxazepane-6-carbonitrile (45 mg, 0.36 mmol, 58% yield) as a colorless oil. m / z (ESI): 127.2 (M+H). + .

[0247] 8-Oxa-3-azabicyclo[3.2.1]octane-6-carbonitrile hydrochloride (Intermediate I) [ka] Synthesized in a manner similar to intermediate H using 3-[(tert-butoxy)carbonyl]-8-oxa-3-azabicyclo[3.2.1]octane-6-carboxylic acid (CAS#: 1251010-77-1, enamine). m / z (ESI): 151.2 (M+H). + .

[0248] 6-Methyl-1,4-oxazepan-6-ol hydrochloride isomer 1 (intermediate J1) and isomer 2 (intermediate J2) [ka]

[0249] Step 1: 4-(4-Methoxybenzyl)-1,4-oxazepan-6-one. To a 20 mL vial was added 1,4-oxazepan-6-one hydrochloride (0.30 g, 1.98 mmol, AA BLOCKS LLC), 4-methoxybenzyl chloride (0.37 g, 0.32 mL, 2.38 mmol, TCI America), DIPEA (0.77 g, 1.0 mL, 5.94 mmol, Sigma-Aldrich Corporation), and DCM (10 mL). The reaction was stirred at room temperature overnight. The crude material was purified by column chromatography on a silica gel column eluted with a gradient of 0-80% 3:1 EtOAc / EtOH (with 1% TEA) in heptane to give 4-(4-methoxybenzyl)-1,4-oxazepan-6-one (0.43 g, 1.83 mmol, 92% yield) as a colorless oil. m / z (ESI): 236.2 (M+H). + .

[0250] Step 2: 4-(4-Methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol. To a 100 mL round bottom flask was added 4-(4-methoxybenzyl)-1,4-oxazepan-6-one (0.87 g, 3.70 mmol) in THF (15 mL). The mixture was cooled to 0° C., then methylmagnesium bromide solution (3 M in Et2O, 3.7 mL, 11.09 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred for 1 h. The reaction mixture was diluted with saturated NH4Cl (15 mL) and extracted with EtOAc (2×15 mL). The organic extract was washed with saturated NaCl (15 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-50% 3:1 EtOAc / EtOH in heptane to give 4-(4-methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol (0.65 g, 2.59 mmol, 70% yield) as a yellow oil. m / z (ESI): 252.1 (M+H). + .

[0251] Step 3: Chiral separation 4-(4-Methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol (0.65 g, 2.59 mmol) was purified by SFC using a mobile phase of 20% methanol with 0.2% triethylamine using a Chiralpak AD, 30×150 mm 5 μm column at a flow rate of 200 mL / min to yield 246 mg of peak 1 (ee>99%) and 292 mg of peak 2 (ee>99%).

[0252] Step 4: 6-Methyl-1,4-oxazepan-6-ol hydrochloride. 4-(4-Methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol (0.24 g, 0.96 mmol, peak 1) was dissolved in ethanol (5.8 mL). Palladium on activated carbon (0.25 g, 0.23 mmol, Sigma-Aldrich Corporation) and aqueous HCl (2N, 0.7 mL, 1.33 mmol, Sigma-Aldrich Corporation) were added and the mixture was stirred at room temperature under H2 atmosphere for 5 h. The catalyst was removed and the solution was concentrated to give 6-methyl-1,4-oxazepan-6-ol hydrochloride (quantitative yield, isomer 1, intermediate J1). Isomer 2, intermediate J2, was obtained by the same method.

[0253] 6-((trimethylsilyl)ethynyl)-1,4-oxazepan-6-ol hydrochloride (intermediate K) [ka] Step 1: tert-Butyl 6-hydroxy-6-((trimethylsilyl)ethynyl)-1,4-oxazepane-4-carboxylate. To a 50 mL round bottom flask was added (trimethylsilyl)acetylene (0.27 g, 0.27 mL, 2.79 mmol, Combi-Blocks Inc.) in THF (3.7 mL). The mixture was cooled to -78°C before adding a solution of n-butyllithium in hexanes (2.5 M, 0.9 mL, 2.32 mmol, Sigma-Aldrich Corporation). The reaction was stirred for 15 minutes before warming to 0°C and tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (0.20 g, 0.2 mL, 0.93 mmol, Combi-Blocks Inc.). The reaction was stirred at this temperature for 2 hours. The reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with EtOAc (2 x 15 mL). The organic extract was washed with saturated NaCl (15 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-80% 3:1 EtOAc / EtOH in heptane to give tert-butyl 6-hydroxy-6-((trimethylsilyl)ethynyl)-1,4-oxazepane-4-carboxylate (0.24 g, 0.77 mmol, 82% yield) as a yellow oil.

[0254] Step 2: 6-((trimethylsilyl)ethynyl)-1,4-oxazepan-6-ol hydrochloride. tert-Butyl 6-hydroxy-6-((trimethylsilyl)ethynyl)-1,4-oxazepan-4-carboxylate (0.12 g, 0.38 mmol) was dissolved in 2 mL of DCM and 0.5 mL of TFA. The reaction was stirred for 1 h. The mixture was then concentrated in vacuo. To the residue was added 0.6 mL of 1N aqueous HCl and the mixture was lyophilized to give 6-((trimethylsilyl)ethynyl)-1,4-oxazepan-6-ol hydrochloride (quantitative yield). m / z (ESI): 214.2 (M+H). + .

[0255] 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (Intermediate L) [ka] Step 1: 4-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane. To a solution of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine (33 g, 0.13 mol, LabNetwork) and DIPEA (42 g, 57 mL, 0.33 mol) in MeCN (500 mL) was added 1,4-oxazepane hydrochloride (14 g, 0.10 mol) in portions at -40°C. The mixture was stirred at -40°C for 1 h. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (250 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 5:1 to 3:1 petroleum ether / EtOAc to give 4-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (22 g, 70 mmol, 53% yield, 91% purity) as a yellow solid. m / z (ESI): 317.1 (M+H). + .

[0256] Step 2: 4-(7-chloro-2,8-difluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane. To a solution of 4-(2,7-dichloro-8-fluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (32 g, 0.10 mol) in DMSO (330 mL) was added KF (59 g, 1.01 mol). The mixture was stirred at 80° C. for 12 h. The reaction mixture was diluted with H2O (700 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (350 mL×2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 3:1 to 1:1 petroleum ether / EtOAc to give 4-(7-chloro-2,8-difluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (20 g, 67 mmol, 66% yield) as a yellow solid. m / z (ESI): 301.2 (M+H). + .

[0257] Step 3: 4-(7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane. To a solution of 4-(7-chloro-2,8-difluoro-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (31 g, 0.10 mol) in THF (310 mL) was added NaSMe (20% purity in H2O, 33 mL, 0.10 mol) dropwise at 0°C. The mixture was stirred at 20°C for 2 hours to give a yellow suspension. The reaction mixture was filtered and the cake was concentrated under reduced pressure to give a residue. The filtrate was concentrated under reduced pressure to give a residue and the cake was triturated with 8:1 petroleum ether / EtOAc (250 mL) at 20°C for 30 minutes. The suspension was filtered and the cake was washed with 8:1 petroleum ether / EtOAc (100 mL x 3) and concentrated under reduced pressure to give 4-(7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (37 g, 0.10 mol, 98% yield, 90% purity) as a yellow solid. m / z (ESI): 329.0 (M+H). + .

[0258] Step 4: 4-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane. To a solution of 4-(7-chloro-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (10 g, 30 mmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14 g, 40 mmol, PharmaBlock), Cs2CO3 (9.9 g, 30 mmol) in toluene (200 mL) and H2O (25 mL) under N2, cataCXium A Pd G2 (2.0 g, 3.04 mmol) was added. The mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (150 mL×2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 2:1 to 0:1 petroleum ether / EtOAc to give 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (11 g, 17 mmol, 57% yield, 91% purity) as a yellow solid. m / z (ESI): 527.3 (M+H). + .

[0259] Step 5: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane. To a solution of 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylsulfanyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (11 g, 22 mmol) in DCM (400 mL) at 0° C., m-CPBA (4.4 g, 22 mmol, 85% purity) was added in portions. The mixture was then stirred at 0° C. for 1 h. The reaction mixture was quenched by adding Na2S2O3 (1000 mL) at 25 °C, then diluted with H2O (600 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 100% EtOAc to 10:1 EtOAc / MeOH to give 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-8-fluoro-2-methylsulfinyl-pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (6.5 g, 11 mmol, 52% yield, 95% purity) as a yellow solid. m / z (ESI): 543.1 (M+H). + .

[0260] 6-Methyl-1,4-oxazepan-6-ol hydrochloride isomer 1 (intermediate M1) and isomer 2 (intermediate M2) [ka] Step 1: 6-Ethyl-1,4-oxazepan-6-ol 2,2,2-trifluoroacetate. To a 100 mL round bottom flask was added tert-butyl 6-oxo-1,4-oxazepan-4-carboxylate (0.55 g, 2.56 mmol, Combi-Blocks Inc.) in 2-MeTHF (10 mL) at 0° C. A solution of ethylmagnesium bromide, 1.0 M (6.4 mL, 6.40 mmol) in tetrahydrofuran was added dropwise. The reaction mixture was stirred at room temperature for 1 h, then diluted with saturated NH4Cl solution (15 mL) and extracted with EtOAc (2×15 mL). The organic extract was washed with saturated NaCl solution (15 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material. TFA (2 mL) was added dropwise to the above material dissolved in 10 mL of DCM at 0° C. After stirring at 0° C. to room temperature for 2 h, the reaction mixture was concentrated completely and used in the next step without further purification.

[0261] Step 2. 6-Ethyl-4-(4-methoxybenzyl)-1,4-oxazepan-6-ol. To a 100 mL round bottom flask was added 6-ethyl-1,4-oxazepan-6-ol 2,2,2-trifluoroacetate (0.66 g, 2.56 mmol), 4-methoxybenzyl chloride (0.48 g, 0.42 mL, 3.07 mmol), and N,N-diisopropylethylamine (0.99 g, 1.34 mL, 7.68 mmol) in DCM (10 mL). After stirring at room temperature overnight, the crude material was absorbed onto a silica gel plug and purified by column chromatography on silica gel eluting with a gradient of 0-80% 3:1 EtOAc / EtOH (with 1% TEA) in heptane to give 6-ethyl-4-(4-methoxybenzyl)-1,4-oxazepan-6-ol (0.40 g, 1.51 mmol, 59% yield) as a colorless oil. m / z (ESI): 266.2 (M+H). + .

[0262] Step 3: Chiral separation 6-Ethyl-4-(4-methoxybenzyl)-1,4-oxazepan-6-ol (0.4 g, 1.5 mmol) was purified by SFC with a mobile phase of 15% methanol using a Chiralpak AZ, 20×250 mm 5 μm column, flow rate of 80 mL / min to yield 163 mg of peak 1 (99% ee) and 163 mg of peak 2 (99% ee).

[0263] Step 4: 6-Ethyl-1,4-oxazepan-6-ol hydrochloride. 6-Ethyl-4-(4-methoxybenzyl)-1,4-oxazepan-6-ol (0.16 g, 0.61 mmol, peak 1) was dissolved in ethanol (3.1 mL). Palladium on activated carbon (0.13 g, 0.12 mmol) and aqueous HCl (2N, 0.35 mL, 0.7 mmol) were added and the mixture was stirred at room temperature under H2 atmosphere for 5 h. The catalyst was removed and the solution was concentrated to give 6-ethyl-1,4-oxazepan-6-ol hydrochloride (quantitative yield, isomer 1, intermediate M1). Isomer 2, intermediate M2, was obtained by the same method.

[0264] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Example 1) [ka] Step 1: 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane. To a stirred solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.00 g, 7.92 mmol) in dichloromethane (31.7 mL) at -40°C was added 1,4-oxazepane (0.80 g, 7.92 mmol) followed by DIPEA (3.07 g, 4.2 mL, 23.77 mmol). The reaction was stirred at -40°C for 1 h. The reaction mixture was diluted with DCM, washed with aqueous citric acid and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated to give 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (2.73 g, 8.61 mmol, 109% yield, 87% purity). The isolated product was used in the next reaction without further purification. m / z (ESI): 317.1 (M+H). + .

[0265] Step 2: 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane. To a suspension of 4-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (1.25 g, 3.94 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.75 g, 4.73 mmol) in acetonitrile (15.8 mL) was added DIEA (1.53 g, 2.1 mL, 11.82 mmol). The reaction was stirred at 75° C. overnight. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel eluting with 0-100% 3:1 EtOAc / EtOH blend in heptane with 2% triethylamine additive to give 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (0.67 g, 1.51 mmol, 38% yield) as a light yellow powder. m / z (ESI): 440.2 (M+H). + .

[0266] Step 3: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane. To a solution of 4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (0.12 g, 0.27 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.15 g, 0.41 mmol) in tetrahydrofuran (2.5 mL) and water (0.2 mL) was added potassium phosphate (0.17 g, 0.82 mmol) and cataCXium A Pd G3 (40 mg, 0.055 mmol). The reaction mixture was aerated with argon, sealed, and stirred at 70° C. for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was concentrated. The crude product was purified by column chromatography on silica gel eluting with 0-100% 3:1 EtOAc / EtOH blend in heptane with 2% triethylamine additive to give 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (0.17 g, 0.26 mmol, 95% yield) as an off-white powder. m / z(ESI): 638.1(M+H) + .

[0267] Step 4: 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol. To a solution of 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (0.17 g, 0.26 mmol) in acetonitrile (5.2 mL) was added hydrogen chloride solution (4.0 M in dioxane, 1.3 mL, 5.17 mmol). The reaction was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated and the crude product was purified by reverse phase HPLC to give 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (0.12 g, 0.14 mmol, 55% yield) as its TFA salt as a light yellow powder. m / z (ESI): 594.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6)δ ppm 10.61-10.84(br s,1H)9.78-10.08(br s,1H)9.24(s,1H)7.78(dd,J=8.99,6.06Hz,1H)7.26-7.44(m,2H)7.02(d,J=2.51Hz,1H)5.45 -5.71(m,1H)4.50-4.67(m,2H)4.11-4.30(m,4H)3.68-4.01(m,7H)3.68-3.80(m,4H)3.32(br s,1H)1.90-2.43(m,10H)0.74(t,J=7.32Hz,3H).

[0268] [Table 6]

[0269]

Table 7

[0270]

Table 8

[0271]

Table 9

[0272]

Table 10

[0273]

Table 11

[0274]

Table 12

[0275]

Table 13

[0276]

Table 14

[0277]

Table 15

[0278]

Table 16

[0279]

Table 17

[0280] [Table 18]

[0281] [Table 19]

[0282] Further steps for Example 12 [ka] To a 10 mL round bottom flask was added 4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (14 mg, 0.02 mmol) in DMF (0.2 mL). At 0° C., cesium fluoride (15 mg, 0.10 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred overnight. The crude mixture was purified by reverse-phase HPLC to give 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol as the 2,2,2-trifluoroacetate and as a brown solid (4.0 mg, 6.1 μmol, 30% yield).

[0283] Further steps for Example 33 [ka] To a vial was added 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)pyrrolidine-3-carbonitrile (34 mg, 0.06 mmol) and formaldehyde 37% solution (58 mg, 53 μL, 0.72 mmol, Sigma-Aldrich Corporation) in dichloromethane (0.3 mL) at 0° C. To the reaction mixture was added one drop of acetic acid and the reaction was stirred at 0° C. for 10 minutes. Sodium triacetoxyborohydride (38 mg, 0.18 mmol, Sigma-Aldrich Corporation) was then added at 0° C. and the reaction was stirred at room temperature for 2 hours. Upon completion, the solution was transferred to a separatory funnel and extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4. The resulting solution was filtered and concentrated in vacuo to give the crude product, which was purified by reverse phase HPLC to give 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-1-methylpyrrolidine-3-carbonitrile as bis(2,2,2-trifluoroacetate) and as a light yellow solid (15 mg, 0.02 mmol, 31% yield).

[0284] [Table 20]

[0285] [Table 21]

[0286] [Table 22]

[0287] [Table 23]

[0288] [Table 24]

[0289] [Table 25]

[0290] 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine 1-oxide (Example 34) [ka] Step 1: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine 1-oxide. To a 20 mL vial was added 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine (0.10 g, 0.16 mmol) and DCM (3.1 mL). To the resulting solution was added mCPBA (70.1 mg, 0.31 mmol) and the reaction mixture was stirred at room temperature for 1 h. Upon completion, the reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with 0-100% 3:1 EtOAc / EtOH blend in heptane with 2% triethylamine additive to give 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine 1-oxide (21 mg, 0.031 mmol, 20% yield) as a yellow solid. m / z(ESI): 656.2 (M+H) + .

[0291] Step 2: 4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine 1-oxide. Synthesized in a similar manner to Example 1. The product was isolated as the TFA salt. m / z (ESI): 612.2 (M+H). + . 1H NMR(400MHz,DMSO-d6):δ ppm 9.21(s,1H),7.78(dd,J=9.1,6.0Hz,1H),7.31-7.41(m,2H),7.02(d,J=2.7Hz,1H),5.47-5.71(m,1H),4.51-4 .70(m,4H),4.20-4.32(m,2H),3.68-3.93(m,4H),2.97-3.30(m,6H),2.08-2.40(m,7H),0.74(t,J=7.4Hz,3H).

[0292] 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6 -Thiomorpholine 1-oxide (Example 35) [ka] Step 1: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6-thiomorpholine 1-oxide. To an 8 mL vial was added 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholine (0.10 g, 0.16 mmol) and methanol (3.1 mL). To the resulting solution was added ammonium carbamate (24 mg, 0.31 mmol) and iodobenzene diacetate (0.13 g, 0.39 mmol) and the mixture was stirred at room temperature for 2 hours. Upon completion, the reaction is concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 0-100% 3:1 EtOAc / EtOH blend in heptane with 2% triethylamine additive to give 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6 -Thiomorpholine 1-oxide (77 mg, 0.115 mmol, 73% yield) was obtained as a yellow solid. m / z (ESI): 671.25 (M+H). + .

[0293] Step 2: 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6 -Thiomorpholine 1-oxide. Synthesized in a manner similar to Example 1. The product was isolated as the TFA salt. m / z (ESI): 627.20 (M+H). + . 1H NMR(400MHz,DMSO-d6):δ ppm 9.21(s,1H),7.78(dd,J=9.0,6.1Hz,1H),7.31-7.41(m,2H),7.02(d,J=2.5Hz,1H),5.48-5.70(m,1H),4.60-4.72(m,2H) ),4.44-4.57(m,2H),4.08-4.26(m,3H),3.82-3.84(m,2H),3.26-3.55(m,7H),1.96-2.40(m,8H),0.74(t,J=7.3Hz,3H).

[0294] 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide (Example 36) and 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide (Example 37) [ka] Step 1: 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide and 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide. To a 20 mL vial was added 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane (54 mg, 0.083 mmol), tetrahydrofuran (6.3 mL), and water (0.06 mL). The resulting solution was cooled to 0° C., OXONE®, monopersulfate (51 mg, 0.083 mmol) was added, and the reaction mixture was stirred at 0° C. After 45 min, the reaction mixture was allowed to warm to 23° C. After an additional 19 h, 10% aqueous Na2S2O3 (3 mL) was added, and the mixture was stirred vigorously for 5 min. The aqueous layer was extracted with CHCl (2×5 mL) and the combined organics were dried over anhydrous NaSO and concentrated to dryness to give a crude mixture of 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide and 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide as a light yellow solid. m / z(ESI): 670.2, 686.1(M+H) + .

[0295] Step 2: 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide and 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide. Synthesized in a similar manner to Example 1. The product was isolated as a TFA salt. 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide. m / z (ESI, +ve ion): 626.1 (M+H) + . 1 H NMR(400MHz, methanol-d4)δ ppm 9.29(s,1H),7.70(dd,J=9.0,5.9Hz,1H),7.34(d,J=2.5Hz,1H),7.28(t,J=9.4Hz,1H),7.07(dd,J=12.3,2.5Hz, 1H),5.46-5.73(m,1H),4.62-4.71(m,1H),4.31-4.58(m,3H),4.15-4.27(m,1H),3.82-4.11(m,3H),3.34-3.58(m ,4H), 2.83-3.00 (m,2H), 2.13-2.81 (m,10H), 0.71-0.91 (m,3H). 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1,1-dioxide. m / z(ESI):642.0(M+H) + . 1H NMR (400MHz, methanol-d4) δ ppm 9.27(s,1H),7.71(dd,J=9.0,5.9Hz,1H),7.34(d,J=2.5Hz,1H),7.28(t,J= 9.4Hz,1H),7.08(d,J=2.7Hz,1H),5.46-5.73(m,1H),4.61-4.75(m,2H),4. 31-4.52(m,4H),3.84-4.14(m,3H),3.76(t,J=5.5Hz,2H),3.37-3.57(m,3H ),2.29-2.83(m,8H),2.22(ddd,J=14.0,7.0,4.0Hz,2H),0.76-0.88(m,3H).

[0296] 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-imino-1λ 6 ,4-Thiazepane 1-oxide (Example 38) [ka] Synthesized in a manner similar to Example 35. The product was isolated as the TFA salt. m / z (ESI): 641.1 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 9.27(s,1H),7.71(dd,J=9.0,5.9Hz,1H),7.34(d,J=2.5Hz,1H),7.28(t,J=9.4Hz,1H),7.07(d,J=2.3Hz,1H),5.49-5.78(m, 1H),4.79-4.98(m,1H),3.67-4.61(m,12H),3.41-3.56(m,1H),2.32-2.72(m,8H),2.11-2.28(m,2H),0.81(t,J=7.3Hz,3H).

[0297] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Example 39) [ka] To a 20 mL vial was added (S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (31 mg, 0.05 mmol, sodium hydride (5.8 mg, 0.14 mmol, TCI America) synthesized during Example 25) in tetrahydrofuran (1.0 mL) at 0° C. The reaction was stirred at 0° C. for 20 minutes. Iodomethane (14 mg, 6.0 μL, 0.10 mmol, Sigma-Aldrich Corporation) was added and the reaction was allowed to warm to room temperature. After 1 h, the reaction mixture was diluted with water and extracted with CHCl. The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a light yellow solid, which was added to a 20 mL vial. HCl in dioxane (4 M, 0.3 mL, 1.20 mmol, Sigma-Aldrich Corporation) and acetonitrile (0.9 mL) were added at 0°C. After 30 min, the solvent was removed under reduced pressure. The crude material was purified by reverse phase HPLC to give 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol as a light yellow solid (14 mg, 0.02 mmol, 40% yield). m / z(ESI):624.3(M+H) + . 1H NMR (400MHz, methanol-d4) δ ppm 9.35-9.43(m,1H),7.70(dd,J=9.2,5.9Hz,1H),7.34(d,J=2.7Hz,1H),7.24- 7.31(m,1H),7.08(s,1H),5.46-5.71(m,1H),4.72(dd,J=9.2,2.1Hz,2H),4. 32-4.48(m,3H),3.97-4.27(m,4H),3.82-3.96(m,5H),3.49(d,J=4.6Hz,3H) ,2.69-2.81(m,1H),2.31-2.67(m,6H),2.13-2.28(m,2H),0.75-0.87(m,3H).

[0298] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thiomorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Example 40) [ka] Step 1: (4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholin-2-yl)methanol. To a 40 mL vial was added 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.46 g, 1.80 mmol, LabNetwork), thiomorpholin-2-ylmethanol (0.24 g, 1.80 mmol, Intermediate E), and acetonitrile (7.0 mL). The resulting suspension was cooled to -40°C and DIPEA (1.16 g, 1.6 mL, 9.01 mmol, Aldrich) was added. The resulting mixture was allowed to warm to 23°C over 30 min. Upon completion, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (0.57 g, 3.60 mmol, LabNetwork) was added and the mixture was heated to 80° C. for 16 h. The mixture was purified by column chromatography on silica gel eluting with a gradient of 0-30% MeOH in DCM to give (4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholin-2-yl)methanol (0.85 g, 1.79 mmol, 99% yield) as an orange solid. m / z (ESI): 472.2 (M+H). + .

[0299] Step 2: (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholin-2-yl)methanol. A 1-dram vial was charged with (4-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholin-2-yl)methanol (0.30 g, 0.64 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.34 g, 0.95 mmol, LabNetwork), potassium phosphate (0.41 g, 1.91 mmol, Sigma Aldrich corporation), and cataCXium A Pd G3 (93 mg, 0.13 mmol, Sigma Aldrich Corporation). The vial was purged with nitrogen and the reaction was suspended in degassed tetrahydrofuran (5.8 mL) and water (0.6 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 0-30% MeOH in DCM to give (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholin-2-yl)methanol as an orange oil. Yield not determined. m / z(ESI): 670.3 (M+H) + .

[0300] Step 3: 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thiomorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol. The above (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)thiomorpholin-2-yl)methanol was dissolved in MeCN (3.0 mL) and HCl in 1,4-dioxane (4M, 4.0 mL, 15.89 mmol, Sigma-Aldrich Corporation) was added. The reaction was then stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and purified by reverse phase HPLC to give 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(hydroxymethyl)thiomorpholino)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol bis(2,2,2-trifluoroacetate) (0.13 g, 0.16 mmol, 24% yield) as a light yellow solid. m / z (ESI, +ve ion): 626.1 (M+H). + . 1 H NMR(400MHz,DMSO-d6):δ ppm 10.58-10.90(m,1H),9.20(d,J=1.3Hz,1H),7.78(dd,J=9.0,6.1Hz,1H),7.31-7.41 (m,2H),7.03(dd,J=5.9,2.7Hz,1H),5.49-5.67(m,1H),4.34-4.79(m,8H),4.03(br dd,J=13.6,7.9Hz,1H),3.75-3.95(m,4H),3.50-3.68(m,2H),3.18-3.37(m,2H),2.89-3. 10(m,2H),2.53-2.70(m,1H),2.31-2.42(m,2H),2.02-2.24(m,4H),0.74(t,J=7.3Hz,3H).

[0301] [Table 26]

[0302] [Table 27]

[0303] [Table 28]

[0304] [Table 29]

[0305] [Table 30]

[0306] [Table 31]

[0307] [Table 32]

[0308] [Table 33]

[0309] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Example 54) [ka] Step 1: (R)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methyl-1,4-oxazepane. To a stirred solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (18 mg, 0.03 mmol, intermediate A) in N,N-dimethylacetamide (0.20 mL) was added DIPEA (21 mg, 0.03 mL, 0.16 mmol, Sigma-Aldrich Corporation) and HATU (49 mg, 0.13 mmol, Combi-Blocks Inc.). The resulting mixture was stirred at room temperature for 5 minutes. (R)-5-Methyl-1,4-oxazepane hydrochloride (7.4 mg, 0.05 mmol, enamine) in N,N-dimethylacetamide (0.20 mL) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse phase HPLC to give (R)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methyl-1,4-oxazepane (11 mg, 0.02 mmol, 52% yield) as a yellow solid, which was used directly in the next step. m / z (ESI, +ve ion): 652.2 (M+H). + .

[0310] Step 2: 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol. (R)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5-methyl-1,4-oxazepane (11 mg, 0.02 mmol) was dissolved in acetonitrile (0.50 mL). HCl solution (4.0 M in dioxane, 0.04 mL, 0.17 mmol, Sigma-Aldrich Corporation) was added and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was purified by reverse phase HPLC to give 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-5-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol as bis(2,2,2-trifluoroacetate) and as a yellow solid (11 mg, 0.01 mmol, 79% yield). m / z(ESI): 608.0 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 9.11(d,J=5.4Hz,1H),7.71(dd,J=9.2,5.9Hz,1H),7.25-7.35(m,2H),7.07(dd,J=17.1,2.5 Hz,1H),5.47-5.70(m,1H),4.88-4.99(m,1H),4.71-4.76(m,1H),4.54-4.69(m,2H),4.18(br t,J=10.0Hz,1H),3.89-4.07(m,5H),3.76-3.86(m,1H),3.41-3.54(m,2H),2.11-2.79(m,10H),1.59(d,J=6.3Hz,3H),0.83(q,J=7.1Hz,3H).

[0311] [Table 34]

[0312] [Table 35]

[0313] [Table 36]

[0314] [Table 37]

[0315] [Table 38]

[0316] [Table 39]

[0317] [Table 40]

[0318] Further steps for Example 70 [ka] 4-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-((trimethylsilyl)ethynyl)-1,4-oxazepan-6-ol (64 mg, 0.09 mmol) was dissolved in methanol and treated with potassium carbonate (25 mg, 0.18 mmol, Sigma-Aldrich Corporation) in water (1.0 mL). The reaction was stirred for 3 h. The material was purified by reverse phase HPLC to give 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-ethynyl-1,4-oxazepan-6-ol as the 2,2,2-trifluoroacetate and as a yellow solid (8 mg, 11 μmol, 12% yield).

[0319] [Table 41]

[0320] [Table 42]

[0321] [Table 43]

[0322] [Table 44]

[0323] 6-Ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (Example 73) [ka] To a 10 mL round bottom flask was added 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one (20 mg, 0.03 mmol, synthesized during Example 67) in THF (0.6 mL). The reaction was cooled to 0° C. before adding ethylmagnesium bromide (1M in THF, 0.09 mL, 0.09 mmol, Sigma-Aldrich Corporation). The reaction was stirred for 1 h. The crude material was quenched with MeOH and acetic acid. The crude mixture was purified by column chromatography on silica gel eluting with a gradient of 0-100% 3:1 EtOAc / EtOH with 1% TEA in heptane to give 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol, which was dissolved in 2 mL of acetonitrile. The mixture was cooled to 0° C. before adding HCl (4M in dioxane, 0.4 mL). The reaction was stirred for 1 h. The mixture was concentrated under reduced pressure and then purified by reverse phase HPLC to give 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol as the 2,2,2-trifluoroacetate and as an off-white solid (8.0 mg, 0.01 mmol, 35% yield). m / z (ESI): 638.2 (M+H). + . 1H NMR(400MHz, methanol-d4)δ ppm 9.57-9.87(m,1H),7.60-8.01(m,1H),7.17-7.45(m,2H),6.86-7.14(m,1H),5.45-5.83(m,1H),4.42-4.81(m,4H),3.61-4.3 4(m,8H),3.47-3.58(m,1H),2.31-2.82(m,6H),2.11-2.27(m,2H),1.46-1.80(m,2H),1.00-1.19(m,2H),0.72-0.93(m,3H).

[0324] 6-Cyclopropyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol (Example 74) [ka] Synthesized in a manner similar to Example 73 using cyclopropylmagnesium bromide in THF. The product was isolated as the TFA salt. m / z (ESI): 650.2 (M+H). + . 1 H NMR(400MHz, methanol-d4)δ ppm 9.56-9.79(m,1H),7.51-7.86(m,1H),7.18-7.44(m,2H),6.94-7.12( m,1H),5.22-6.00(m,1H),4.56-4.74(m,4H),4.18-4.34(m,1H),3.80- 4.11(m,7H),3.64-3.80(m,1H),3.46-3.59(m,1H),2.05-2.91(m,8H), 0.91-1.12(m,1H),0.84(s,3H),0.51-0.69(m,2H),0.33-0.50(m,2H).

[0325] 4-(4-(2-(difluoromethyl)morpholino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 75) [ka] 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (20 mg, 0.04 mmol, intermediate B) was dissolved in N,N-dimethylacetamide (0.50 mL). HATU (60 mg, 0.16 mmol, Combi-Blocks Inc.), DIPEA (25 mg, 34 μL, 0.20 mmol, Sigma-Aldrich Corporation), 2,4-dimethoxytoluene (12 mg, 12 μL, 0.08 mmol, Aurum Pharmatech LLC), and 2-(difluoromethyl)morpholin-4-ium chloride (11 mg, 0.06 mmol, enamine) were added and the mixture was stirred at room temperature overnight. Water (0.5 mL) was then added and the mixture was stirred overnight. The crude reaction mixture was purified using HO and 0.1% formic acid in MeCN as mobile phase on an XSelect column (19×100 mm, 5 um), MS mode: ESI + to give 4-(4-(2-(difluoromethyl)morpholino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (5.3 mg, 7.8 μmol, 20% yield) as the formate. m / z(ESI): 630.2 (M+H). + . 1H NMR(500MHz,DMSO-d6)δ ppm 9.95(s,1H),9.24(s,1H),7.77(dd,J=6.4,3.1Hz,2H),7.34(d,J=2.8Hz,3H),7.00-7.03(m,1H),7.01(d,J=2.3Hz,1H),6.10-6 .37(m,1H),5.45-5.65(m,1H),4.42-4.69(m,5H),4.06-4.17(m,3H),3.52-3.90(m,5H),2.01-2.39(m,7H),0.71-0.75(m,4H).

[0326] 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)morpholine-2-carboxamide (Example 76) [ka] Synthesized in a similar manner to Example 75 using morpholine-2-carboxamide (CAS#: 135072-13-8, enamine). Purification was performed on an XSelect column (19x100mm, 5um) using 0.1% TFA in HO and MeCN as the mobile phase. m / z (ESI): 623.2 (M+H). + . 1 H NMR(500MHz,DMSO-d6)δ ppm 9.29(d,J=1.3Hz,1H),7.75(ddt,J=6.4,3.3,1.0,1.0Hz,1H),7.43-7.52(m,2H),7.33-7.40(m,2H),7.00-7.04(m,1H),5.47-5. 64(m,1H),4.54-4.69(m,3H),4.21-4.37(m,2H),4.04-4.12(m,1H),3.61-3.93(m,6H),2.00-2.39(m,6H),0.73(t,J=7.4Hz,3H).

[0327] 5-Ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (Example 77) [ka] Step 1: (1-(((7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol. To a 20 mL vial was added [1-(hydroxymethyl)cyclopropyl]methanol (11 mg, 0.11 mmol, enamine) and potassium tert-butoxide (16 mg, 16 μL, 0.14 mmol, AK Scientific, Inc.) in tetrahydrofuran (0.3 mL) at 0° C. The reaction was stirred for 10 min. Then 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(methylsulfinyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane (50 mg, 0.09 mmol, intermediate L) was transferred and the reaction was stirred at 0° C. until completion. The reaction was carefully quenched with water. The solution was transferred to a separatory funnel and extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4. The resulting solution was filtered and concentrated in vacuo to give the crude product. The resulting crude was purified by column chromatography on silica gel eluting with a gradient of 5-10% MeOH in DCM (with 10% 2N NH3) to give (1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (31 mg, 0.05 mmol, 58% yield) as a yellow solid. m / z (ESI): 581.0 (M+H). + .

[0328] Step 2: 5-Ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol. (1-(((7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (31 mg, 0.05 mmol) was dissolved in MeCN (2 mL) and HCl in dioxane (4 M, 0.23 mL, 0.92 mmol, Sigma-Aldrich Corporation) was added. The reaction was stirred at 0° C. Upon completion, the reaction was cooled to room temperature and concentrated under reduced pressure to provide a crude mixture. The crude product was then purified by reverse phase HPLC to give 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (7.0 mg, 0.01 mmol, 14% yield) as a light yellow solid. m / z (ESI): 537.2 (M+H). + . 1 H NMR (600MHz, DMSO-d6) δ ppm 9.55-9.62(m,1H),8.18(dd,J=9.0,5.9Hz,1H),7.73-7.78(m,2H),7.44(d, J=2.6Hz,1H),5.06(t,J=5.6Hz,1H),4.68-4.76(m,2H),4.52-4.62(m,4H), 4.36(t,J=4.7Hz,2H),4.13-4.19(m,2H),3.77-3.84(m,3H),2.92(dt,J=3. 5,1.9Hz,1H),2.52-2.83(m,2H),1.15(t,J=7.4Hz,3H),0.90-0.99(m,4H).

[0329] Biological evaluation In this section, a biological evaluation of the embodiments provided herein is provided.

[0330] 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) from a Labcyte Echo. His-tagged KRAS G12D protein (Amgen) was diluted to 20 nM in assay buffer (20 mM HEPES, pH 7.4, 10 mM MgCl2, 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 μM MGDP) and 2 μL was added to the appropriate wells of the 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 hour. Detection reagent (0.4 nM LANCE Eu-W1024 Anti-6xHis (Perkin Elmer AD0401), 5 nM streptavidin-d 2 (Cisbio 610SADLA)) was prepared in assay buffer, then 4 μL was added to the plate and incubated at room temperature for 1 h. Plates were read using a PerkinElmer En Vision (ex: 320 nm, em1: 665 nm, em2: 615 nm) and the em1 / em2 data was used to generate a curve fit using a 4-parameter logistic model to calculate IC 50 values ​​were calculated.

[0331] 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 pre-incubated with a dose-response titration of compound in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2 and 0.01% Triton X-100) for 2 hours. Following compound pre-incubation, purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 minutes. 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 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader using AlphaScreen® technology and the data was analyzed using a 4-parameter logistic model to determine IC 50 The value was calculated.

[0332] 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). 16 h prior to compound treatment, AsPC-1 cells were seeded into 96-well cell culture plates at a density of 25,000 cells / well and incubated at 37° C., 5% CO2. Compound dose-response titrations were diluted in growth medium and added to the appropriate wells of the cell culture plate, then incubated for 2 h at 37° C., 5% CO2. After compound treatment, cells were incubated in ice-cold Dulbecco's phosphate-buffered saline, Ca2+ 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 four-parameter logistic model to determine IC 50 The value was calculated.

[0333] [Table 45]

[0334] [Table 46]

[0335] [Table 47]

[0336] [Table 48]

[0337] 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): 【Chemical 1】 [In the formula, 【Chemistry 2】 is a single or double bond; W is C, CH, or N, and when W is CH or N, 【Chemistry 3】 is a single bond; X is O, S, S(O), S(O)(NR ｚ ), or S(O) ２ and n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; Each R ｘ is hydroxyl, halogen, oxo, cyano, -N(R ｚ ) ２ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C ３～６ cycloalkyl, 5- to 7-membered heteroaryl, -T-R ｙ or two R ｘ together with the adjacent carbon atom, ３～７ can form a cycloalkyl or a 5- to 7-membered heterocycloalkyl, where each C ３～７ The cycloalkyl or 5- to 7-membered heterocycloalkyl has 0 to 3 R ｙ or two R ｘ can be taken together to form a bridged ring, said bridge being: -C １～４ Alkylene, -C １～４ Alkylene -O-C １～４ Alkylene-, —O—, —S—, or —C １～４ Alkylene -S-C １～４ alkylene-, wherein each C １～４ Alkylene is 0 to 2 R ｙ is further replaced by the appearance of L is C １～６ Alkylene, —O—C １～６ Alkylene, —S—C １～６ Alkylene, NR ｚ , O, or S, where each C １～６ Alkylene, —O—C １～６ Alkylene, and —S—C １～６ The alkylene chain is a chain consisting of 0 to 2 R ２ is replaced by an occurrence of; R １ is hydroxyl, aryl, heteroaryl, C ３～８ cycloalkyl, or 0 to 3 R ５ is a heterocycloalkyl substituted with occurrences of R ２ is a halogen, hydroxyl, C １～４ alkyl, or two R on the same or adjacent carbon atoms ２ Let's get together and C ３～７ can form a cycloalkyl; R ３ is aryl or 0 to 3 R ６ is heteroaryl substituted with 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 ３～７ cycloalkyl or cyano; Each R ５ is halogen, oxo, hydroxyl, amino, cyano, or C １～４ is alkyl; Each R ６ is halogen, hydroxyl, cyano, -N(R ｚ ) ２ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C ２～４ Alkynyl, or C ３～６ is cycloalkyl; T is C １～４ Alkylene, —S(O) ２ -, -C(O)-, -C １～４ Alkylene-C(O)-, C １～４ Alkylene-S(O) ２ - or -S-; R ｙ is a halogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, hydroxyl, cyano, or —N(R ｚ ) ２ and R ｚ is hydrogen or C １～４ is alkyl, When X is O, R ３ is one R ６ and R is an aryl substituted with an occurrence of ６ is hydroxyl and p is not 0] or a pharmaceutically acceptable salt of said compound.

2. R ３ but, 【Chemistry 4】 and R ４ is fluorine, 【Chemistry 5】 but 【Chemistry 6】 2. The compound of claim 1, wherein:

3. R ３ but, 【Chemistry 7】 and R ４ is fluorine, 【Chemistry 8】 but 【Chemistry 9】 2. The compound of claim 1, wherein:

4. R ３ but, 【Chemistry 10】 and R ４ is fluorine, 【Chemistry 11】 but 【Chemistry 12】 2. The compound of claim 1, wherein:

5. R ３ but, 【Chemistry 13】 and R ４ is fluorine, 【Chemistry 14】 but 【Chemistry 15】 2. The compound of claim 1, wherein:

6. R ３ but, 【Chemistry 16】 and R ４ is fluorine, 【Chemistry 17】 but 【Chemistry 18】 2. The compound of claim 1, wherein:

7. R ３ but, 【Chemistry 19】 and R ４ is fluorine, 【Chemistry 20】 but 【Chemical 21】 2. The compound of claim 1, wherein:

8. R ３ but, 【Chemical 22】 and R ４ is fluorine, 【Chemical 23】 but 【Chemistry 24】 2. The compound of claim 1, wherein:

9. R ３ but, 【Chemistry 25】 and R ４ is fluorine, 【Chemical 26】 but 【Chemical 27】 2. The compound of claim 1, wherein:

10. R ３ but, 【Chemical 28】 and R ４ is fluorine, 【Chemical formula 29】 but 【Chemistry 30】 2. The compound of claim 1, wherein:

11. L is 0 to 2 R ２ -O-C substituted with occurrences of １～６ The compound of any one of claims 1 to 10, which is alkylene (for example -O-methylene-, -O-ethylene-, or -On-propylene-).

12. L is 0 to 2 R ２ 12. The compound of claim 11, wherein the compound is -O-ethylene or -On-propylene- substituted with occurrences of:

13. R １ is hydroxyl or 0 to 3 R ５ 13. The compound of claim 12, wherein the heterocycloalkyl is substituted with an occurrence of:

14. R ５ But halogen, cyano, C １～４ The compound of any one of claims 1 to 10, which is alkyl or oxo.

15. -L-R １ but, 【Chemical 31】 15. The compound of claim 14, wherein:

16. -L-R １ but, 【Chemical 32】 16. The compound of claim 15, wherein:

17. R ３ But 0 to 3 R ６ The compound of any one of claims 1 to 10, wherein the aryl is substituted with an occurrence of:

18. R ３ But 0 to 3 R ６ 18. The compound of claim 17, wherein the compound is phenyl or naphthyl substituted with an occurrence of:

19. R ３ But 0 to 3 R ６ 19. The compound of claim 18, wherein the compound is heteroaryl substituted with an occurrence of:

20. R ６ However, hydroxyl, halogen, C １～４ Alkyl, C １～４ Haloalkyl, C ２～４ Alkynyl, C ３～６ cycloalkyl, or —N(R ｚ ) ２ 19. The compound of claim 18, wherein:

21. R ６ is hydroxyl, methyl, ethyl, trifluoromethyl, difluoromethyl, ethynyl, fluorine, chlorine, cyclopropyl, or —NH ２ 19. The compound of claim 18, wherein:

22. R ３ but, 【Chemical 33】 19. The compound of claim 18, wherein:

23. R ３ but, 【Chemical 34】 23. The compound of claim 22, wherein:

24. W is N, 【Chemistry 35】 The compound according to any one of claims 1 to 10, wherein is a single bond.

25. X is S, S(O) ２ , S(O), or S(O)(NR ｚ 11. The compound according to claim 1, wherein

26. 26. The compound of claim 25, wherein p is 0, 1, or 2.

27. Each R ｘ is -T-Ry, or two R ｘ together form a bridged ring, said bridge being composed of 0 to 2 R ｙ Further substituted with -C １～４ 26. The compound of claim 25, which is an alkylene.

28. Each R ｘ Ga-CH ２ OH or two R ｘ together form a bridged ring, said bridge being composed of 0 to 2 R ｙ 28. The compound of claim 27, wherein the aryl group is methylene or ethyl further substituted with .

29.

36. but 【Chemical 37】 26. The compound of claim 25, wherein:

30. The compound of any one of claims 1 to 10, wherein X is O.

31. 31. The compound of claim 30, wherein n is 1 and m is 1.

32. Each R ｘ But C １～４ Alkyl, C １～４ Haloalkyl, oxo, or -TR ｙ or two R ｘ together form a bridged ring, said bridge being composed of 0 to 2 R ｙ Further substituted with the appearance of -C １～４ alkylene, or two R ｘ together with the adjacent carbon atoms, 0 to 3 R ｙ Further substituted C with the appearance of ３～７ 32. The compound of claim 31 which forms a cycloalkyl.

33. Each R ｘ is methyl, difluoromethyl, -CH ２ C.N., C.H. ２ OH, -C(O)NH ２ , or -CH ２ OMe or two R ｘ together form a bridged ring, said bridge being composed of 0 to 2 R ｙ or two R ｘ together with the adjacent carbon atoms, 0 to 3 R ｙ 33. The compound of claim 32, wherein occurrences of form a further substituted cyclopropyl.

34.

38. but 【Chemical 39】 32. The compound of claim 31 , wherein:

35. 31. The compound of claim 30, wherein n is 1 and m is 2, or n is 2 and m is 2.

36. Each R ｘ But, oxo, C １～４ Alkyl, C １～４ Alkoxy, C ２～４ Alkynyl, C ３～６ cycloalkyl, hydroxy, halogen, cyano, or -T-R ｙ or two R ｘ are taken together to form a bridged ring, and the bridge is -O- or -C １～４ alkylene, wherein the —C １～４ Alkylene is 0 to 2 R ｙ 36. The compound of claim 35, further substituted with occurrences of:

37. Each R ｘ is methyl, ethyl, ethynyl, fluorine, cyclopropyl, cyano, oxo, hydroxy, methoxy, —C(O)N(H)(Me), —C(O)NH ２ , -CH ２ OH or -SO ２ NH ２ or two R ｘ taken together form a bridged ring, said bridge being —O— or methylene, wherein the methylene is selected from 0 to 2 R ｙ 37. The compound of claim 36, further substituted with occurrences of:

38.

40. but 【Chemistry 41】 36. The compound of claim 35, wherein:

39. R ４ But C １～４ Alkyl, C １～４ Alkoxy, hydroxyl, halogen, or C １～４ The compound of any one of claims 1 to 10, which is haloalkyl.

40. R ４ But, -C １～４ 40. The compound of claim 39, which is alkyl, hydroxyl, or halogen.

41. The compound is the following compound: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethynyl-4-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 3-chloro-4-cyclopropyl-5-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)phenol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((S)-6-methoxy-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepane-6-carbonitrile; 4-(4-(6-oxa-3-azabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; or (S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol 2. The compound of claim 1, wherein the compound is selected from one of:

42. The compound is the following compound: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aR)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 4-(4-(6,6-difluoro-1,4-oxazepan-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthalen-2-ol; 5,6-difluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; 6-ethyl-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol; 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((R)-6-(hydroxymethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (isomer 2); 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,3-thiazinane 1,1-dioxide; or 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-one 2. The compound of claim 1, wherein the compound is selected from one of:

43. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

44. 44. A compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound, or a pharmaceutical composition according to claim 43, for use as a medicament.

45. 44. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 43, for use in the treatment of cancer.

46. 44. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 43, for use in treating cancer, wherein one or more cells express a KRAS G12D mutant protein.

47. 46. The compound or pharmaceutical composition for use according to claim 45, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small intestine cancer, appendix cancer, cancer of unknown primary origin, endometrial cancer, mixed cancer of unknown primary origin, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

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

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

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

51. 44. A medicament for use in a method of treating cancer in a subject in need thereof, said medicament comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 43, said method comprising administering said medicament to said subject.

52. 44. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject the compound of claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 43, wherein one or more cells express a KRAS G12D mutant protein.

53. The drug of claim 51, wherein the cancer is non-small cell lung cancer, small intestine cancer, appendix cancer, colorectal cancer, cancer of unknown primary origin, endometrial cancer, mixed type cancer of unknown primary origin, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine carcinoma, bladder cancer, myelodysplastic / myeloproliferative neoplasm, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

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

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

56. 55. The method of claim 54, wherein the cancer is colorectal cancer.

57. 55. The method of claim 54, wherein the cancer is pancreatic cancer.

58. 52. The method of claim 51, wherein the subject has a cancer determined to have one or more cells that express the KRAS G12D mutant protein before being administered the compound or a pharmaceutically acceptable salt thereof.

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